ATDEPARTMENT OF HEALTH AND HUMAN SERVICES

> FOOD AND DRUG ADMINISTRATION
>
> CENTER FOR FOOD SAFETY AND APPLIED NUTRITION
>
> **DIETARY SUPPLEMENT SUBCOMMITTEE MEETING**
>
> **A DISCUSSION OF THE TERM \"METABOLITE\"**
>
> **AS CONTAINED IN THE STATUTORY DEFINITION**
>
> **OF A DIETARY INGREDIENT**
>
> Tuesday, March 25, 2003
>
> 8:45 a.m.

This transcript has not been edited or corrected, but appears as
received from the commercial transcribing service. Accordingly the Food
and Drug Administration makes no representation as to its accuracy.

> Holiday Inn
>
> 1000 Baltimore Avenue
>
> College Park, Maryland
>
> PARTICIPANTS
>
> Johanna Dwyer, D.Sc., R.D., Chair
>
> Constance J. Hardy, FDA
>
> MEMBERS:
>
> Nancy M. Childs, Ph.D.
>
> Harihara M. Mehendale, Ph.D.
>
> Michael Wayne Shannon, M.D., M.P.H.
>
> TEMPORARY VOTING MEMBERS:
>
> Eric P. Brass, M.D., Ph.D.
>
> Paul L. Schiff, Jr., Ph.D.
>
> CONSUMER REPRESENTATIVE:
>
> Edward Blonz, Ph.D., M.S., C.N.S., F.A.C.N.
>
> NON-VOTING ACTING INDUSTRY REPRESENTATIVE:
>
> Annette Dickinson, Ph.D.
>
> [C O N T E N T S]{.underline}
>
> Regulatory Perspective and Challenges,
>
> Christine Taylor, Ph.D. 4
>
> Robert J. Moore, Ph.D. 16
>
> Administration Issues, Constance J. Hardy 22
>
> Remarks by Chairperson, Johanna Dwyer, D.Sc., R.D. 33
>
> Biochemical Facts Behind the Definition and Properties of Metabolites,
> Edward D. Harris, Ph.D. 38
>
> Questions and Discussion by Subcommittee Members
>
> on Dr. Edward Harris\' Presentation 65
>
> Public Comment:
>
> Philip Harvey, Ph.D. 111
>
> Steven Dentali, Ph.D. 122
>
> Discussion of Charge and Questions by the Subcommittee 130
>
> [P]{.underline} [R]{.underline} [O]{.underline} [C]{.underline}
> [E]{.underline} [E]{.underline} [D]{.underline} [I]{.underline}
> [N]{.underline} [G]{.underline} [S]{.underline}
>
> **Welcome**
>
> DR. TAYLOR: Good morning and welcome to FDA\'s Food Advisory
> Subcommittee for Dietary Supplements. This is the first meeting of
> this particular subcommittee. I do want to extend my personal
> appreciation to the members of the committee. They are not only
> experts of renown, but they come from quite far away from us. Thank
> you for agreeing to participate in this particular subcommittee.
>
> The subcommittee is, as we have mentioned, under the auspices of the
> Food and Drug Administration, particularly the Office of Nutritional
> Products, Labeling and Dietary Supplements.
>
> My welcome is not only on my behalf, Christine Taylor\--I am the
> Director of the Office\--but I also am extending a welcome for Mr.
> Joseph Levitt, who is the Center Director. He ordinarily does attend
> the first meeting of every subcommittee. Today, he was unable to
> attend so I bring his apologies but also his best wishes for a very
> good meeting.
>
> Basically, the session agenda starts this morning with the overview,
> which is inclusive of some advisory logistics as well as an overview
> put together both by Mr. Levitt and myself, what he calls \"the
> dietary supplement state of play.\" Again because this is the first
> meeting of the subcommittee, we will spend just a few moments on that.
>
> We will then put up the charge to the subcommittee for this particular
> meeting and, from there, we will move to a presentation from one of
> the FDA staff on the regulatory process which will consider again
> those charges. We will then do an official handoff to your
> Chairperson, Dr. Johanna Dwyer. From there, she will introduce the
> members or you can introduce yourselves, however Johanna prefers to do
> it. There will be a \"white paper\" presentation on the topic today
> and then you will move to your discussion and your recommendations.
>
> Just a little bit of a reason for the existence, now, of
> subcommittees. Many of you may remember that for many years the Center
> for Food Safety and Applied Nutrition had a food advisory committee.
> That one food advisory committee handled all of the issues within the
> Center for Food Safety and Applied Nutrition.
>
> A few things have happened in the last couple of years that have made
> us look at a way of enhancing that particular process. One is that
> there is clearly an increased need for scientific input on the part of
> the Center. What is envisioned is a chance for the agency to make the
> possible regulatory decisions based on scientific input and one way to
> get that kind of scientific input is through advisory subcommittees.
>
> But also over the last couple of years there has been an increased
> need for a notion that a more broad food advisory committee could
> revive that kind of input for a variety or topics that became
> increasingly difficult. So, several years ago the agency began to work
> to develop subcommittees of the Food Advisory Committee and there are
> now six official subcommittees. There is a contaminants and toxicology
> one. There is a biotechnology one. There will be one for infant
> formula. There is now one for food additives. There will be one for
> nutrition and this is the sixth subcommittee, dietary supplements.
>
> From our perspective, the establishment of these subcommittees is
> extremely useful because you will have the chance to develop what I
> call a standing relationship. That is, the folks who are members of
> the subcommittee will come together perhaps once, twice or three times
> a year, depending on the topics at hand, and begin to develop a
> relationship with the regulatory issues that they are providing
> scientific advice for.
>
> There also will an effort to stagger rotations on these subcommittees
> so that it is not as if a whole new committee meets each and every
> time, but people have various lengths of their terms and, therefore,
> people are integrated in and then rotated out.
>
> The general theme for these kinds of advisory committees is that the
> focus is on scientific input. Regulatory matters, as you would expect
> are retained by the agency and what we are seeking is scientific input
> that can better inform our regulatory decisions. It is very important
> that the FDA staff present here in the room do not influence or lead
> the discussion. We do kick it off. We do present charges to you, but
> then we are available at a side table to clarify questions but not to
> participate in your discussion per se. We are always available to try
> and answer your questions but we don\'t want to influence or lead you
> in any way.
>
> We do have several FDA scientists present and I will introduce them at
> this point in time. We have Dr. Susan Walker, who is the Acting
> Director of our Division of Dietary Supplement Programs. She is here,
> on the end. Very shortly Dr. Beth Yetley will be joining us. She is
> the Center\'s lead scientist for nutrition. Then, we have available
> Dr. Robert Moore, who is the Branch Chief of one of our organizations
> within the Dietary Supplement Division. As I have mentioned before, I
> am Christine Taylor and I am the Director of the Office of Nutritional
> Products, Labeling and Dietary Supplements.
>
> We also have an FDA Executive Secretary in the form of Connie Hardy,
> who is sitting with the Chair to help with the logistics of the
> meeting. I do believe our ethics representative, Mary Anne Kelley,
> might be coming today. We do have an ethics representative with us
> today.
>
> I will just spend a minute or two talking about our perspective of the
> dietary supplement state of play. In our parlance, legislation that
> happened in 1994 is really relatively new legislation. At the time
> DSHEA occurred there were a number of studies within the agency that
> looked at implementing legislation, and the rule of thumb was that it
> takes almost ten to twenty years before a new piece, a major piece of
> legislation really becomes a comfortable vehicle for the agency to
> operate in.
>
> I think it is fair with DSHEA to characterize it as a primarily
> post-marketing set of provisions, and what anyone can tell you at FDA
> is that a post-marketing paradigm is not easier than a pre-marketing
> paradigm. There is a great deal of work in either paradigm and it is
> important to recognize that DSHEA was a switch for the agency and,
> therefore, it is taking us some time to better understand kind of what
> the boxes are that we operate in. The government does bear a
> considerable burden in a post-marketing world and has a considerable
> amount of responsibility. As you can probably tell, this is leading up
> to the need for an advisory committee.
>
> Because the statute happened in 1994, was passed by Congress in 1994,
> we are in the stage of interpreting and implementing the statute.
> Clearly, the notion of what Congress intended by the statute is
> foremost on our plate. When the statute was enacted all legislative
> history, that is, the background discussion of the committees, was
> struck from the record so we don\'t have the advantage of legislative
> history to help clarify some of the phrases and the meanings of the
> provisions in that Act.
>
> No matter what kind of statute you are dealing with, you do rely
> heavily on precedent actions and case law, and that is why it is a
> ten- to twenty-year process to fully implement the statute. We are in
> that process now.
>
> The feeling that Mr. Levitt wanted us to sound today is that building
> a foundation for implementation is slow work. From his perspective, he
> is having to muster resources. DSHEA did not come with resources and,
> therefore, he is working to put in place resources to implement the
> statute. Then, there is a whole series of policy questions in terms of
> what do you address as precedent issues. Where do you want to put your
> efforts in order to better clarify the intention of the statute? That
> is highlighted in yellow, here. An important role is clarifying the
> science that drives that implementation. That is one of the purposes
> of having the advisory committee, to help with that particular set of
> issues.
>
> In many ways, some of the plans that were put in place three or four
> years ago, as you would expect, have been overtaken by other issues
> and pressures, and dietary supplements are in a state of flux at the
> moment in terms of implementing the statute, interpreting the statute
> and defining it.
>
> One important evolving issue is the notion of fraudulent claims. For
> those of you who have followed FDA\'s activities in the area of the
> Dietary Supplement Health and Education Act, given the resource
> limitations, much of the effort, the focus on the limited resources
> was what Mr. Levitt termed safety first. He will be perfectly frank
> about his lack of resources to deal with the issue of fraudulent
> claims.
>
> This really did change last December when our new Commissioner put in
> place an initiative. He entitled it \"Consumer Health Information for
> Better Health\" and one of the aspects of that initiative was to
> enhance enforcement against false or misleading claims or otherwise
> unapproved drug claims. So, you will now see FDA in a much more active
> mode in terms of not only safety but this whole issue of fraudulent
> claims and labels on dietary supplements.
>
> As I look to the future, I am sure that there will be some need for
> guidance on substantiating these claims clearly if you expect the
> claims to be truthful and not misleading. The agency does have some
> responsibility to clarify what that basis is. So, I do see us in the
> future seeking some input.
>
> The evolving safety standard is the whole question of significant and
> unreasonable risk. The statute is clear that dietary ingredients can
> be removed from the market if they present significant and
> unreasonable risk. The big question is how do you determine when
> something has reached the threshold of a significant and unreasonable
> risk? What is the standard? What is the role of adverse events or
> sentinel events versus a cause and effect relationship?
>
> Some of you may have noticed recently that in the Federal Register
> there were some provisions for some warning statements, as well as a
> series of I think very important questions. The agency is seeking
> comment on whether evidence of significant concerns, short of a
> definitive demonstration of a risk profile, is sufficient to declare
> significant and unreasonable risk. So, again, the agency is going to
> have to look for clarification and definition on the standard and I
> think again, we will be seeking input.
>
> A third one is the whole issue of manufacturing standards that are
> known as GMPs, good manufacturing standards. Less than two weeks ago
> the agency published a proposed rule for dietary supplement GMPs which
> did focus on the quality and purity of the products. The idea here is
> to ensure that the product is what it says it is and contains amounts
> of what it is supposed to contain and that manufacturers of
> ingredients know what they are putting in their particular products.
>
> This particular proposal has a phenomenal amount of technical
> interpretive aspects, as well as questions about appropriateness. This
> will be an important process for the agency as it works to a final
> rule and, again, I think we will be seeking input.
>
> Finally, where we are today\--an evolving issue of definitions. Let me
> tell you that a plan for dietary supplements was put in place in the
> year 2000. Quite a bit of space was given to the concept that you need
> to define boundaries for dietary supplements. Congress gave us words
> as to what dietary supplements are but, as I think you will see from
> your discussions today, a lot of that evolves around what do these
> words mean. As I have mentioned, we don\'t have legislative history
> which is important for clearly having a good handle on what these
> definitions are. But it is very important that these definitions be
> grounded in sound science and that is one of the purposes of having an
> advisory committee.
>
> Part of today\'s overall umbrella though is what is the definition of
> a dietary supplement. So among other things today, you will find out
> that a dietary supplement is defined as a metabolite of a vitamin,
> mineral, amino acid, herb or other botanical, or dietary substance for
> use by man to supplement the diet, and the word that is the issue
> today is metabolite. We are asking consideration of the meaning and
> the application of that word, metabolite. What substances are or are
> not metabolites of other substances is the key question.
>
> In a few moments you will get the regulatory context from Dr. Moore,
> who will then revisit the notion of the charges to the committee, but
> I will just highlight them now before I turn over the microphone to
> Dr. Moore.
>
> There are basically three charges to the committee for your discussion
> today. The first is, is it possible to identify particular scientific
> criteria, principles or conventions that enable a determination to be
> made about when a substance is or is not a metabolite of another
> dietary ingredient? Again, Dr. Moore will review this.
>
> Second, consider and discuss the scientific strengths and weaknesses
> of the following concepts with respect to their usefulness in
> identifying whether a substance is or is not a metabolite of another
> dietary ingredient. As you will see, there are four components that we
> have asked you to consider and, again, these will be reviewed in some
> detail.
>
> The third charge to the subcommittee is to discuss the scientific
> validity and likely usefulness for identifying when a substance is or
> is not a metabolite of another dietary ingredient. If so, what
> characteristics associated with the criterion makes it valid or
> useful?
>
> Those are basically FDA\'s charges or questions to the advisory
> subcommittee, and we very much look forward to your discussion and
> appreciate the chance to hear from you. Dr. Moore? I know at one point
> we are going to turn it over to the exec. sec. but I think right now
> we will move right into Dr. Moore\'s presentation and then turn it
> over to Connie.
>
> **Regulatory Context**
>
> DR. MOORE: Thank you. What I am going to cover is just briefly, you
> know, a brief summary of the legal framework that applies.
>
> As Chris has already said, in 1994 the law was amended and among other
> requirements that DSHEA added was a definition for dietary supplements
> that really forms the basic element of the statute from which
> everything else flows.
>
> In general, in implementing any provision the issues that are raised
> fall into two categories, the nice, simple, straightforward ones, for
> example with DSHEA that required us to withdraw an advanced notice of
> proposed notice of rule-making that doesn\'t require a great deal of
> thought or insight. Then, there are more complicated provisions that
> ask us to interpret an ambiguous phrase within the statute in a way
> that fairly and even-handedly applies that provision to the
> marketplace.
>
> Today\'s purpose is one of those ambiguous phrases in the statute. It
> is important to recognize that what we are considering is not so much
> defining the term metabolite; we are looking for principles or
> conventions that allow us to determine when something that may be a
> metabolite is a metabolite of something, of another substance. I will
> walk through the definition that is in the statute and will make it
> more clear why that sort of parsing of the phrase is important.
>
> I don\'t know if you heard that in the back, but Dr. Dwyer was
> mentioning that there is sort of a one-page summary of my discussion
> somewhere in that book.
>
> One of the things that DSHEA did was define what dietary supplements
> are. The statutory definition defines them as a product, other than
> tobacco, intended to supplement the diet that contains one or more
> \"dietary ingredients.\" It then went on to define the universe of
> substances that would be eligible to be used as dietary ingredients.
> It defined dietary ingredients as a vitamin, a mineral, an amino acid,
> an herb or other botanical, a dietary substance for use by man to
> increase total dietary intake. Then, in the last provision, it
> included a category that was a metabolite, a constituent, a
> concentrate, an extract or a combination of any preceding dietary
> ingredient and that brings us to the point we are at today.
>
> As Dr. Taylor mentioned, the statement of agreement that constitutes
> the legislative history for DSHEA doesn\'t directly address the issue
> of metabolite. It is not defined elsewhere in the statute and the
> plain language is simply ambiguous. Clearly, it envisions not just any
> metabolite because it redirects to metabolites related to other
> substances.
>
> So the question, is in the face of ambiguity, of no legislative
> history and the lack of a definition in the statute, how does one go
> about interpreting and adding meaning to this phrase? The basic
> question then is because only metabolites that are metabolites, if you
> will, of something previously named in the statute, what we have to do
> to decide which substances may or may not be lawfully used in
> ingredients is find out when is a substance or is not a substance a
> metabolite of something else.
>
> The reason that is important, just to reemphasize what I just said, is
> that the statute doesn\'t say any metabolite necessarily is a dietary
> ingredient but only those substances that are metabolites of something
> else that has been previously named.
>
> In trying to reach a starting point to parse out a definition when the
> legislative history is silent, one generally looks to the plain
> language of the statute. Again, the term metabolite is ambiguous so
> one looks to the ordinary meaning of the term that one finds in
> authoritative references, in dictionaries and in other types of texts,
> and what one comes up with is a series of potential definitions of a
> metabolite, but all sort of condensed down as largely a substance that
> is consumed or produced in metabolism.
>
> That sort of general plain meaning of the term then leads you to the
> conclusion that anything is a metabolite and yet, as I have mentioned,
> it doesn\'t address the basic question of when or if a particular
> substance is a metabolite of some other substance and that is the
> basic question that we need to consider.
>
> \"Anything goes\" is meaningless. The agency has an obligation, under
> general rules of statutory construction, to interpret portions of the
> Act in a way that gives them meaning and so to interpret metabolite in
> a way that renders the phrase meaningless or reads it out of the Act
> simply isn\'t an option available to us.
>
> More importantly, if it is undefined and is undefined in such a
> general or meaningless way, it provides no basis or guidance to firms
> trying to make good faith efforts to decide whether a novel substance
> may or may not be a dietary ingredient. So, this adds certainty to the
> marketplace that is obviously a necessary requirement for firms that
> are trying to make business decisions for the long-term.
>
> If one looks at is there even a need, and I am not going to go through
> any of these in any detail because that is why Dr. Harris is here, but
> there are a series of things in the marketplace that when one looks at
> them, it raises or begs the question as to are they metabolites of
> some other dietary ingredient. Some of these examples are many of the
> hormones and bioactive molecules, some of which may be simple one- or
> two-reaction steps from the parent compound; others may reside at the
> end of very multi-level branched metabolic pathways.
>
> The question is from the time we start the cholesterol or arachidonic
> acid and reach steroid hormone or prostaglandin if there are twenty
> steps in there, is there a way to tell how one approaches that and say
> this is or isn\'t a metabolite of all of the things that preceded it?
> In a very general way that is setting the stage, hopefully, for what
> Dr. Harris will address.
>
> So, the basic question that we come back to is that the issue at hand
> isn\'t defining metabolite per se. What it is, is looking at how a
> scientist looks at a substance and reaches a conclusion that it is or
> is not a metabolite of some substance that may have preceded it in
> that metabolic pathway.
>
> Real briefly since Dr. Taylor mentioned it, what we are really looking
> for is not so much to reach a conclusion necessarily today, but to
> explore the thought process and the principles, the scientific
> principles that biochemists and metabolic physiologists, and the like,
> would apply to reaching these types of conclusions and then weigh the
> usefulness and the merits or the arguments against relying on one or
> more of these principles, and how useful they are in the context of
> what we are required to do in the statutory framework to decide these
> things are or are not metabolites of some other substance that
> preceded them in the pathway. I will leave it at that.
>
> DR. TAYLOR: Thank you, Bob. As I mentioned, we will be available to
> answer clarifying questions from the committee but at this point we do
> need to begin our hand-off to the chair of the committee, and it
> begins with some input from the executive secretary on how the meeting
> is managed logistically as one aspect, and there are also some ethical
> and procedural concerns that Ms. Connie Hardy will now present to the
> committee. At that point we will turn it over to Johanna Dwyer who
> will introduce the committee and begin the discussion. Thanks.
>
> **Administrative Issues**
>
> MS. HARDY: Good morning. I am Constance Hardy, the Executive Secretary
> of the Dietary Supplement Subcommittee of the Food Advisory Committee.
> I want to welcome everybody and take a few minutes to go over a few
> procedural rules in terms of advisory committee operations since this
> is the first meeting of Dietary Supplement Subcommittee.
>
> Subsequent to that, I will read into the record the conflict of
> interest statement. Each of the subcommittee members should have
> received a copy of the committee member guide to the FDA advisory
> committees and a video. The video\'s title is \"A Panel Member\'s
> Responsibility.\" There are copies of the member guide available at
> the registration desk for anyone who may be interested. The committee
> member guide is in need of updating but, by and large, provides a good
> operational overview.
>
> As a scientific regulatory agency, FDA needs access to highly
> qualified expert external advisors who can provide scientific and
> technical advice. Thus, FDA uses advisory committees to supplement the
> agency\'s internal expertise to help the agency staff stay current
> with state-of-the-art technology. Committee members participate in an
> advisory capacity and final decisions are ultimately made by agency
> officials.
>
> With respect to the committee members, the chair of the committee
> presides at and conducts the meeting. She may ask FDA staff for
> clarification at any time during the meeting. Each committee member
> contributes their unique scientific and technical background and
> education experience to the committee process. The standing committee
> members generally are voting members, including a consumer
> representative who is voting and an industry representative who is
> non-voting, as specified in the charter. All members of advisory
> committees are appointed by the Commissioner. Voting members are
> appointed as special government employees following a conflict of
> interest review.
>
> Conflict of interest reviews are also conducted immediately prior to
> each meeting to determine whether a voting member might have a
> conflict based on the specific topic to be addressed at a particular
> meeting.
>
> Other advisory committee participants may include guest speakers. A
> guest speaker will present pertinent information to the committee and
> will not participate in the committee discussions or vote. However, we
> do request that in the interest of fairness, guest speakers report any
> financial interest that may be affected by the committee\'s
> discussions.
>
> Additionally, the advisory committee process encourages public
> interaction with the agency in arriving at decisions. Not only is
> there a consumer representative, in this case a voting member,
> appointed to serve on the committee, but the public is invited to
> appear before the committee during the open public comment period.
>
> FDA participates in a listening mode and is available to respond to
> questions and provide clarification if such service is requested by
> the chair. FDA relies on its advisory committees to provide the best
> possible scientific advice available to assist us in making complex
> decisions. Our goal is to do this in as open and transparent manner as
> possible. Part of that openness carries with it a request for members
> to try to avoid giving the appearance that issues are being decided or
> conclusions are being reached outside the actual meeting.
>
> We understand that issues raised during the meeting may well lead to
> conversations over breaks or during a meal. In fact, we hope the
> discussions are thought provoking. We have had instances where members
> have come back from a break and said, \"well, you know, we were
> talking in the break and we would like to request that FDA provide us
> some additional information so we can better understand
> thus-and-such.\" This is a perfectly acceptable thing that can occur.
> What we don\'t want is to have a situation where, after a break,
> members come back and say, \"well, we were talking in the break and we
> decided that the answer to question one is\...\" From our perspective,
> that would be particularly troublesome because neither the agency nor
> the public would have had the benefit of listening to the entire
> discussion, the questions raised, the responses, etc.
>
> In fact, FDA has recently adopted a policy that only procedural
> matters can be decided by a show of hands. For example, all comments
> must be placed on the record, each being attributed to the member
> making the statement. The policy goes even further. If a member has to
> leave a meeting early, the member waives the right to vote. You may
> wonder why a person loses their right to vote and the answer is fairly
> simple. FDA believes all parts of the meeting and the discussions are
> important. Consequently, voting on issues without having the benefit
> of all the discussions would be premature.
>
> The issue of openness is larger than what transpires during the course
> of a meeting. I would like to call your attention to the section in
> the member\'s guide entitled, \"member interaction before, during and
> after a meeting.\" In essence, this section underscores the fact that
> all communication with the members should be routed through the
> committee\'s executive secretary. No one, not even the FDA staff with
> the exception of the executive secretary, should be contacting members
> about upcoming meetings, topics, etc. The same guidance applies to
> consultations between members prior to a meeting. If a member receives
> an inappropriate contact, the member should feel free to notify the
> executive secretary and/or refer the person making the contact to the
> executive secretary. All contacts should be routed through the
> executive secretary so that we can minimize any situation that could
> be misinterpreted.
>
> Appearance issues are always difficult because, as true of many
> things, appearances can be deceiving. We ask that all members, guest
> speakers and everyone attending the meeting be mindful of how an
> interaction between a committee member and anyone might be perceived.
>
> Please let me be clear. It is not my intention to question anyone\'s
> motives or integrity but, as you can imagine, we do not want to see
> respected individuals becoming objects of negative attention based on
> misperception and we wouldn\'t want anyone in this room to become such
> a target. I am confident that everyone here recognizes these issues
> and can appreciate that my comments are intended as a general
> reminder.
>
> Moving on to the issue of conflict of interest, the following
> announcement addresses that issue with respect to this meeting, and is
> made part of the record to preclude even the appearance of such at
> this meeting.
>
> By the authority granted under the Food Advisory Committee Charter of
> July, 2002, the following individuals have been appointed by Joseph A.
> Levitt, Director of the Center for Food Safety and Applied Nutrition,
> as temporary voting members for the March 25th meeting on the term
> metabolite as contained in the statutory definition of a dietary
> ingredient: Edward Blonz, Ph.D.; Eric Brass, M.D., Ph.D.; Paul L.
> Schiff, Jr., Ph.D.
>
> The issues to be discussed at this meeting are issues of broad
> applicability. Unlike issues in which a particular sponsor\'s product
> is discussed, the matters on today\'s agenda do not have a unique or
> distinct impact on any particular product or manufacturer but, rather,
> have widespread applications with respect to all dietary supplement
> ingredient products and/or manufacturers. To preclude even the
> appearance of a conflict of interest, the subcommittee participants
> have been screened for interests in dietary supplement manufacturers
> or dietary supplement suppliers.
>
> As a result of this review, in accordance with 18 U.S.C., Section
> 208(b)(3), Dr. Johanna Dwyer, Dr. Eric Brass, Dr. Nancy Childs and Dr.
> Harihara Mehendale have been each granted a particular matter of
> general applicability waiver that permits each of them to participate
> fully in the matters at issue.
>
> With respect to screening our guest speaker, Dr. Ed Harris, he has
> reported that he has no financial interest related to today\'s meeting
> topic. Dr. Harris is employed by Texas A&M University.
>
> A copy of the waiver statements for each of these individuals can be
> obtained by submitting a written requirement to the agency\'s Freedom
> of Information Office, room 12A-30 of the Parklawn Building. We would
> also like to note for the record that Dr. Annette Dickinson is
> participating in this meeting as the acting industry representative
> and a non-voting member of the committee.
>
> In the event that discussions involve any other issues not already on
> the agenda for which FDA participants have a financial interest, the
> participants are aware of the need to exclude themselves from such
> involvement and their exclusion will be noted for the record. With
> respect to all other meeting participants, and this will be our public
> commentors, we ask in the interest of fairness that they address any
> current or previous financial involvement with any firm that is
> involved with dietary ingredients or dietary supplements.
>
> As this meeting is being transcribed, I would request that you please
> use your microphone when speaking and that you clearly identify
> yourself for the record.
>
> At this point we will have a three minute presentation by Dr.
> Catherine McComus who is here doing a survey on FDA advisory
> committees.
>
> MS. MCCOMUS: Good morning. My name is Catherine McComus and I am a
> faculty member at the University of Maryland. I am conducting a study
> with collaborators at the FDA on public understanding of the
> procedures that the FDA uses to monitor and manage real or potential
> conflicts of interest of its advisory committee members.
>
> So, I am responsible for the surveys that are on your chairs, and for
> the AC members I have a special survey that I will be distributing to
> you also. Your participation is voluntary but, of course, it is going
> to be appreciated because it will help us to accurately portray what
> people perceive and understand about the conflict of interest
> procedures that the FDA uses.
>
> This survey takes about 15 minutes to fill out. It is anonymous. If
> you complete it today, there will be a box on the registration desk
> and you can just drop it in there. Otherwise, there is a postage-paid
> envelope inside and you can drop it in the mail as soon as you can
> once you leave this meeting.
>
> Again, we really appreciate your assistance in helping us to
> understand what the public understands about the conflict of interest
> procedures. It is not for the FDA people to fill out at this time. I
> will be contacting them for another aspect. I will be around today, as
> well as my research assistance, to answer any questions or provide any
> sort of background on this questionnaire and research. Again, anybody
> is welcome to have a copy of the results. There is a letter with my
> contact information inside. Feel free to contact me separately and,
> again, thank you very much for your time.
>
> DR. BRASS: Can you clarify who is the sponsor?
>
> MS. MCCOMUS: Yes, it is being sponsored by the Joint Institute for
> Food Safety and Applied Nutrition, which is a collaborative research
> effort between the University of Maryland and the FDA. So, CFSAN
> actually provides some of the funding for this.
>
> DR. DWYER: You are aware that this is the first meeting?
>
> MS. MCCOMUS: Yes, I am.
>
> DR. DWYER: Fine, as long as you are aware.
>
> MS. MCCOMUS: And I appreciate it whether you have gone to one meeting
> or fifty, I appreciate your feedback; your perceptions.
>
> DR. DWYER: And you have IRB approval?
>
> MS. MCCOMUS: Yes, this has gone through the University of Maryland
> Institutional Review Board.
>
> DR. DWYER: Just checking!
>
> MS. MCCOMUS: Definitely so. Thank you very much for your time.
>
> MS. HARDY: That should clear up all the administrative matters at this
> point and I am going to turn the meeting over to Dr. Johanna Dwyer.
>
> DR. TAYLOR: I would like to begin just by introducing Dr. Dwyer. She
> is the chair of this particular subcommittee. And, to the extent that
> we need to discuss what just occurred, it was unknown to me it was
> occurring, Johanna, so I will be glad to talk to you about that. Dr.
> Dwyer, the meeting is now yours and you are free to introduce your
> members and begin the discussion.
>
> **Remarks by Chairperson Johanna Dwyer**
>
> DR. DWYER: Thank you. Welcome to everybody on the committee. It has
> taken two years to get this together but it is nice to finally be
> here. Welcome to everyone who has come all the way out to the far
> reaches of Maryland for this meeting.
>
> What I would like to do is just tell you that I am a professor at
> Tufts. I have just come back from a year, about a year and a half,
> over at USCA where I was on IPA, interagency personnel acquisition,
> working a fair amount of time there and also at Tufts. I was the
> assistant administrator for human nutrition at the U.S. Department of
> Agriculture and have been back at Tufts since the first of the year.
>
> I am a clinical nutritionist and I do a lot of work as well with
> databases that are very much involved in some of the emerging
> components, trying to characterize where they are in food and
> developing databases.
>
> Why don\'t we just go around the table and people can say why they are
> here. Annette, would you start, please?
>
> DR. DICKINSON: I am Annette Dickinson. I am president of the Council
> for Responsible Nutrition, which is a trade association of dietary
> supplement manufacturers and, as was mentioned earlier, I am the
> acting industry representative on this subcommittee.
>
> DR. SHANNON: I am Michael Shannon. I am a pediatrician and a
> toxicologist at Children\'s Hospital Boston and Harvard Medical
> School.
>
> DR. SCHIFF: I am Paul Schiff. I am a professor of Pharmaceutical
> Sciences in the School of Pharmacy, University of Pittsburgh.
>
> DR. BLONZ: My name is Ed Blonz. I am a nutrition scientist. Currently
> I am the consumer representative on the committee. I am a newspaper
> columnist as well. I answer consumer questions about nutrition, foods,
> food science, health, dietary supplements, interpreting science and
> answering questions correctly for the consumers. This is a syndicated
> column and I work at home. I have been doing this for twelve years,
> and I am really pleased to be here.
>
> MS. HARDY: Connie Hardy, the executive secretary. DR. MEHENDALE:
> Harihara Mehendale, from the University of Louisiana, School of
> Pharmacy. I am interested in toxicology. I am interested in mixture of
> toxicology, diet, caloric restriction and toxicities and mechanisms of
> toxicities in general.
>
> DR. CHILDS: I am Nancy Childs, professor in the Department of Food
> Marketing, St. Joseph\'s University.
>
> DR. BRASS: I am Eric Brass, from the Department of Medicine at
> Harbor-UCLA Medical School.
>
> DR. DWYER: Thank you. Yes, Dr. Dickinson?
>
> DR. DICKINSON: Would you accept one or two comments before Dr. Harris
> begins his presentation?
>
> DR. DWYER: Yes, I think we have time.
>
> DR. DICKINSON: I thank the FDA representatives for a thorough summary
> of the definitional issues here, but I would just like to add the
> notion that there are other aspects, of course, of DSHEA that limit
> what ingredients can be used in dietary supplements.
>
> I have read Dr. Harris\' excellent presentation that was distributed
> earlier, and I just would like to make a comment so that everybody
> doesn\'t assume that everything that is listed as part of the
> definition or any metabolite is necessarily eligible to be sold as a
> dietary supplement. I am sure we will get into these other aspects
> later, but there are requirements about whether the ingredient was
> grandfathered, which means that it was on the market as a dietary
> supplement prior to 1994.
>
> There are also provisions that require that if it was not
> grandfathered, there are certain safety provisions that have to be
> observed. In most cases this takes the form of a 75-day notice that a
> manufacturer must submit to FDA providing information as to why the
> ingredient would reasonably be expected to be safe. In addition, if
> the ingredient\--and some of the examples that Dr. Moore and Dr.
> Taylor mentioned earlier are clearly pharmaceutical ingredients, that
> is, the end metabolite in some cases is a pharmaceutical
> ingredient\--there is a provision in DSHEA that that prevents a
> pharmaceutical ingredient from being marketed as a dietary supplement.
>
> So, there are a number of safeguards, that I am sure we will come to,
> that limit the scope to some extent of the marketing of ingredients
> even if they are covered by the definition.
>
> DR. DWYER: Thank you, Annette. Are there any other comments or
> questions from the committee from the presentation we have heard so
> far?
>
> I have one, Dr. Moore. It will take a while so you may want to think
> about it. On one of your slides you mentioned examples and mentioned
> the number of steps, and I wondered if later on you could give us a
> rough idea of the steps from cholesterol to steroid hormones,
> arachidonic acid to prostaglandins, amino acids to catecholamines and
> there was one more. I just don\'t have those pathways in my brain and
> I would like to get whether it is two or 25, what the order of
> magnitude is.
>
> **Biochemical Facts Behind the Definition and**
>
> **Properties of Metabolites**
>
> DR. HARRIS: Good morning to the members of the subcommittee. First let
> me say I am very happy to be here, and work with you, and help you in
> arriving at a definition of what in biochemistry is a very common word
> that we use almost on a daily basis, and that is a metabolite. I say
> it is a common word, implicating that it is almost invisible to us,
> much the same as numbers are to a mathematician or words to a
> grammarian. We simply use the term and never really think about what
> its implications are.
>
> So, in addressing this assignment I really had to try to step back,
> keeping my profile as a biochemist and, yet, try to arrive at a
> definition of what is and what is not a metabolite. In my presentation
> I hope to bring to you some historical perspective and some examples
> that will, hopefully, help you see how these general principles have
> evolved.
>
> I found this quotation, which I found extremely interesting primarily
> for the date, and that was 1839. This is a quotation that was
> basically derived right after the realization that life was a process
> that occurred within cells. We are looking at a quotation by Theodor
> Schwann where he said, \"one must first consider the combination of
> molecules to form a cell and secondly those which result in chemical
> change in the cell itself.\" So, this is the first recognition, you
> might say, that we are dealing with a process carried out by cells
> that are involved in chemical changes.
>
> When we think of a metabolite we have to think in a larger context.
> Certainly, it is an element of metabolism but what do we mean when we
> say the word metabolism? That, again, is a syllabus for a historical
> search here and, as you can see, we go down the list here and we can
> see that the word metabolism was first introduced back around the turn
> of the nineteenth century. A German, Johann Reil, represented it as
> something that said that matter is changing or
> [stoffwechsel]{.underline} which is changing components. The French
> referred to this as [le changement du materiel]{.underline} and that
> has again given us the implication that chemistry is evolving in cells
> and in living systems. Actually, the word metabolism, which implies
> something happening after the fact in a changing context, was
> introduced by Sir Michael Foster in a Textbook of Physiology for the
> first time.
>
> So, if we are looking at the historical perspective here, we certainly
> want to be caught up with today\'s interpretation. Obviously, our
> earlier ancestors and pioneers in science did not have the opportunity
> to see the things that we simply know today. Things happen inside
> cells certainly but what are these things? Can we define them in a
> more precise manner?
>
> Let\'s take a look at what textbook markers in biochemistry have to
> say. I think this will sort of fortify some of the definitions that
> you have seen in the pamphlet that really came from dictionaries. Here
> we can see a little more in well-renowned textbooks on biochemistry.
> In this quotation, metabolites are the basis of metabolism. I will
> read a quotation from Bohinski who wrote a very authoritative book on
> biochemistry: \"metabolic expression is due to the integration of
> individual reactions into a dynamic reaction circuitry of intricate
> design controlled by sensitive regulatory checks and balances.\" Wow!
> What does he mean?
>
> Well, he provides us with a picture. When I show this to my class in
> Texas A&M to show them what metabolism is all about, half of the class
> decides they want to be finance majors and the other half want to know
> if it is going to be on the exam.
>
> \[Laughter\]
>
> What is a metabolite? Well, if we look at some of the definitions we
> see it is a chemical intermediate in the enzyme-catalyzed reactions of
> metabolism. That was by Lehninger who is probably one of the most
> authoritative authors in biochemistry.
>
> Here is a more recent quote by Voet, Voet and Pratt: \"a metabolite is
> a reactant, intermediate, or product of a metabolic reaction.\" Well,
> they seem to be saying the same thing. Here is a quotation I put in my
> book: \"a molecule considered an intermediate in a series of reactions
> generally those in a pathway.\"
>
> From each of these definitions we can probably glean some very key
> words to help us reach a definition. For instance,
> enzyme-catalyzed\--that means a metabolite has to be recognized by an
> enzyme. It is a reactant or an intermediate or a product. It means a
> series of reactions. Finally, a series of reactions that we would
> consider and define as a pathway. As I mentioned to you, a pathway is
> simply a convenient way of putting some order and focus on different
> things that are happening inside the cells.
>
> Let me give you some definitions that follow from this. Metabolites
> are products of metabolic events occurring within cells. Metabolites
> are substrates, products and intermediates in defined biochemical
> pathways; and metabolites arise by the action of enzymes acting on
> defined precursors. If we want to put this in more simplistic terms,
> let\'s just say that a metabolite is something that is made by the
> body, used by the body, recognized by the body and is essential to
> body functions and, of course, it is benign in its many ways.
>
> Here is a principle that I am going to elaborate a little bit later at
> the end of my talk, but I want you, in arriving at this definition, to
> see it from many different perspectives. The more perspectives I can
> introduce to you, perhaps the more you can get a feeling of what this
> is all about. So, let me give you this thought, that only through
> chemical change can a molecule yield energy to a cell or provide
> material that will be used for cell structure. Such molecules that are
> in the act of changing chemically going out to something more global
> in cell function, these are what we call metabolites.
>
> Let\'s address the question of when something is and when it is not to
> be considered a metabolite. These are some factors for you to
> consider. Most obvious, to be considered a metabolite an unknown must
> have some semblance of structure to a naturally occurring reference
> compound. That is obvious; that is intuitive. We can all see the
> relationship to that.
>
> But we have to be careful. I have to point that out to you because I
> am going to add a few more statements to that. I am going to say it
> must also be a substrate, product, or intermediate of a defined
> biochemical pathway in the cells. It must arise from another
> metabolite, which itself is a product of cellular activity. It must
> enter into enzyme-catalyzed reactions. Finally, it must be both a
> product and a substrate of successive reactions. I will point out to
> you why I feel that is important in the definition. The last point I
> want to leave you with is that a metabolite has to undergo metabolic
> turnover. It cannot accumulate in a cell.
>
> So, if those are the definitions of what we would say would define an
> acceptable realization of a metabolite, let\'s address the question of
> what is not a metabolite and see the other perspective. Obviously, a
> metabolite is a chemical that is not recognized by the cell or has no
> connection with the living system; or any substance that is not
> derived in the biochemical pathway; any substance that is not a
> product of a substrate within a biochemical pathway; or any molecule
> that cannot be acted upon by an enzyme; any substance that interacts
> unfavorably with a living system; and any substance that is unable to
> undergo metabolic turnover. These, I would tend to feel, would be more
> excluded from being considered as metabolites.
>
> I am going to address the question of metabolism itself. I am going to
> bring to your attention that metabolism occurs inside cells. I have
> stressed the importance of why metabolism requires enzymes and enzymes
> are only found inside cells. Enzymes are functioning in altering
> chemical structures. These are cellular events.
>
> Then, I want to just bring something to your attention here just to
> show you what I am getting at. Here we have a very well-known cycle
> that occurs in physiology of biochemistry. It is called the Cori
> cycle. What it represents is an interplay between the liver and the
> muscle. It is an interplay because it shows an interdependence of
> these two organs on one another. Liver, we know, can make glucose. It
> can make it from smaller precursors. It can pour the glucose into the
> blood and provide the muscle, therefore, we a source of nourishment
> for energy. Glucose. The muscle will take the glucose once it has
> received it. It will metabolize it and create lactate or lactic acid.
> Lactic acid then is released back into the blood where it now again
> travels back to the liver only to be reformed into glucose. This is a
> Cori cycle, so defined in about 1935 or so, whose authors won the
> Nobel Prize for recognition of this.
>
> What does this have to do with metabolism and metabolites? Well, we
> can see, if we look at this from a more careful perspective, that all
> the chemical changes we are talking about, for instance the making of
> the glucose all the way through to these intermediates here, and all
> of these intermediates are metabolites, derived from preceding
> intermediates, pouring into the blood. In the blood we see pretty much
> a reversal of the trend, starting with glucose-6-phosphate and going
> back up to lactate and so forth. So, we get a little better
> perspective of just how this Cori cycle is operating and just where
> the role of metabolites would be in this context.
>
> I am going to show you one more complicated slide here and it gets a
> little more involved with biochemical pathways, but it basically is
> addressing the same issues that I pointed out to you previously. We
> are looking at what happens to a substance once it penetrates the
> cells and become eligible to be considered a metabolite.
>
> Here we see glucose enter the cell and become glucose-6-phosphate.
> That is a biochemical intersection because once it has formed
> glucose-6-phosphate it has many different fates ahead depending upon
> whichever enzyme-determined need the cells has for it. For instance,
> if the cell needs to store the glucose it alters the pathway in that
> direction. If the cell needs energy it will open a pathway down to
> pyruvate. If the cell needs to make nucleic acids it will open the
> pathway that way to DNA and RNA. So, you can see metabolites go every
> which way, every which direction at once. What a biochemist generally
> refers to when we look at these opportunities for multiple
> directionality, a biochemist calls this carbon flux, flow. If a cell
> needs energy the flow is down toward pyruvate and into the
> mitochondria. If the cell doesn\'t need energy and needs to store the
> compound the flow is toward the storage and so forth. My point in
> pointing this out to you is that all these components that get us from
> point A to point B, all of these components are metabolites.
>
> Here is another picture of that. Here we can see that we are talking
> about directionality. You basically have two different enzymes that
> are involved here in controlling blood glucose. One enzyme takes
> glucose into the cell and converts it into glucose-6-phosphate. The
> other enzyme actually takes the glucose-6-phosphate and brings it back
> to glucose for release. Here I have put in just a few other little
> things connecting pathways here. You can see L-alanine, an amino acid,
> flowing to pyruvate, either down to carbon dioxide and water or
> lactate can flow into pyruvate and then, of course, it can go back the
> other way as we saw previously.
>
> This is what I mean when I say a defined biochemical pathway. We know
> precisely every step in that pathway; we know every intermediate, and
> every intermediate that is part of that pathway we call a metabolite.
>
> Let\'s look at this in a more focused way. Let\'s say we have three
> metabolites that are in order, A, B, C, and for the moment let\'s just
> focus on component B, here. To properly define B we would say that it
> is an intermediate in the pathway from A to C. We would know that
> there are enzymes that are involved in the conversion of A and B and
> enzymes involved in the conversion of B to C. But if we think in terms
> of B, relative to B we would call A a precursor metabolite and we
> would call C a product metabolite.
>
> The point here is that B is a product of enzyme A and B is a substrate
> of the starting component or enzyme 1\--enzyme 1; enzyme 2. So, you
> see, in that definition we can see that we formed B from A and gave
> rise to C from B. That is a metabolic sequence. We would very easily
> define B as a metabolite.
>
> Let\'s look at the front of the picture now. Again, we have A, B and
> C. Under these conditions we see that enzyme 1 again catalyzes
> formation to B; enzyme 2 to C. But in this case A has no precursor.
> So, we could consider A something that has just entered the cell or
> has been in the cell for a while and is now about to be chemically
> converted. A, therefore, is a substrate of enzyme B and, in this
> regard, A is a substrate, B is a product and A would be a precursor.
>
> Here is my take-home for you. In a biochemical pathway a metabolite is
> typically the product of one reaction and the substrate of a second
> successive reaction.
>
> Take-home, a compound that has no precursor can still be considered a
> metabolite but only if ensuing metabolic changes occur via a known
> series of reactions. That is important because we could make compound
> B, let\'s say, through some event and then stop at that point. So,
> would that say then that A is a metabolite? We would say no because it
> is not a successive series of events.
>
> I am going to give you some examples here, and I am going to draw some
> from some arbitrary definitions here. Please don\'t try to connect it
> with something that you already know, but basically it is to
> illustrate some of the points that I am making here.
>
> Let\'s talk about compound X. Let\'s call it an artificial sweetener.
> Let\'s say that X has the unusual property, favorable really, of not
> yielding calories, which makes it a very attractive sweetener.
> Compound X has the basic formula of sucrose with the exception that in
> that structure it contains three chlorine atoms. The question is, is
> compound X to be considered a metabolite? Well, if compound X is to be
> considered a metabolite, we know that as mentioned from the previous
> talk it has to have a precursor and it has to be converted into a
> product. All right, so we need two enzymes to do that. Reminding you
> again of that basic principle, to be considered a metabolite, a
> compound must be the product of one enzyme and the substrate of a
> second.
>
> So, let\'s look at what we would consider favorable in calling
> compound X a metabolite. First of all, it resembles sucrose
> structurally, and has biological function that emulates sucrose. So,
> in this regard it appears to have the functionality and the structure
> that we would desire if we limited our definition to those two
> parameters. But let\'s look at the non-favorable factor here. The
> non-favorable is that because it does not generate any calories
> compound X is not metabolized. Compound X, therefore, is not being
> treated as a sucrose in the system.
>
> The other thing we would call to your attention is that compound X has
> chlorine atoms in its structure. If we look back into biochemical
> pathways and biochemical events that occur in all different cells, we
> will see that the ability of the cell to put chloride onto a sucrose
> molecule does not exist by any known biochemical mechanism, any known
> biochemical system. Therefore, compound X cannot be considered a
> metabolite in that regard. It is not a product of a metabolic event. I
> put enzymes very strongly into your perspective here. I want to make
> sure you are very clear on this. This is really what is going to
> determine or put real boundaries around what we would call a
> metabolite and what is not a metabolite.
>
> As I said, there are substrates for enzymes that cross over products.
> Let me make sure you understand what I am referring to. Here we have a
> chemical reaction. Like all chemical reactions that occur in a cell,
> this reaction requires an enzyme so let\'s bring that into the
> picture. Let\'s say that in this chemical reaction our goal is to add
> this component to this structure, here. Let\'s call this structure
> glucose; let\'s call that phosphate. Let\'s say our goal is to make
> glucose-6-phosphate. Here is an enzyme that does that. Now, the enzyme
> has catalytic sites that you see here. They are designed to interact
> with the substrate and in the process of doing that they form what we
> call an enzyme-substrate complex. This is an intermediate. This can
> only be formed when a substrate has found a proper recognition site on
> the surface of the enzyme. Once that has occurred, we can now bring in
> the second substrate, carry out a catalytic event and produce a
> product.
>
> After that has taken place, the enzyme, once it has freed the product,
> is now a free enzyme, capable of recycling back into the system again
> for another go-around. So, here we can see how enzymes typically work
> in the living system.
>
> Here is a caveat that we have to bring to our attention. Enzymes in
> many respects are stereospecific. What do I mean by that? It simply
> means that if the substrate is going to engage that enzyme, it has to
> do so in a stereospecific manner, stereo meaning in spatial
> relationship to the structure of the enzyme. If you will, a key and
> lock type fit here tends to occur. So, there has to be proper
> orientation.
>
> Stereospecificity can also be very subtle. For instance, your left
> hand is different from your right hand and no matter how hard you try
> you can\'t superimpose your right hand on your left hand. This is the
> principle of handedness that we talk about. We find that when we are
> dealing with molecules that have four different constituents attached
> to a central carbon. We call these stereoisomers, isomer implicating
> that they are similar in structure but, yet, have slightly different
> properties. For purposes of designation we call one a D-isomer and one
> an L-isomer. What I want to convince you of is that these are not the
> same molecule. You might look at them and say, oh, they are the same
> but let me make sure that you see what the enzyme is seeing.
>
> Here we have a molecule. Let\'s make this a duplicate image, and that
> would look like this. So, you would agree with me that these are now
> identical molecules. But suppose I put a mirror up here and I brought
> this other molecule so it now looks in the mirror and it sees itself.
> The question that we would ask is, is this molecule and the one in the
> mirror the same? Let\'s see if we can answer that question by putting
> the molecule into the mirror. You can see that the yellow matches up
> with the blue; the blue matches up with the yellow\--it doesn\'t fit.
> So, the mirror image is not the same molecule.
>
> How does this apply a little more realistically to what we can
> consider? Let\'s talk about D- and L-glucose. Here is D-glucose. Here
> is a mirror. Here is L-glucose, the mirror image. If you look closely,
> it does look like this molecule is looking at itself in the mirror.
> All right, if we look at some of the parameters, chemical parameters,
> we would see that they both have the same chemical formula. They both
> have the same chemical properties. They both have the same molecular
> weight. Yet, the molecule on the left is a nutrient and the molecule
> on the right is not a nutrient. On that basis we can call this
> molecule a metabolite and this molecule, even though it has all the
> same parameters, except for this handedness here, we would have to say
> that it is not a metabolite.
>
> Here is our take-home for that, stereospecificity must be observed for
> those metabolites that engage enzymes that have the capacity to select
> specific stereoisomers. The bottom line here is you just can\'t put
> your left shoe on your right foot.
>
> Dr. Moore alluded to the point that metabolism can be an event where
> as a molecule it is away from its parent compound loses its
> visibility. It loses its identity to its parent structure. This is a
> very true principle in biochemical. The further down the metabolic
> pathway you go, the more your molecule becomes mixed in with the cell,
> and mixed in with metabolites from many other different sources. So, I
> would give you a little rubric here to remember and just say that
> metabolism is an explosive process. When we see a metabolic event
> taking place, we see the molecule scattering every which way. You
> might say, well, in that context does that actually occur? The answer
> is yes.
>
> Let\'s look at a fatty acid for instance. This is a fatty acid that is
> about to undergo metabolism. You can see it has eight carbons to its
> chain. Well, during the course of metabolism, that gorgeous, beautiful
> looking, well-structured, long chain fatty acid is going to be clipped
> in three different positions. The explosion comes when the molecule
> completely dissipates, disappears from sight and becomes four
> acetyl-CoA units. These acetyl-CoA units could be derived from amino
> acids. These acetyl-CoA units could be derived from carbohydrates.
> They don\'t have to be fats. So, we can see that these molecules would
> just blend into the general maven of the cell, what I would call a
> mixed pool.
>
> Let\'s examine this idea that there may be structural similarity which
> is the real criteria that we need to observe at the top of our list. I
> am going to show you a molecule of cholesterol. You can see this is a
> very complicated molecule. It contains a series of fused rings of
> different sizes. This molecule contains 27 carbons. It is assembled
> from those acetyl-CoA units that you saw previously in a series of
> well-defined\--and I can assure you cholesterol metabolism is very
> well understood in biochemical\--well-defined metabolic steps.
>
> If we wanted to put the molecule of cholesterol together, let\'s go
> ahead and build it. What we find, as we build the molecule is that we
> build it on five carbon units. As we continue to clip these units
> together, keeping a linearity in all cases, you can see that we start
> to bring into perspective the cholesterol structure. As you see here,
> we have six isoprene units that brought that molecule about. This open
> change isoprene type molecule we call squalene, which is a precursor
> of cholesterol.
>
> If we took the next metabolic steps, that would be to close these
> rings. So let\'s close them. When we close them we no longer have
> squalene. We now have the molecule that is getting closer to
> cholesterol. We are pretty much there, almost at the point where we
> want to be.
>
> Let me call your attention to an article that appeared in this March
> issue of [Journal of Nutrition]{.underline}. It concerns a compound
> which we call lycopene. Lycopene, I think you know, is the red
> coloring matter of the tomato. Here you can see a paper that is
> pointing out that lycopene product, tomato product enhances lycopene
> concentrations and it activates the capacity of an oxidant. So, it
> reacts against reactive oxygen species, a very important role for
> these type of molecules with that structure.
>
> So, here is the question I raise to you, is lycopene a metabolite?
> Let\'s take a look at the structure. What do we see when we look at
> the structure of lycopene? It basically has the same 5-carbon unit we
> saw previously that we used to build the cholesterol molecule but, of
> course, this is not cholesterol. It is very close in its resemblance
> to squalene, with the exception that lycopene contains ten more
> carbons but it bears a very strong resemblance to the open chain
> cholesterol precursor squalene.
>
> Let\'s look at this a little more closely. We see that lycopene in the
> tomato is actually converted into beta carotene, which we all know is
> vitamin A for us. That brings us to my point which is very important
> here. We can take beta carotene. We can break the molecule in half and
> derive two molecules of vitamin A, otherwise known as retinol. But we
> are unable to take lycopene and converted it into carotene. Wouldn\'t
> it be nice if we could do that, but we can\'t. Therefore, we cannot
> metabolize lycopene.
>
> So, I would raise the point with you that lycopene should not be
> considered a metabolite. Even though it has this very interesting
> structural similarity, it should not be considered because no human
> enzyme is capable of changing it structurally to be a useful product.
>
> By the way, in preparing these comments I went into a database to look
> for anything that talked about the metabolism of lycopene and I could
> not find it. This is a compound that we need to study more carefully
> to know just exactly how a living system handles this. But, as far as
> I know, right now there is no metabolic following compound from this
> through our pathways.
>
> Let me point out some other things regarding metabolites. I think I
> have given you a very good idea of what it is not. I want to give you
> a little more insight into the properties of metabolites. I think this
> is something else that you have to take into your considerations here,
> particularly when we bring up an issue of safety, though that is not
> the issue I want to address with you today.
>
> I want to address this issue in the context of how metabolites work.
> Here we have a pathway of A going to B going to C, in that direction.
> The reason this pathway goes in this direction\--there are a number of
> reasons why it is favoring going from left to right. First of all, we
> have to think of energy considerations. If we go from A to C are we
> releasing free energy? That literally means that this is the
> spontaneous reaction or one favorable. Well, what happens if we
> suddenly raise the level of C? We have the potential now of driving
> the pathway in the reverse direction.
>
> So, this indicates that a metabolite is generally kept in what we call
> a steady-state concentration. Don\'t mistake that for equilibrium; it
> is not. Steady-state simply means that it is being formed and being
> used at the same rate so there is no build-up of that compound. If it
> is formed faster than it is being used there will be a build-up and,
> of course, if it is used faster than it is formed there will be a
> diminution. So, steady-state just simply implies that we reach a point
> where we keep that level so we can drive that steady-state reaction
> back the other way by increasing concentration of C.
>
> Here is a principle I am going to leave you with, because metabolites
> tend to exist at a constant concentration within a pathway, changes in
> the steady-state levels are able to control carbon flux. This could
> determine whether a movement towards synthesis or degradation take
> precedence.
>
> The other principle I want to leave you with, and this is what I
> alluded to and didn\'t expand on but I think you can certainly see the
> implications here, metabolites have free existence. Metabolites
> turnover. In the parlance in a metabolic sense, they are constantly
> being replaced. They are constantly being renewed. So, this is a very
> important fact because this keeps a cell from building up any one
> particular metabolite.
>
> Some of you might say, wait a minute, what about storage fat? I don\'t
> like that word but that is how it is called, like we have a closet
> where we stick fats away and forget about it. Actually, if we look at
> it we would see that what we call storage fat is really steady-state
> fat. Fat is being stored and it is being broken down. I should say it
> is being synthesized and it is being broken down. When we shove the
> direction in the form of lowered synthesis and breakdown, then we
> start to accumulate fat. If we have just the opposite, like in
> conditions that favor breakdown, then we have less fat being stored
> or, favorable to us as we start seeing ourselves lose weight. The
> principle I would leave you with is this one, that nothing is
> permanent in a living system.
>
> Let me just summarize some of the points that I have made. I have
> provided some statements here that will perhaps help you as you
> consider what we mean. A liberal definition of a metabolite can
> include practically any substance that occurs in a cell. That seems to
> be fair game but you can see that there are some restrictions we have
> to place on that.
>
> There are six principles that can serve as a guide here. I have tried
> to list them in order of priority. I am kind of imposing on you here
> and telling you what I think should be the most important
> consideration but, certainly, you have to decide that.
>
> I would say it is important that we recognize that a metabolite has to
> be something created by itself. It has to be something that is a
> product of a biological event. A substance that is an intermediate in
> a pathway, this comes to play when we start talking about it is not
> alien to a pathway; it is actually being recognized and being changed
> within a pathway.
>
> What is bringing about those changes\--item number three\--it has to
> be a recognized and acted upon by an enzyme. Item number four, it has
> to have a limited biological time of existence. As I told you, nothing
> is permanent. It has to not violate stereospecificity principles. This
> will not apply to all metabolites but, certainly\--certainly, it will
> apply to many molecules that would appear to be structural like D- and
> L-glucose, but that have that subtle difference that would make them
> alien in the system. Finally, it has to have a useful purpose. I would
> say that that is something that tells us metabolites are serving a
> cell, keeping the cell alive.
>
> This is the closing thought that I want to leave you with, and it
> expands on something that I told you a little bit earlier: In a living
> system, chemical changes never occur suddenly. One of the things that
> we do in our class is we ask the students how do you know that this
> piece of bread has this many calories in it? The student says, well,
> you put it in a bomb calorimeter. He is correct, absolutely. You take
> that piece of bread, put it in a bomb calorimeter, turn on the
> electrical current, put some oxygen in there and, wham, we get carbon
> dioxide and water and we can measure the heat. Imagine if that
> happened inside a cell. You take a piece of bread and, wham, you get
> carbon dioxide and water.
>
> The point is that in a living system chemical changes occur gradually
> and at each step we are either moving forward, making a more complex
> molecule or making a molecule less complex and deriving energy from
> that transformation. So, metabolism is a series of well-engineered
> steps that gradually sap the energy or remodel the features of the
> molecule and take it in from the environment as nourishment. It is
> characteristic of a living system to make chemical changes gradually
> and to generate intermediates that meet other biochemical priorities.
> It is the residues of these chemical changes\--that is what we call
> metabolites.
>
> **Questions and Discussion on Dr. Harris\'**
>
> **Presentation**
>
> DR. DWYER: Thank you, Dr. Harris. That was great. Before we take a
> break, we will take some questions. Dr. Brass?
>
> DR. BRASS: I have a number of questions so tell me to shut up whenever
> you want. I would just like to probe some of the underlying thinking
> behind some of your proposals and principles.
>
> First of all, I listened to the phrase precursor metabolite and that
> sounds to me like an oxymoron. To me, X is a metabolite of Y. Just
> because X is a metabolite of Y, why would it not be a metabolite of
> other molecules? It might be but it might not be. And, why incorporate
> the precursor implicitly as a metabolite?
>
> DR. HARRIS: I didn\'t bring that up in my talk but in the paper I did,
> I would consider a metabolite as something that is about to undergo
> chemical change. I would say that a precursor that is a metabolite
> would be like blood glucose. You cannot change glucose in blood. You
> can only change it once penetrates a cell. There are certain
> metabolites that you cannot change unless they can enter the organelle
> or compartment in a cell. For instance, you can\'t oxidize a fat until
> it enters the mitochondria and then it becomes a metabolite. But you
> could, in that same context, say it is a metabolite in the cytosol.
>
> DR. BRASS: I agree with your concept that we are thinking in the
> context of human metabolites. I think that is a very important point.
> I agree to that discussion. For example, is an essential amino acid a
> human metabolite?
>
> DR. HARRIS: If I would see an amino acid in the blood, and there are
> plenty of course, I don\'t think I would call those metabolites.
>
> DR. BRASS: In the cell?
>
> DR. HARRIS: In the cell, I would.
>
> DR. BRASS: I think that generates a confusion because I think if it is
> a metabolite it has to be generated, not only be a precursor. But I
> understand now.
>
> DR. HARRIS: I am just one step ahead of you, only from the standpoint
> that what we call a metabolite seems to be a derived substance. Now,
> if the answer to your question is did the cell make that amino acid,
> yes. But did that amino acid come from the diet and now is a digested
> product of a dietary protein, I would say that is not a metabolite.
>
> DR. BRASS: I think that is why we focus on human metabolites\--
>
> DR. HARRIS: Yes.
>
> DR. BRASS: \--and if we don\'t we get in a morass quickly. I think if
> we don\'t make that distinction to be able to be generated by a human
> reaction, we open up a large morass. That is why with a precursor I am
> uncomfortable because of a variety of substances.
>
> The second question is you explicitly, in your definition, exclude end
> products of metabolic reactions as being metabolites.
>
> DR. HARRIS: Yes.
>
> DR. BRASS: That is not clear to me either. Why, if it is generated
> clearly in a sequence of enzyme reactions that dead ends and is
> excreted in the urine without further change, should it not be
> considered a metabolite of the precursors that generate it?
>
> DR. HARRIS: Again, I am looking at the subsequent step. If something
> has now been passed into the blood the subsequent step is excretion or
> some other byproduct. No, I would not say that those are metabolites
> but I am beginning to see what your point is. As you can see, in my
> definition I am always looking at the next step. I am telling you that
> a metabolite has to be recognized by an enzyme and if that substance
> in the blood, indeed, came from an enzymatic reaction that assembled
> that component, that is a metabolite, yes. I agree with that. But if
> it came from the diet\--
>
> DR. BRASS: I agree; I agree. Again, this is semantics but the whole
> discussion is semantics. Yyou said inside of a cell.
>
> DR. HARRIS: Yes.
>
> DR. BRASS: If the enzyme is located on the outside of the
> extracellular membrane, is that inside the cell?
>
> DR. HARRIS: Now, that is a grey area. I would say that we could taper
> that down with a definition of recognized in the immediate environment
> of the cell or in the act of penetrating the cell. But a lot of times
> going through a cell is nothing more than a transport process.
>
> DR. BRASS: I agree. I agree that it has to be enzymatic transformation
> but where that enzyme is located appears less critical. I also have a
> problem with the concept of proximity in a metabolic pathway for the
> definition of whether or not it is or isn\'t a metabolite. Let\'s
> imagine we have a 26-step pathway where A goes to Z. Y is clearly far
> away from A but unquestionably A goes to B and B is a metabolite. B
> goes to C, C is clearly a metabolite. I could extend that logic until
> I get all the way to Y and clearly Y is a metabolite. Even though it
> is really far from A, it has to be a metabolite simply by deductive
> reasoning. So, I think we have to think about proximity for the number
> of steps as being absolutely intrinsic to this definition.
>
> DR. HARRIS: No, I disagree in some respects because ultimately
> everything goes into carbon dioxide and water. So, if something
> becomes carbon dioxide in water, then it is a metabolite, or is it a
> metabolite of a substance we are looking at?
>
> DR. BRASS: Well, to me, this transforms into utility and application
> but I think, yes, carbon dioxide is a metabolite of glucose.
>
> DR. HARRIS: Or a metabolite of a hundred\--
>
> DR. BRASS: That is correct. This is about defining a metabolite in an
> absolute sense, not whether or not a specific molecule is a specific
> metabolite of another specific substance.
>
> DR. HARRIS: Yes, let me back up one second. You are touching on a very
> important point, I realize that. If compound B or compound C that is
> formed maintains much of the parent structure so that we could say
> that those compounds actually came from the substance that we looked
> at as a reference compound, then we are on good grounds. But if that
> has gone all the way down to a point where now, as I showed you, it is
> an explosive process where we cannot identify its origin\--well,
> technically it is a metabolite\--
>
> DR. BRASS: I think, for reasons you said, similarity is a trap because
> there are many molecules that are very subtly different that are
> biologically worlds apart and other structures that look very
> different and have very similar functions. To me, the important point
> is whether or not increasing the precursor results in net synthesis or
> net increase in flux\--
>
> DR. HARRIS: That is a kinetic argument.
>
> DR. BRASS: That is why, for example, glucose can\'t be considered a
> metabolite of palmitate even though we label palmitate or bicarbon in
> glucose. That seems to me a more compelling argument than proximity or
> similarity.
>
> DR. DWYER: Before you answer, would you repeat what you pointed out
> about the precursor?
>
> DR. BRASS: Yes, it seems to me that if something has a
> precursor-metabolite relationship, if I increase the amount of the
> precursor I have to increase the amount of metabolite and that has to
> be a net result. The counter example is if I put radioactivity in
> palmitate I can follow that radioactivity into all kinds of molecules
> in metabolism that are really not net metabolism. To me, that is the
> difference between a mish-mash of metabolism and a precursor
> metabolite reaction that I can actually change.
>
> DR. HARRIS: I agree with you. I didn\'t want to approach this from an
> experimental perspective but that is exactly the type of experiment so
> people could identify potential metabolites. As you pointed out, there
> are a great many traps here, mine fields that you can fall into. The
> bottom line is you cannot make glucose from palmitate in a net way but
> you can still find the carbons there.
>
> DR. DWYER: Ed?
>
> DR. BLONZ: My name is Ed Blonz, and I want to thank you for your
> presentation. As a biochemist, I also would like to make some comments
> because here we are talking about dietary supplements and with dietary
> supplements we have botanical products and botanical products are not
> necessarily essential to the human body. That was one of your points,
> for being a metabolite it has to be essential to the human body. As a
> biochemist dealing with nutritive substances, obviously this would be
> an exception to that and I wanted your comments on that. Then I have
> one other question.
>
> DR. HARRIS: I don\'t know why you would say they are not essential.
> Obviously beta carotene is a botanical. You can\'t make that.
>
> DR. BLONZ: There may be some botanicals but would you say that
> kava-kava is essential to the human body?
>
> DR. HARRIS: I am not sure what kava-kava is.
>
> DR. BLONZ: There will be many dietary supplements that are botanicals
> that at the present time we could not define as essential.
>
> DR. HARRIS: I suppose that is going to have to come down to what you
> mean by essential. You are a biochemist so you know the nutritional
> definition. If the body can\'t make it to maintain the pace of
> metabolism, then it becomes essential. If the body can make it, it
> still can be a metabolite but not necessarily, in that context,
> essential. Essential means that it can only be supplied by the body.
>
> DR. BLONZ: Well, I think the definition of essential would actually
> delve into the realm of philosophy with some botanicals. But I
> personally would tend to think that that might be an exception for the
> need for a metabolite to be essential in terms of nutritional
> substance of the human body.
>
> DR. HARRIS: Yes, I almost look at the word essential as indispensable.
> Yes, I am trying to see if we are talking about two different things
> in that regard.
>
> DR. BLONZ: The other thing had to do with recognition by an enzyme.
>
> DR. HARRIS: Yes.
>
> DR. BLONZ: There might be many botanicals which will not be recognized
> by an enzyme and they might leave through the kidney or through some
> other route\--
>
> DR. HARRIS: Those are what I would rule as not being metabolites. I
> would exclude them. Lycopene was the example that I brought to your
> attention.
>
> DR. DWYER: Any other questions? Yes, Dr. Schiff? DR. SCHIFF: I think
> it gets very difficult when you start to compare a vitamin or a single
> product with a botanical which, in essence, is a mixture of hundreds
> and hundreds of different compounds. Maybe the structure of all those
> compounds are known or maybe they are not known. Maybe something about
> their typical kinetic metabolic fates is known and maybe they are
> unknown. That is a whole leap in a whole other direction. The
> variables are incredible.
>
> So, you know, I would thank you for placing perspectives on it but I
> want to emphasize single products. I also tend to agree with Dr. Brass
> and a lot of his comments as far as some of the concerns he has. Thank
> you for asking those. Those were questions that I had. I wouldn\'t
> want us to refer to a botanical in the same sense as we refer to a
> single amino acid or a single vitamin because of the complexity.
>
> DR. BRASS: If I could just follow-up on that. It seems to me, to
> answer both those questions if it is not further metabolized in the
> body is not relevant. The metabolite generated from a botanical is a
> constituent of a substrate or a metabolic enzyme.
>
> DR. SCHIFF: My issue would be is that if there would be a product that
> would be one step away from an existing botanical, that would be
> metabolized outside of the human milieu but might be marketed as a
> supplement under the metabolite definition. If this would be a
> substance that would not be recognized by an enzyme inside a
> biochemical system, would it then not be subject to that inclusion?
>
> DR. BRASS: That is why I emphasized the human metabolite because
> clearly one could find bacteria or other cellular species that can
> generate all kinds of metabolites that are formed in human metabolism.
> That is not in any of the regulatory documents but it seems to me that
> we have to be talking about human generated metabolites in this
> conversation.
>
> DR. HARRIS: Let me comment on that too. I think that is a very
> important point. When you talk about a substance being recognized by
> an enzyme that is not necessarily a natural substrate within that
> cell, let\'s say a xenobiotic comes in, we have many instances where
> that happens, like cytochrome p450. This enzyme is designed to rid the
> body of substances that it is not naturally producing in its metabolic
> ways but simply taken in by accident, benzothyrines and things like
> that from cigarette smoke. These are enzymes that will act on the
> substance and they will recognize it and cause some kind of a change.
> That is why I emphasized that the next step, after you make that
> change, is important. Let\'s say an enzyme changes a compound to
> another, if that compound now stops at endpoint, that first compound
> is not a metabolite.
>
> DR. BLONZ: But the second\--
>
> DR. HARRIS: But the second compound would be.
>
> DR. BLONZ: Yes.
>
> DR. DWYER: Dr. Shannon?
>
> DR. SHANNON: I am struggling with the definition that the substance be
> recognized and acted upon\--
>
> DR. HARRIS: Can you say that again?
>
> DR. SHANNON: If you have a definition that a substance must be
> recognized and acted upon by an enzyme, and it seems to me if my
> recollection isn\'t in error, at least some reactions that occur in
> the body don\'t require an enzyme and they produce a product. I
> remember the term non-enzymatic hydrolysis for example. So, I wonder
> why an enzyme has to be absolute in order to talk about a product as a
> metabolite of something else.
>
> DR. HARRIS: I think I could probably name the number of non-enzymatic
> events. I am talking now about chemical change. I am not talking about
> changing the state of a molecule or maintaining its structure pretty
> much intact. That would be something like folding a protein. Those
> could be spontaneous events. But even those, we find, require certain
> outside agents that affect their properties.
>
> The only non-enzymatic event that I am aware of is cross-linking
> collagen. Once you form those residues that allow cross-linking to
> occur, then it becomes a spontaneous event. I am not aware of too many
> biochemical processes that do not require enzymes. The ones I could
> name I could put on my first two or three fingers.
>
> DR. SHANNON: But there are some.
>
> DR. HARRIS: I am waiting to hear them.
>
> DR. SHANNON: No, no, that is what you just said. Right?
>
> DR. HARRIS: I am illustrating the points where spontaneity occurs
> mainly from the standpoint of finished molecules, not molecules that
> are going to be changed. All right, let me be a bit more specific.
> When I take the elements of collagen I have two groups that I am going
> to use to form the Schiff base to link them together. Those groups are
> there. All I need to do is put those two together and the chemical
> reaction occurs. But the enzymes prepared me for that step, and the
> proximity of the molecules lying next to one another rolled the
> reaction in that direction. So, I have to say that is a non-enzymatic
> reaction at that last step, but to say collagen cross-linked is
> non-enzymatic is wrong. Enzymes are involved in all the steps to that
> point where they actually performed the condensation product.
>
> DR. SHANNON: Explain to me again why non-enzymatic hydrolysis
> wouldn\'t be included.
>
> DR. HARRIS: I am trying to think of illustrations or instances where
> there is non-enzymatic hydrolysis.
>
> DR. DWYER: Glycosylation\--
>
> DR. HARRIS: Johanna, I am sorry?
>
> DR. DWYER: Glycosylation of hemoglobin in the blood.
>
> DR. HARRIS: That I really can\'t comment on. I am not sure. I would
> have to project that there are glycosyl transferases that put those
> carbohydrate units on that hemoglobin. Wait a minute, if the
> hemoglobin is unmodified and you are forming glycosidic bonds, I am
> sorry, that is not a spontaneous reaction; that is energy dependent.
> Is that wrong? Okay, I will step aside on that then. Some of you may
> be much more aware of that particular reaction.
>
> DR. DWYER: Dr. Mehendale?
>
> DR. MEHENDALE: Substances are biotransformed in the gut by bacteria.
> This is a well-known phenomenon, as you are aware. I didn\'t hear
> anything in your presentation that addressed the issues where
> botanicals might be metabolized by bacterial flora in the gut.
>
> DR. HARRIS: We are talking about microflora here.
>
> DR. MEHENDALE: I don\'t think there are many individuals in this room
> who do not carry bacteria in their stomachs.
>
> DR. DWYER: You need to use the mike.
>
> DR. HARRIS: I have to stay at the podium, I am afraid. I understand
> your question about microflora and definitely they are in the human
> gut, yes. So, should we consider anything that is metabolized by
> microflora, which are really bacteria? Should we feel that is fair
> game? I am going to have to let you decide that.
>
> DR. MEHENDALE: I can also think of endogenous or exogenous compounds
> that get into what is known as enterohepatic cycle, the enterohepatic
> recirculation.
>
> DR. HARRIS: Like cholesterol.
>
> DR. MEHENDALE: Like cholesterol.
>
> DR. HARRIS: Bile salts.
>
> DR. MEHENDALE: Therefore, they are very much part of the definition
> because they will go out of bacterial metabolism in the gut and then
> in and out of the human cell metabolism.
>
> DR. HARRIS: Yes, but there again those reactions are well defined.
> What are the bacteria providing other than enzymes to carry out those
> reactions?
>
> DR. MEHENDALE: One further question I have is, you know, the
> requirement of enzymatic action\--there are compounds that, to me,
> undergo metabolism and interact with the substance and, therefore,
> evoke a response. Where would we put this, this kind of substance?
> Generally we consider protein as enzymes but the substrates may not
> undergo a change and, therefore, I suspect\--
>
> DR. BRASS: If that would be a metabolite of catecholamines, I would
> say no.
>
> DR. BLONZ: What about final estrogen that would bind to an estrogen
> receptor?
>
> DR. BRASS: What is the question?
>
> DR. BLONZ: Well, it is not acted upon\--
>
> DR. BRASS: But it is not a metabolite. Its chemical structure isn\'t
> changed. The example that was posed is, does binding a receptor lead
> to a chemical reaction where a molecule is changed, whether or not you
> have a product precursor relationship, that was implicit in my
> thinking.
>
> DR. DWYER: Dr. Dickinson?
>
> DR. DICKINSON: I would like to go back to your example about lycopene
> and vitamin A. As I understood it, you said that the reason it
> wouldn\'t be a metabolite is that although it may be broken down to
> beta carotene, it doesn\'t eventually goes to vitamin A and,
> therefore, it isn\'t a metabolite. But there are hundreds of
> carotenoids that are broken down into various other compounds in the
> body, and I am troubled by the conclusion that simply because it
> doesn\'t go to vitamin A, all those metabolites wouldn\'t necessarily
> count as metabolites although they might have functions.
>
> DR. HARRIS: What I was trying to point out when I brought the lycopene
> up is simply the first step in the metabolism of lycopene is something
> that we can\'t do. But a tomato can convert it into beta carotene. I
> said we could take beta carotene which we would then consider a
> metabolite because we have enzymes to conduct further metabolism with
> that compound. What I tried to indicate is that we have no enzymes for
> lycopene.
>
> DR. DICKINSON: In the case of other carotenoids that might break down
> into component parts, would those component parts then be metabolites
> of those carotenoids?
>
> DR. HARRIS: If they themselves could undergo further chemical change
> through enzyme-catalyzed reactions, yes.
>
> DR. BRASS: But what if they are end products? What if they go through
> a couple of steps and you get an end product? I think has to be
> considered a metabolite, the original dietary ingredient. Just like I
> think that something that is a botanical and is metabolized into p450
> and gets hydroxylated, that hydroxylated product is a metabolite of
> what you gave. I think linking function to the metabolite is
> fallacious. I mean, the precursor-metabolite relationship is a
> biological chemistry one, not a functional one. In fact, the
> metabolite could be a detoxification. Just like your concept in the
> written document that says it must not represent a threat to
> homeostatic mechanisms. That is a concentration argument. So, I think
> trying to evoke all these non-chemical, non-biochemical definitions
> into what a metabolite is cloud the water rather than clarify it for
> what is a much more straightforward precursor-product relationship
> that occurs in the body.
>
> DR. HARRIS: My strongest point that I want to make to you is that we
> are talking about defined biochemical pathways and if we are talking
> about intermediates in those pathways, we would be perfectly
> legitimate.
>
> DR. BRASS: Okay, p450, a non-metabolic pathway. It hydroxylates a
> botanical precursor to a hydroxylated product that has no function in
> man.
>
> DR. HARRIS: That is why I emphasized the next step as being important.
>
> DR. BRASS: That is why I emphasized not to count end products because
> end products are generated by metabolism. Just because B doesn\'t go
> any further doesn\'t mean it didn\'t come from A.
>
> DR. HARRIS: You are saying that a chemical reaction is a pathway.
>
> DR. BRASS: An enzymatic pathway can occur in one step, a natural
> product exposed to p450 gets hydroxylated and excreted in the urine.
> Because a hydroxylated compound was generated by the body from a
> precursor I don\'t know how to avoid concluding it is a metabolite. I
> don\'t know any theological reason\--
>
> \[Laughter\]
>
> \--that says it has to be greater than one step. Obviously I am biased
> because as a pharmacologist this is what we do all the time. We give a
> foreign substance to the body, most of which are derived from natural
> products, metabolized by reactions to the body to metabolites. Some of
> those are active and some of those are inactive but they are clearly
> metabolites. Again, the implication of that definition, that is
> somebody else\'s problem but it seems to me that trying to put
> arbitrary boundaries on what is or isn\'t just makes it more
> confusing.
>
> DR. HARRIS: Well, I can see your argument and I can also see the
> danger in the argument because if I can take any compound, stick it
> inside p450 and hit it, it is a metabolite, I don\'t like that.
>
> DR. BRASS: Well, many of us have problems with parts of the law but
> that is not our charge. I mean, it is to come up with a working
> definition of what a metabolite is. Under the law, if that precursor
> turns out to meet any of the precursor definitions that are in the law
> and a metabolite may be p450 I feel trapped. I don\'t like being
> trapped. I don\'t understand the negative potential consequences of it
> but I feel trapped in trying to come up with a definition of a
> metabolite trying to avoid these traps just leads me into semantic
> traps.
>
> DR. DWYER: I think it is time for coffee. I just wanted to mention
> that Dr. Yetley came in while we were in the midst of this. Why don\'t
> we take a break and give Dr. Harris a rest and be back here in 15
> minutes?
>
> \[Brief recess\]
>
> DR. DWYER: Could everybody sit down, please? We are going to start
> again. There are a couple of issues that emerged as we were
> metabolizing coffee. The first is, I hate to keep getting you up to
> the mike but I wondered if you could go back and just give us a little
> bit perspective on the kava-kava question that came up, the whole
> issue of dietary ingredients and where metabolite fits in that whole
> thing?
>
> DR. MOORE: Do you want to wait for a couple of your AWOL committee
> members? Do you want me to wait until they all get back?
>
> DR. DWYER: Well, while you are waiting could you please tell us where
> you come from in your terms of your background? What are you? A
> lawyer?
>
> DR. MOORE: Oh, no.
>
> DR. DWYER: A doctor.
>
> DR. BRASS: That wasn\'t very nice; what did he do to you!?
>
> DR. MOORE: Before I say no to that, I should ask the lawyers to raise
> their hands so I will know how to answer that! No, my undergraduate
> and doctoral training was in nutritional sciences. Then I spent six
> years and did my postdoc. at Grand Forks, USDA lab, and then spent six
> years in the Army\'s Occupational Medicine Research Program. I came
> here in \'94 and had the misfortune or good fortune, depending on your
> perspective\--I was hired right when DSHEA was happening. I have been
> there ever since.
>
> DR. DWYER: Thanks. Are you a metabolite of DSHEA?
>
> \[Laughter\]
>
> DR. MOORE: The question that Dr. Dwyer asked, to sort of walk through
> again, is the construct for in the statutory definition for dietary
> supplement. It is important to recognize that the dietary ingredient
> clauses is but one of many, many requirements that a product would
> have to meet before it could be lawfully marketed. The issue of
> dietary ingredients is really the gatekeeper clause. You don\'t have
> to worry about whether it is safe, or is approved as a drug, or it is
> intended to supplement the diet or anything else because if it isn\'t
> statutorily \"a dietary ingredient\" it can\'t be a supplement and all
> those other requirements go away.
>
> Once it becomes a dietary ingredient, then you superimpose on that all
> of the other requirements, does it meet the safety standards? Is it
> excluded? Is it thrown out of the box by one or more of these
> exclusion clauses? If it is a dietary ingredient, is it then a new one
> that would require a notification or is it eligible for exemption for
> notification? So the issue of the dietary ingredient definitional
> construct is simply that it possibly gets you into being a lawful
> ingredient but it is not the end-all. What that section says is that
> dietary ingredients are vitamins, minerals, amino acids, herbs or
> other botanicals, the sort of dietary substance for use by man. In a
> broad sense, things that are articles of the usual food or drink of
> man is the way to look at that.
>
> Then, the last one is that it is a constituent, a metabolite, a
> concentrate, an extract or a combination of any of those others. For
> example, to use kava which came up earlier, it gets into the dietary
> ingredient box because it is an herb or botanical. The things in it
> may get into the box because they are a metabolite of it, a
> constituent in kava, a concentrate or an extract of it. So, metabolite
> isn\'t the only way a particular substance can get into the dietary
> ingredient box. It is simply one of a myriad possibilities, and
> something that is a metabolite might also be a constituent where it
> might fit into some other category but this is simply one of many.
>
> DR. DWYER: Just to follow-up on that, could you tell us, lycopene
> could also be in the box by other ways, couldn\'t it?
>
> DR. MOORE: Right. The most straightforward way is it is simply a
> constituent. You know, herb or other botanical means plants, if you
> will. So, tomatoes are clearly plants, bioengineered or not. So,
> lycopene clearly is a constituent of a plant material and that is the
> simple, straightforward way to get in.
>
> DR. BRASS: Again, as I read your background summary and your list of
> vitamin, mineral, amino acid and herb, in my construct of
> precursor-metabolite relationships I view that upper list as the
> precursor which might be a substrate to generate a metabolite in the
> final clause.
>
> DR. MOORE: Clearly, that is what the statute envisioned because that
> is what it says, a metabolite of something aforementioned.
>
> DR. BRASS: Right.
>
> DR. MOORE: So, it can be a metabolite of some ephemeral substance. If
> that ephemeral substance isn\'t listed above, than that metabolite
> isn\'t a dietary ingredient.
>
> DR. BRASS: Right, but trying to keep my syntax consistent, those would
> be the precursors and I wouldn\'t have to argue whether they were
> metabolites or not. They are already the precursors and not
> metabolites.
>
> DR. DWYER: So, those are amino acids, vitamins, minerals, herbs,
> botanicals and what is the last?
>
> DR. MOORE: Dietary substance for use by man to increase the dietary
> intake. That, like metabolite, is also not explicitly defined or
> discussed in the statement of agreement. How we have applied that or
> interpreted it is simply that those dietary substances are those
> substances that are in the usual food and drink of man. So, that is a
> fairly broad category.
>
> DR. DWYER: Shall we go around the table? Any questions? Annette?
>
> DR. DICKINSON: No, I thought your clarification earlier that many of
> these substances that we have been talking about, like lycopene, would
> be dietary ingredients in and of themselves for other reasons,
> regardless of the metabolite clauses, is a point that I am glad you
> made.
>
> DR. MEHENDALE: I have a question.
>
> DR. DWYER: Identify yourself.
>
> DR. MEHENDALE: This is Hari Mehendale. I have a question concerning
> whether we have some historical perspective. When this law was
> introduced somebody framed this metabolite. Surely, somebody had input
> into this and I wonder if there is any information on people who might
> have been involved at that time who introduced this term metabolite.
> That might be helpful, if somebody has that information, what was
> thought at that time when whoever did this introduced this term
> metabolite.
>
> DR. DWYER: That is a very good question and I will answer what I know
> and then the experts can answer from what they know. There is no
> legislative history for this. It was the first thing I asked when I
> was told the purpose of this business. So, that means whatever was
> discussed was expunged from the record. What that leaves you with is
> the analog of a hundred people feeling different parts of the elephant
> and explaining\--what is it?\--a hundred blind people trying to
> explain what the elephant was. So, there doesn\'t seem to be very much
> common agreement on what the dialogue was that led to this particular
> thing. Perhaps there are others who would like comment on it.
>
> DR. MOORE: No, I think you are correct from a purely legal perspective
> for interpreting and applying the law. While I am sure one could mine
> the Congressional Record and find what was the Congressional Record,
> for legal purposes it is struck and can\'t inform whatever decision we
> make or consider.
>
> DR. DWYER: Anyone else over here have any comments on that?
>
> DR. BLONZ: This is Ed Blonz. I don\'t know the exact pathway but let
> us say we are dealing with a substance such as garlic. Garlic, when it
> is in its full state has a set of compounds, but when you crush garlic
> you activate an enzyme system which then breaks down one compound into
> another compound that would be a metabolite of the naturally occurring
> compounds in garlic. Now, if we were to take those metabolites of
> garlic and use those as a supplement, see, we have an enzyme system
> outside the human body acting on a naturally occurring compound. How
> would that fit into our definition of a dietary supplement?
>
> DR. MOORE: Probably simply as constituents again because the limited
> statement of agreement says that physical acts, if you will, on things
> that are dietary ingredients don\'t change anything. So, to the extent
> that garlic, at least in some normal way of use is squashed, that is
> still the plant or botanical and the substances that are in that are
> constituents of it. Regardless of how they got there, they are still
> constituents.
>
> DR. DWYER: Dr. Schiff?
>
> DR. SCHIFF: Paul Schiff. I think the point is well taken but it goes
> back to the big picture versus many small pictures. So, if a plant has
> its own set of metabolites that it has produced, you grind it up, the
> constituents mix, there is some water, there are enzymes present. A
> glycoside in one cell becomes an A-glycan and a human being ingests
> ultimately both the glycoside and the A-glycan\--they are all
> metabolites I think.
>
> DR. BRASS: Except I think it is important to think about the
> separation. In the context of this they are constituents and not
> metabolites because, to me, if you open the metabolite to non-human
> fates\--
>
> DR. SCHIFF: No, no, pardon me, they are phytometabolites, I agree with
> you.
>
> DR. DWYER: We will get back to that definition again. There are a
> couple of other questions, Dr. Moore\--you are not off yet. One was
> Dr. Mehendale\'s question but maybe you can phrase it better. It is
> this whole business of the human rumen. Again, it is sort of like the
> crushed garlic question, but the issue of some of the isoflavonoids, I
> can\'t remember which one it is that is converted in the gut by the
> bacteria and the question is whether the bacteria in the gut are in or
> out. What is the FDA\'s official view of that?
>
> DR. MOORE: I don\'t think we have an official view.
>
> \[Laughter\]
>
> DR. DWYER: This is a first, isn\'t it?
>
> DR. MOORE: That is one of those areas of ambiguity that aren\'t
> readily clear from the plain language of the statute or the statement
> of agreement. I think that discussion as to where those types of
> metabolites or transformed substances fit may be part of your
> discussion that will inform our consideration of that, but we have not
> outlined a policy about that.
>
> DR. DWYER: Probionics?
>
> DR. MOORE: As to where they fit in the dietary ingredient mode?
> Probably, again, to the extent that some microorganisms are typical
> parts of fermented foods, some of their constituents, some of them
> have a long history of use simply as food maybe not in the U.S. but in
> other cultures. So, arguably, depending on the bug, they would be
> either dietary substances for use by man or constituents of other
> foods.
>
> DR. DWYER: One other thing, are metabolites organic?
>
> DR. MOORE: The statute is silent on that. I don\'t think it limits it
> to inorganic or organic or any other.
>
> DR. DWYER: I guess it is time to get Dr. Harris back up.
>
> DR. MOORE: Okay.
>
> DR. DWYER: We are giving him training as an expert witness for a
> murder trial. You make big money when you do murder trials; here it is
> nothing!
>
> \[Laughter\]
>
> Could you tell me if you think metabolites are organics?
>
> DR. HARRIS: No, I would not limit it to that, no.
>
> DR. DWYER: What is an example of one that is?
>
> DR. HARRIS: Well, up until probably the last fifty years or so a lot
> of attention has been placed on inorganic elements in living systems.
> I don\'t have to tell you Tufts is very famous for work on calcium and
> iron and my work on copper. We now know that these elements are
> clearly metabolized, not in the usual sense that they are being broken
> down to other things; obviously not, but they are able to engage in
> compounds that assist in their transport around the cell and
> ultimately determine their positioning into enzyme structures, and so
> forth. So, these are well-defined pathways that are now coming into
> more common understanding and, hopefully, more in the literature so
> you won\'t have to ask that question again.
>
> DR. DWYER: Thank you. Let\'s start back with some questions for you.
>
> DR. HARRIS: Can I raise one question?
>
> DR. DWYER: Of course.
>
> DR. HARRIS: Regarding the comment about microflora again and returning
> to that, by a physiologist, quite some time ago, I was told that
> anything in the gut is outside the body, waiting until until we enter
> the system. The case in point here could easily be seen, you don\'t
> produce antibodies to bacteria even though the bacteria are in the
> gut. They don\'t form any type\--it is more of a symbiotic
> relationship. So, I raise that question with you. When you talk about
> the gut are you talking about in the body or out of the body?
>
> DR. BRASS: I was with you until you got into the immunity part. There
> is mucosal native immunity. I think this is a grey area, but I think
> to incorporate both Dr. Shannon\'s comment and the comment about the
> gut flora, if you take that definition, then for example the stomach
> acid is outside the body and, clearly, the stomach acid may be a
> mediator of a chemical modification of a dietary substance. So, it
> seems to me that one is trapped into some kind of precursor-metabolite
> relationship following oral ingestion, or some other kind of exposure
> to the body that incorporates all the body functions and that includes
> natural flora to the degree that that is a natural constituent. It
> seems to me that, again, there is a little bit of a trap here, that
> you are talking about oral ingestion and the fate of the precursors
> after oral ingestion and another molecule that is generated is a
> metabolite.
>
> DR. DWYER: Thank you. Dr. Childs, you had a very interesting thing
> that we were just sort of chatting about in the break in terms of your
> thinking about toxicity and the whole issue of where these things all
> fit.
>
> DR. CHILDS: I think we have already covered that with Dr. Moore. I had
> been concerned about going back to the language in the original
> statute in the sense that there were multiple pathways to be
> considered a dietary supplement or dietary ingredient. I believe,
> Johanna, that is what we had talked about.
>
> DR. DWYER: Did Dr. Moore\'s explanation clarify what you were
> thinking?
>
> DR. CHILDS: Yes, it did, although I am still in a grey area over the
> bacteria issue. I am not as certain how that will shake out. Then, I
> am also just wondering, just trying to leap ahead for how this
> language might be applied in the future, thinking about GMO organisms
> and thinking about other methods of ingestion that might not be
> dietary, particularly if you think of aroma and if we see that
> emerging as a channel for dietary supplements. I am just trying to be
> very far out there in what ways this might move forward.
>
> DR. DWYER: I think there are already B12 inhalers.
>
> DR. DICKINSON: Right, but the Act defines dietary supplement as
> something that is ingested.
>
> DR. BLONZ: You have to swallow.
>
> DR. DICKINSON: Yes.
>
> DR. CHILDS: All right, so that takes care of that.
>
> DR. MEHENDALE: I know the examples to illustrate a metabolite and
> metabolism\--the examples that you used generally dealt with
> intermediate metabolism and production of energy, important areas and
> you did a very, very good job. But if you think about benefits,
> obviously we can have many, many benefits outside of those areas as
> well, not just production of energy. You could also have
> interventional benefits in people who might have other metabolic
> disorders or may not have what we would like to prevent, disorders,
> and there are many other areas of benefit even coming from
> intervention in toxicities, pharmacological interventions; there are
> many of those.
>
> So, I don\'t know if benefit with regard to definition of metabolite
> can be extended in those areas as well. You may not have limited that
> but your presentation was primarily using those examples, and I wanted
> your comments on that.
>
> DR. HARRIS: As I understand it, you want me to justify why the word
> benefit was put into my perspective of what it should be.
>
> DR. MEHENDALE: Right.
>
> DR. HARRIS: I suppose looking at how cells function, obviously cells
> have all kinds of different mechanisms that are really geared toward
> cell survival and basically that is to sustain life. So, I am looking
> at certain events here, and they could be protective measures but
> actually let\'s look at it from the standpoint of keeping alive,
> stepping aside from anything that might harm us. That is where I put
> metabolism, in that perspective.
>
> I see metabolism as basically two processes. Typically biochemistry
> talks about anabolism, which is building new structures from smaller
> molecules, or catabolism, which is breaking down for the purpose of
> either yielding energy or other purposes. I see all of these as
> well-designed steps that keep a cell alive. I also see where mutations
> in any enzyme systems can lead to diseases and these diseases
> ultimately feed back into some malfunctioning pathway. So, I am
> looking at maybe more of a divine nature of a living system rather
> than a practical nature.
>
> DR. DWYER: Your definition implies that there is sort of\--
>
> DR. HARRIS: Ultimate purpose.
>
> DR. DWYER: \--a purpose.
>
> DR. HARRIS: Yes.
>
> DR. DWYER: One doesn\'t have to assume if one doesn\'t want to.
>
> DR. HARRIS: That is correct.
>
> DR. BRASS: I agree with everything you said but I don\'t think it is
> relevant to the definition of what a metabolite is or isn\'t. A
> metabolite relationship, again, is a chemical, biochemical,
> precursor-product relationship. Even for the natural intermediates
> there are concentration considerations so let\'s take a molecule like
> propionate. Propionate is a natural product of odd-chain fatty acid
> breakdown, branched amino acid production. It is important for
> generating Krebs cycle intermediates. But in high concentrations it is
> clearly toxic to cells, unambiguously toxic to cells. Carbon monoxide
> is a metabolite of heme breakdown in man. Carbon monoxide is pretty
> toxic but it is generated in endogenous metabolism and it is clearly a
> metabolite, in my mind.
>
> So, I think trying to prejudge or demand some kind of benevolence or
> malevolence in the definition of what a metabolite is really clouding
> the issue. I think for relevant dietary supplements those issues are
> taken care of, to the degree they are, in other aspects of the law.
>
> DR. HARRIS: Eric, pardon me for saying this but I think some of those
> comments are a cloudy issue. Water. Water is a metabolism product.
> Obviously, water is a dangerous substance. I mean, if you want to sit
> here and drink a barrel of water, be my guest but you will not
> survive. You will upset all your homeostatic mechanisms.
>
> I guess what I am saying really is looking in the context of
> normal\--if you want to call it normal\--
>
> DR. BRASS: Again, we are talking about exposure to compounds that are
> not endogenous to man. We are talking about xenobiotics. We are
> talking about other molecules that are not endogenous when we talk
> about plants that contain a number of molecules that are not
> endogenous to man. Therefore, their metabolism and generated
> metabolites don\'t mimic human metabolism, and trying to force the
> square peg into the round hole doesn\'t work if I am trying to simply
> define whether or not an individual molecule is a metabolite of
> another molecule.
>
> DR. DWYER: Let me make sure, your point is that dietary supplements
> include xenobiotics in some cases.
>
> DR. HARRIS: Let\'s make sure we understand the meaning of xenobiotic.
>
> DR. DWYER: Sorry?
>
> DR. HARRIS: I said let\'s make sure we understand the meaning of
> xenobiotic.
>
> DR. DWYER: Fair enough. Do you want to comment on that?
>
> DR. HARRIS: I think Eric brought it up.
>
> DR. BRASS: Well, I included it in molecules that are contained in
> other organic matter that are not endogenous to human metabolism.
> Fair?
>
> DR. HARRIS: Yes.
>
> DR. BRASS: Without being judgmental about them.
>
> DR. DICKINSON: But by that definition a vitamin would be a xenobiotic.
>
> DR. BRASS: That is a good point.
>
> DR. DICKINSON: One thinks of a xenobiotic as things other than
> naturally occurring materials. One thinks of xenobiotics as being a
> synthesized\--
>
> DR. BRASS: No.
>
> DR. DICKINSON: Well, in nutrition we do.
>
> DR. BRASS: But, again, I think a substance that is present in a plant
> that is not used in normal metabolism but can be metabolized by p450
> is going to be a xenobiotic.
>
> DR. DICKINSON: But it is not a xenobiotic to the natural biological
> system\--
>
> DR. BRASS: When you ingest it.
>
> DR. DICKINSON: \--to a biological system generally though.
>
> DR. HARRIS: There is an important point here that has to be made and
> that is, is it a xenobiotic before the fact or after the fact? If you
> are talking about after the fact, then a vitamin is not a xenobiotic
> because it is acted upon by a series of enzymes that converts it into
> a profactor so it cannot be foreign to the body.
>
> DR. BRASS: I don\'t want to get distracted into an argument about what
> xenobiotics are. Everyone will grant me there are molecules in organic
> matter that you can put in your mouth that are not part of endogenous
> human metabolism. Those molecules can get metabolized and generate
> metabolites. That is my point, and without deciding whether those
> metabolites are benevolent or malevolent.
>
> DR. CHILDS: I was just wondering if phytoestrogens are an example.
>
> DR. HARRIS: I think Ed brought up the point\--I think it was your
> point that phytoestrogens will interact with estrogen receptors.
>
> DR. BLONZ: They will, but they are also naturally occurring
> constituents of a number of\--
>
> DR. BRASS: And undergo metabolism in man.
>
> DR. HARRIS: Yes.
>
> DR. BRASS: And those metabolic products are metabolites of
> phytoestrogens.
>
> DR. HARRIS: Yes.
>
> DR. BLONZ: Clearly, one of the things that we are dealing with here is
> once we get past many of the ingredients that are entailed or are
> included in the definition of a dietary supplement, the one category
> which is problematic is the botanicals because we are not dealing with
> essential nutrients per se, although there can be essential nutrients
> in botanicals. So, this is where we introduce a lot of the compounds
> which might be foreign to the human body but they are still within our
> definition and we need to understand how the definition of metabolites
> applies to them.
>
> DR. HARRIS: I think I would argue with you that mere interception with
> a receptor type mechanism is not sufficient to say that chemical
> changes have taken place.
>
> DR. BRASS: I agree with that.
>
> DR. DWYER: Could everybody turn to these questions because I don\'t
> know how long you get to stay, Dr. Harris\--
>
> DR. HARRIS: I will be here all day.
>
> DR. DWYER: You will be here all day? But I would still like to focus
> on those and we do want to go back to these out of body experiences.
>
> \[Laughter\]
>
> Miss Hardy just asked whether we want two public comments before the
> questions. What I want first though is to get Dr. Harris right now,
> while it is fresh in our minds, to make sure there are no questions we
> want to ask him right now.
>
> So, question one, is it possible to identify particular scientific
> criteria, principles, or conventions that enable a determination to be
> made about when a substance is or is not a metabolite of another
> dietary ingredient?
>
> First of all, do you have any additional comments you want to make
> having listened to our questions so far? You will have other chances
> but we want to focus on the issue because these are the questions the
> agency wants us to answer.
>
> DR. HARRIS: One of the comments I would make, first of all, is I
> really enjoy the intercourse that is taking place between us. When I
> bring you a strictly biochemical perspective, I realize there are
> exceptions. For example, the exception of non-enzyme-catalyzed
> reactions, and other exceptions could be brought to the fold.
>
> I found it rather difficult trying to give you numbers. So, if I said
> a metabolite has to be within a certain distance number-wise,
> reaction-wise from a reference compound, I found that difficult. I
> think you don\'t want to do that but, at the same time, we want to
> observe the principle.
>
> I think for everything we are going to be saying there is going to be
> an exception and what I am really concerned about is that we don\'t do
> a carte blanche here. Let me return to the p450. We have been talking
> about that enzyme quite a bit. That enzyme is called a mixed function
> oxidase. That means we haven\'t really nailed it down as to what
> molecules it actually acts upon because there is such a wide spectrum
> of molecules. I think Eric would agree with me on that.
>
> Just because that enzyme is acting on anything we throw at it, is that
> enough to say that we have seen metabolism taking place and that we
> have generated a metabolite? So, that is why I really wanted to bring
> up the idea that, in a metabolic sense, we are dealing with both a
> substrate and a product. In other words, we are going to make
> something but that something we made has to be converted into
> something by an enzyme reaction. To me, I would be relaxed when I
> think of that being a metabolic event.
>
> DR. DWYER: Thank you. Are there any other questions on question one
> now?
>
> DR. MEHENDALE: I just wanted to comment. Before we realized that the
> mixed function oxygenases consist of individual members of a family, I
> think the mixed function probably applied to the time when we realized
> this group of enzymes carries out many, many functions. After the
> advent of the individual isozymes being separated, now cloned and so
> on and so forth, I think we are using those terminologies less and
> less even though we realize that individual members have some
> overlapping activities. I just wanted to clarify that.
>
> DR. DWYER: Very good. For question two, are there any things that
> immediately come to mind?
>
> DR. BLONZ: Let me ask you a procedural question. I have looked through
> the materials and I have comments to make on all of them, but I also
> would like to make sure that I have listened to all the public comment
> before I come to any conclusions. So, how do we handle the conduct of
> the meeting as regards that?
>
> DR. DWYER: We are going right to the public comments as soon as you
> ask any questions of Dr. Harris you want to ask.
>
> DR. BLONZ: So, this is only as regards addressing Dr. Harris?
>
> DR. DWYER: That is correct. We are just trying to make sure that any
> immediate type of questions are raised but public comments are coming
> right along. Then we will go back to the issues again. Anything on
> question two? Anything on question three that you want to ask now that
> you have jotted down? If not, I think we are ready. The public comment
> can proceed. I don\'t know if the people are here. If they are, we
> would love to hear their views. Thank you, Dr. Harris.
>
> MS. HARDY: We have two people that are on the agenda that are going to
> speak today, the first one being Dr. Philip Harvey. Each commentor
> will be permitted to talk for ten minutes. The timer is on the podium
> while you are up there and then I will be watching it too and I will
> give you a signal when you have two minutes left. So, Dr. Harvey?
>
> DR. DWYER: Dr. Harvey has written a thoughtful letter.
>
> **Open Public Comment**
>
> DR. HARVEY: The letter was written by Scott Bass and Emily Marden. You
> have the letter. I mean, I was just going to read through that. I
> don\'t know if it is redundant or not.
>
> MS. HARDY: Many of the people in the audience do not have the letter.
>
> DR. HARVEY: Okay, I am just going to go ahead and read the written
> comments that were submitted by Sidley and Austin. There are some
> introductory points but I will just get to the specifics.
>
> I am chief science officer for the National Nutritional Foods
> Association, or NNFA. NNFA appreciates FDA\'s solicitation of comments
> on the definition of metabolite. NNFA believes that the term has a
> clear scientific definition and was explicitly included in the DSHEA
> definition of dietary supplement on those terms. NNFA, therefore,
> takes the position that there is no need for FDA to redefine or narrow
> the category.
>
> One, the definition of a dietary supplement in DSHEA includes
> metabolites. I think this was discussed extensively in terms of the
> DSHEA definition, defining a metabolite or a vitamin, mineral, herb or
> other botanical, amino acid or dietary substance. Specifically, the
> term dietary supplement means a product, other than tobacco, intended
> to supplement the diet that bears or contains one or more of the
> following dietary ingredients: (a) a vitamin; (b) a mineral; (c) an
> herb or other botanical; (d) an amino acid; (e) a dietary substance
> for use by man to supplement the diet by increasing the total dietary
> intake; or, (f) a concentrate, metabolite, constituent, extract, or
> combination of any ingredient described in clause (a), (b), (c), (d)
> or (e).
>
> Two, the definition of a metabolite is not contested. Metabolite is
> uniformly defined in scientific and general use dictionaries as any
> substance produced by the body\'s metabolism or by one of the body\'s
> metabolic processes. A metabolite thus includes any substance that is
> created by the body as it builds up, breaks down, or converts the
> nutrient.
>
> This inclusion of the term metabolite in the DSHEA definition of
> dietary supplement indicates that the drafters of DSHEA contemplated
> allowing any compound that results from metabolism of one of the other
> defined dietary ingredients to be marketed in dietary supplements.
>
> The range of metabolites is potentially broad, including what are
> called intermediary metabolites, molecules that are not identical to
> the original nutrient/supplement but are created to get to another
> step along a chain of alterations that leads to the molecule the body
> is trying to make or excrete.
>
> Three, a wide array of dietary supplements are already on the market
> as metabolites. A wide range of dietary supplements already on the
> market as metabolites of dietary ingredients, and here are a few
> examples. One would be MSM, a metabolite of DMSO, a garlic-oyster
> smelling substance. Glucosamine sulfate, a metabolite of chondroitin
> sulfate; pantetheine, a metabolite of pantothenic acid; methionine, a
> metabolite of SAMI, or a metabolite of homocysteine. Those are just
> some examples.
>
> Four, like other dietary supplements, metabolites must meet the
> statutory safety standard. The definition of metabolite is, therefore,
> very clear and there is no reason FDA should move to redefine or
> narrow this category.
>
> At the same time, all dietary supplements, including metabolites, are
> subject to the statutory safety standard, which NNFA urges FDA to
> continue diligently enforce. Under this standard, dietary supplements
> must not present a significant or unreasonable risk of illness or
> injury under conditions of use recommended or suggested in labeling,
> or under ordinary conditions of use. Some products on the market
> clearly fail that standard regardless of their definitional status
> under Section 21 of the U.S.C.
>
> Five, new dietary ingredient provisions also apply. The new dietary
> ingredient, or NDI, provisions of DSHEA apply to all dietary
> supplement ingredients including metabolites. NDI is defined as a
> dietary ingredient that was not marketed in the United States before
> October 15, 1994. DSHEA requires that manufacturers of dietary
> supplements containing an NDI file a notification establishing the
> safety of the ingredient 75 days before it is placed on the market.
>
> The safety of a dietary supplement containing an NDI is established if
> there is a history of use or other evidence of safety establishing
> that the dietary ingredient when used under the condition recommended
> or suggested in the labeling of the dietary supplement will reasonably
> be expected to be safe.
>
> Thus, manufacturers of dietary supplements containing NDIs are subject
> to both the general safety standard noted above, as well as the NDI
> standard. NNFA believes that these safety standards, together with FDA
> enforcement, are adequate to ensure that metabolites are adequately
> regulated.
>
> Based on these comments, we urge FDA not to modify its interpretation
> of the term metabolite. Thank you.
>
> DR. DWYER: Could we take questions now or would you be willing to
> answer some questions?
>
> DR. HARVEY: Sure.
>
> DR. DWYER: Yes?
>
> DR. BRASS: Do you agree that human metabolite is implicit in the
> phrase metabolite?
>
> DR. HARVEY: Yes.
>
> DR. SHANNON: Do you really think the definition is not contested?
>
> DR. HARVEY: You know, that is our position.
>
> DR. DICKINSON: Could we ask a question of Dr. Moore related to that?
> Could we ask whether there has been a warning letter or other action
> related to whether something is or isn\'t a metabolite?
>
> DR. MOORE: I don\'t know that there is a warning letter. I know that
> there are untitled letters where we have asserted that certain analogs
> of things that would fit into one of the other categories are not
> metabolites. For example\--I remember the colloquial name but not the
> chemical identity\--but it is an analog of coenzyme-Q. That was argued
> to be a metabolite of and we asserted that it is not a metabolite; it
> is a chemically prepared substance derived from that, that fell
> outside the scope. We haven\'t really defined or carved out much more
> than that for metabolites.
>
> DR. BLONZ: Dr. Harvey, in your definition of metabolite, in the first
> paragraph you say that a metabolite, thus, includes any substance that
> is created by the body as it builds upon, breaks down or converts the
> nutrient. Now, not all of the dietary ingredients are nutrients.
>
> DR. HARVEY: Correct.
>
> DR. BLONZ: Then you also put in the third paragraph to get to another
> step along a chain of alterations that leads to the molecule the body
> is trying to make or excrete. Could you expand on what you mean by
> that?
>
> DR. HARVEY: You know, listening to the prior comments, I mean these
> compounds are precursor substrates and are making one intermediate
> constituent or are converted to another. Some of those are excreted
> based on metabolism and, you know, it is just that process
> specifically.
>
> DR. BLONZ: It was my thought that in many cases they might be trying
> to make or excrete something in response to the presence of that very
> ingredient. So, it might not be a physiological process that happens
> outside the presence of that ingredient; it could be just a reaction
> to its presence. Again, coming back to our friend cytochrome p450,
> there are many reactions to putting foreign substances in the body.
>
> DR. DWYER: One issue that is troubling here is the purposefulness
> again.
>
> DR. BLONZ: Yes.
>
> DR. BRASS: Yes, I don\'t think you should try to decipher what the
> intent of the body is.
>
> DR. DWYER: Could I ask just probably a very stupid question? In your
> section four, it says all dietary supplements are subject to the
> statutory safety standard. Of course, NNFA is urging diligent
> enforcement. The question is there could be a standard after the fact.
> Right? If you leave that very broad and you don\'t know something is
> harmful and then it turns out to be harmful, what is the protection to
> the consumer? Is this a license to cause trouble?
>
> DR. HARVEY: I am not going to speak specifically for FDA but, you
> know, there is a possibility\--you know, these things are kind of
> living\--that new evidence comes out based on a better understanding
> of these substances that could possibly change that. But generally, as
> we see that as constituents that the body could use or eliminate, and
> there are things for which we still don\'t one hundred percent know
> the exact mechanism or what is going on but unless there is some
> physiological change or condition of abnormality, then there is a
> possibility that that could be addressed. In terms of FDA enforcement,
> you know, they would be looking for some type of an illness or injury,
> some event and a sequence of that and, you know, they may consider
> enforcing on that.
>
> DR. DWYER: Other questions?
>
> DR. BLONZ: Let me just ask one more thing, by this definition you
> would be arguing to say that testosterone or estrogen would be a
> metabolite of a fatty acid and could be included as a dietary
> supplement, as a metabolite of that substance.
>
> DR. HARVEY: Correct.
>
> DR. BLONZ: Thank you.
>
> DR. DWYER: Dr. Dickinson?
>
> DR. DICKINSON: It might under the definition by a metabolite but
> whether it could legally be included would depend on other provisions
> of the law, such as not including ingredients that are drugs or that
> are controlled substances that are otherwise excluded.
>
> DR. BRASS: This is where I think the concept of net product and not
> simply tracing carbons through pathways makes a big difference. Again,
> you can ingest any carbon and find it in any other molecule in the
> body under a wide variety of circumstances, but if it doesn\'t result
> in net structural contribution then I don\'t see how it can be viewed
> as a metabolite.
>
> DR. DWYER: I am troubled again. The word is used in the standard, as I
> understand it, as the last in a paragraph that lists specific things,
> and it seems to me a metabolite is a derivative\--
>
> DR. BRASS: No, it is an alternative way. My interpretation is the
> things above it are the precursors\--
>
> DR. DWYER: Yes, right.
>
> DR. BRASS: \--and metabolites of those things.
>
> DR. DWYER: Of those things.
>
> DR. BRASS: So, again, because glucose is a dietary constituent and
> just because you can feed somebody glucose and find glucose and
> carbons in every molecule in the body doesn\'t mean all the other
> molecules immediately become metabolites of it. There has to be net
> contribution to synthesis.
>
> DR. DWYER: Back to our colleague at the mike, then do you consider
> substances, other than things where precursors were amino acids,
> vitamins, minerals, herbals and botanicals or dietary substances for
> use by man, to be metabolites?
>
> DR. HARVEY: They could be, yes.
>
> DR. DWYER: Would you give an example? Is an example estrogens,
> metabolites of fat?
>
> DR. HARVEY: Estrogens metabolites of fats? I mean, carbon from
> cholesterol is a steroid. You know, it just depends on how far
> downstream.
>
> DR. BRASS: No, but if you eat more lipid, you eat more palmitate you
> don\'t get net incorporation of palmitate into estrogen. You might get
> carbons traced through infinite pathways that end up there, but you
> don\'t get net production so it can\'t be a metabolite.
>
> DR. HARVEY: I am thinking of another example of arachidonic acid into
> cell membranes. I mean, this does occur over a period of time, lipid
> especially. You know, you can change, especially with fatty acids,
> over time net incorporation of those dietary substances from either
> foods or dietary supplements into cell membranes.
>
> DR. BRASS: The specific phospholipids that are metabolized might be
> argued as metabolites because, again, there is a product-precursor
> relationship. But you can\'t say because it is incorporated into the
> cell the cell is a metabolite of the lipid.
>
> DR. DWYER: Any other comments or questions? Are those all clear? Does
> anyone at the table over here have any? I was puzzled by this
> precursor-product relationship. Is that your understanding?
>
> DR. TAYLOR: I think we are here to hear the discussion you folks would
> have about that, and we certainly don\'t have anything in our record
> that would be relevant to it.
>
> DR. DWYER: Thank you. Thank you, Dr. Harvey.
>
> DR. HARVEY: Thank you.
>
> MS. HARDY: Dr. Dentali?
>
> DR. DENTALI: Thanks very much. I am Steven Dentali. I am the Vice
> President for Scientific and Technical Affairs at the American Herbal
> Products Association, a trade group that represents manufacturers of
> botanical products. I don\'t have a written statement. I didn\'t come
> prepared with one but I would like to respond to the interesting
> discussion from this morning.
>
> I have a doctorate in pharmaceutical sciences, a minor in pharmacology
> and specialization in botanical and natural products chemistry.
>
> From the natural products chemistry, from botanicals, I just want to
> say for the record that flavonoids, terpinoids, alkaloids but not
> altoids but certainly the menthol in the peppermint oil that goes in
> the altoids, all these others fall into a class of secondary
> metabolites. That doesn\'t really have relevance here for the
> discussion because we are talking about metabolites of compounds, and
> botanicals is already included, and constituents of botanicals are
> already included. So, if you are taking menthol, that is already
> included but it is well within the definition of the metabolite
> standard within natural products chemistry. I know Dr. Schiff can back
> me up on that.
>
> In the same way\--I am sorry, I have forgotten your last name\--Brass,
> thank you\--I took a course in pharmacology called drug disposition
> and metabolism. So, I was uncomfortable with the limitation of the
> excellent discussion on metabolism, of intermediate metabolism and
> human cellular metabolism to be limited to just that. It is clear the
> course I took was talking about xenobiotic metabolites. So, the design
> of drugs and metabolism of drugs\--this is clearly within the
> definition of what a metabolite is and shouldn\'t be arbitrarily
> excluded.
>
> I think we see some of the limitations and try to limit it to within
> the body and to limit it within the realms of intermediate metabolism
> when, clearly, there are plasma esterases that occur; there are
> reactions that take place outside cells. You know, we seem to move the
> discussion from cells to the body but clearly in plasma metabolites
> are formed. There are non-enzymatic reactions that produce
> metabolites. Neurotransmitter metabolism, just as an example.
>
> That is really the point I wanted to make. I think the point of
> secondary metabolites is something to recognize. There are metabolites
> that plants make. In fact, these are pretty much the compounds of
> interest for botanical products. They don\'t come into play here
> because of the way the statute is written.
>
> I do think that the metabolism as known in pharmacology\--certainly
> there is no reason to exclude that from the definition. I don\'t see
> that we have any charge to do that. That is pretty much what I have to
> say.
>
> DR. DWYER: Come back to the secondary metabolism. What is primary
> metabolism? How do you define that?
>
> DR. DENTALI: Well, it would be the compounds that we know are
> necessary for the structure of the plant, basically proteins,
> carbohydrates, fats. We know exactly what they are for. We didn\'t
> really know exactly why\--I am not sure we still know why coffee beans
> contain caffeine. I don\'t think they are doing it for our benefit.
> But alkaloids are considered a secondary metabolite of a plant
> metabolic process. They may be doing it for their benefit since we eat
> the coffee beans and coffee is still around and is grown quite a bit;
> surviving well; there is a lot of coffee around because it contains
> caffeine.
>
> DR. DWYER: So a secondary metabolite is defined primarily by human
> knowledge?
>
> DR. DENTALI: Human knowledge\--could you repeat that, please?
>
> DR. DWYER: If we went back to 150 years ago, everything would have
> been a secondary metabolite because we didn\'t know about anything\--
>
> DR. DENTALI: Yes, we knew a little bit about alkaloids but not a lot.
> Yes, it is based on our knowledge of plant chemistry; our knowledge of
> human metabolites back about the same time.
>
> DR. DWYER: How about some questions for Dr. Dentali?
>
> DR. DICKINSON: You made the point that, as an intellectual matter,
> metabolites of xenobiotics should still be considered metabolites. But
> would you argue that those are necessarily dietary supplement
> ingredients?
>
> DR. DENTALI: Not necessarily, no. However, for flavonoids in a
> botanical it would be a dietary supplement ingredient. A drug
> metabolite, if it is already sold as a drug, does not make it a
> dietary supplement ingredient.
>
> DR. DICKINSON: And a secondary metabolite in botanicals or the
> botanicals themselves would be dietary ingredients for reasons other
> than that they are metabolites.
>
> DR. DENTALI: They are already constituents.
>
> DR. DICKINSON: Right.
>
> DR. DENTALI: Yes, the garlic was a very good example, made after the
> fact.
>
> DR. SCHIFF: I think when Steven was talking about secondary
> metabolites, I would want to emphasize that he means secondary
> phytometabolites in phytometabolism. He referred to caffeine and, if I
> remember correctly, glycine carbon dioxide and ammonia, assembled
> correctly, gives you caffeine in the plant. To me, something primary
> in a plant would be an amino acid.
>
> DR. DWYER: Fair enough. Any other questions? Anybody over here have
> anything? No? Thank you. It was very enlightening.
>
> DR. DENTALI: Thank you.
>
> DR. DWYER: Let\'s just go around and make sure there are no other
> questions that have come to mind for Dr. Harris or any of the folks
> who have been kind enough to share their views with us, or any
> questions of clarification that are needed from the scientists
> representing the agency. Yes, Dr. Dickinson?
>
> DR. DICKINSON: At the risk of complicating this unnecessarily, I have
> been sitting here, fretting about one thing that Dr. Harris said and
> what it means in the context of other ingredients that we know are
> used in dietary supplements. That is, he put a great deal of emphasis
> on the stereoisomer that is produced naturally in the metabolic
> system, and is suggesting that that be one of our criteria for what is
> an appropriate metabolite of one of these other ingredients as we talk
> about it.
>
> I just want to separate that concept from the established recognition
> that there are many essential nutrients where there are synthetic
> forms of the naturally occurring nutrient that are well accepted as
> equivalent forms of the nutrient, and that that is a separate issue
> from this question of whether a metabolite is the appropriate
> stereoisomer. I wondered if somebody from FDA would comment on that.
>
> DR. BRASS: But you are not quibbling that stereoisomers have to be
> considered distinct molecules\--
>
> DR. DICKINSON: Yes.
>
> DR. BRASS: \--in whatever category one is thinking about?
>
> DR. DICKINSON: Yes.
>
> DR. DWYER: Shall we take an hour for lunch or do you want to take
> less? Let\'s take sixty minutes which will bring us to about 12:35. We
> will be back here at 12:35. So, we are a little ahead of the schedule,
> which is fine with me.
>
> \[Whereupon, at 11:35 a.m., the proceedings were recessed for lunch,
> to be resumed at 1:40 p.m.\]
>
> \- - -
>
> [A F T E R O O N P R O C E E D I N G S]{.underline}
>
> **Discussion of Charge and Questions by Subcommittee**
>
> DR. DWYER: Does everybody have these questions? What is your pleasure?
> Shall we just go through the questions one by one? All right?
>
> DR. BRASS: It might be useful\--I have kind of a conceptualized
> definition that was useful for me in trying to integrate various
> aspects of this. I don\'t pretend it is perfect. It is not
> worth-smithed but it is conceptually how I thought about this. That
> might be helpful?
>
> DR. DWYER: Yes.
>
> DR. BRASS: It is a functional definition. What it says, in my mind, is
> X is a metabolite of Y if ingestion of Y by humans results in net
> production or increased flux of X incorporating structural elements of
> Y.
>
> So, there are two parts to it. First of all, it involves ingestion by
> man. Two, it involves a true precursor-product relationship that Y is
> giving net production of X and it is a direct structural interaction.
> In other words, the fact that catecholamine increases cyclic ANP
> wouldn\'t fit the definition because cyclic ANP incorporates no
> structural elements of catecholamines.
>
> So, it is in two parts. It is ingestion by man which, as we heard, was
> the key for supplements; yields net production of and is structurally
> a precursor of. Those seem to me to be the elements which I thought
> were critical in incorporating the issues we talked about with Dr.
> Harris\' presentation, an attempt to relate those in a way that made
> functional sense to me.
>
> DR. SHANNON: I think that is useful. We would probably need to work on
> what structural similarity means\--
>
> DR. BRASS: Incorporating structural elements of.
>
> DR. SHANNON: Right. What I mean is if that can be quantitated in any
> way because otherwise, again, if it has two carbons\--
>
> DR. BRASS: Well, I was trying to find exceptions where, if there was a
> direct net production and incorporation of the elements\--I was just
> trying to differentiate and gave the cyclic ANP example that was so
> well brought up earlier where these other indirect hormonal effects
> are some downstream effects when you produce a compound. Again, it is
> not word-smithing but that was the concept I was trying to get across.
>
> DR. DWYER: I have one addition to that. It has concerned me all along.
> It is getting all of this to something that is useful from the
> standpoint of the regulators. If you will bear with me while I draw
> some circles\--
>
> DR. BRASS: I didn\'t intend it to be this formal.
>
> DR. DWYER: You talk about metabolites and we are talking about other
> dietary ingredients, and it seems to me that what they are talking
> about here that needs to be defined is this, that intersection in the
> van Dyke diagram. Does everybody agree with that on the committee?
>
> DR. BRASS: So, this was a clever ploy to get me away from the
> microphone! I think that I do disagree.
>
> DR. DWYER: All right.
>
> DR. BRASS: Because I think that from conceptualization, the other
> dietary constituents or ingredients are the precursors of metabolites.
> Now, a metabolite might also turn out, by coincidence\--
>
> DR. DWYER: That is what this is supposed to be.
>
> DR. BRASS: No, I view that as the same thing.
>
> DR. DWYER: How would you draw this diagram?
>
> DR. BRASS: Well, I personally would draw them as two non-overlapping
> circles, acknowledging that it may turn out, by coincidence\--see,
> this again is an interesting definition\--by coincidence it might turn
> out that some of the metabolites also are constituents of dietary
> supplements, but that is not intrinsic to their definition.
>
> DR. DICKINSON: These are dietary ingredients. These are metabolites
> and some of those metabolites are dietary ingredients.
>
> DR. SHANNON: What makes them dietary ingredients? What makes those
> fractions dietary ingredients?
>
> DR. DICKINSON: You are right, I almost need two circles over here,
> don\'t I? These are legitimate dietary ingredients as defined
> elsewhere. These are their metabolites. Actually, all of those
> metabolites that meet that definition are dietary ingredients also.
> But also\--
>
> DR. BRASS: No, they are not.
>
> DR. DICKINSON: \--there are many other metabolites.
>
> DR. BRASS: The way you initially drew it is dietary ingredients
> generate metabolites. It may turn out, purely by coincidence and not
> by definition\--again, I am trying to focus on the definition which is
> our charge\--it may turn out that some of those metabolites turn out
> to be dietary ingredients by coincidence. For example\--
>
> DR. DICKINSON: No, no, I am saying\--
>
> DR. BRASS: \--glucose is a metabolite of sucrose. Right?
>
> DR. DICKINSON: Yes, it may also by itself be a dietary ingredient.
>
> DR. BRASS: And by coincidence glucose turns out to be a dietary
> ingredient but not intrinsic to the definition.
>
> DR. DICKINSON: No, I meant to show just that it is only metabolites of
> ingredients that are already dietary ingredients that are going to be
> ingredients because they are metabolites.
>
> DR. BRASS: What you are doing is defining X.
>
> DR. DICKINSON: Y.
>
> DR. BRASS: Y, I am sorry. You are defining Y by saying Y has to be a
> dietary ingredient or one of those precursors that are listed above.
>
> DR. DICKINSON: Yes.
>
> DR. BRASS: And I agree with that. Again, I was trying to focus on what
> a metabolite was.
>
> DR. DWYER: Come and play with us over here with the circles.
>
> DR. BRASS: I like my own game! You don\'t share!
>
> \[Laughter\]
>
> DR. DICKINSON: All right, what fraction of the second circle is
> relevant to us?
>
> DR. BRASS: A hundred percent.
>
> DR. DICKINSON: All of it.
>
> DR. BRASS: Because that is the definition of a metabolite, and that is
> what our charge is.
>
> DR. DICKINSON: But all of those may not be legitimate dietary
> ingredients.
>
> DR. BRASS: Well, there may be other parts of the statute but in terms
> of defining what a metabolite is, that is the definition.
>
> DR. DWYER: Then there is a whole bunch of other substances that are
> metabolites but not under the law.
>
> DR. CHILDS: Doesn\'t that get you back to your original drawing?
>
> DR. DWYER: Yes, I think so.
>
> DR. CHILDS: Which I thought was a clear portrayal.
>
> DR. BRASS: Again, defining whether it is a metabolite per se doesn\'t
> define whether or not it is an appropriate thing to be marketed under
> DSHEA.
>
> DR. DWYER: Right.
>
> DR. BRASS: And that is what I am trying to keep absolutely separate as
> we define what a metabolite is, or at least for me when I think about
> what a metabolite. That is, I have to keep that separate or I get into
> all kinds of caveats that I can\'t incorporate into a definition.
>
> DR. DWYER: Isn\'t something you said a lot earlier, that the upper
> list, the amino acids, vitamins, minerals, herbals and botanicals or
> dietary substances for use by man, are the precursors?
>
> DR. BRASS: Again, in my definition that is the list of things that are
> in Y. Again, I was trying to write a generic definition because I
> don\'t want to be trying to interpret\--we are having enough problems
> interpreting one word and I am trying to avoid getting us distracted
> and trying to interpret a bunch of other words. So, this seemed to me
> to be a generic way of saying that, but I would agree with you and my
> intent is Y would be that list of precursors.
>
> DR. DWYER: Could you read the definition again, Eric, to make sure I
> understand it?
>
> DR. BRASS: X is a metabolite of Y if, one, ingestion by humans of Y
> results in net production or increased flux of X. The phrase increased
> flux is to recognize that there may be a metabolic intermediate which
> doesn\'t accumulate, as Dr. Harris was referring to, but simply
> increases the flux through it in a way that affects biologic function.
> But the other part is two, that X has to incorporate structural
> elements of Y. That is, there is a direct precursor-metabolite
> structural link. Again, that is to get rid of the hormonal thing. If Y
> was a hormone, there are a variety of Xs that change in response to
> hormones. Those would not be metabolites because they don\'t
> incorporate structural elements of the hormone. Again using Dr.
> Harris\' example, if a molecule was an allosteric regulator of a
> pathway it would affect the concentration or flux of a number of
> substances, but because it didn\'t represent a structural precursor
> those would not be true metabolites of the precursor. So, those are
> the scientific criteria I was trying to incorporate into the syntax.
>
> DR. DWYER: Dr. Schiff?
>
> DR. SCHIFF: Eric, if I could ask you a question because I think this
> is very good conceptually and I just want to make sure I am on the
> right page with you here, let\'s go back to a tougher example. We will
> take a botanical. We will pretend it has 200 ingredients in it. Let\'s
> isolate ingredient 144\--I just picked that, being ingested by a human
> through some process, defined or undefined; it hydroxylates to
> hydroxy-144; hydroxy-144 you would consider a metabolite.?
>
> DR. BRASS: It would be a metabolite of Y.
>
> DR. SCHIFF: That is correct.
>
> DR. BRASS: Absolutely correct. That was my intent.
>
> DR. DWYER: Any other questions or comments? Dr. Harris, do you have
> comments you wish to make on this? Not allowed?
>
> DR. DICKINSON: Can I ask for clarification? We have asked questions
> before at advisory panel meetings of experts who were in the audience.
> No?
>
> MS. HARDY: Well, you know, we had time allotted for questions earlier
> in the day. Now it is supposed to be just you deciding answers to the
> questions, having already heard answers to the questions earlier.
> Technically, he is invited by the FDA so, you know, it is FDA\'s
> perspective.
>
> DR. BLONZ: I had prepared answering each of the individual questions,
> hoping that discussion of each of those points would lead us up to
> formulating a definition. We very well may come back to this but with
> some different understanding with more commentary. Are we going to go
> thorough these individual charge questions?
>
> DR. DWYER: Yes, we are in just a moment. First I need to get what is
> wrong with this diagram in terms of circles, and then we will go to
> the individual questions. Basically, I am still having trouble with
> why this first diagram I drew is not in line with your thinking.
>
> DR. BRASS: Well, it very well may be.
>
> DR. DWYER: I think it is.
>
> DR. BRASS: Okay.
>
> DR. DWYER: What I am saying is that a dietary ingredient, other than
> amino acids, vitamins, minerals, herbals and botanicals or dietary
> substances for use by man, a metabolite of those substances is what we
> are talking about. We are only talking about metabolites in that
> defined way, that a substrate or a precursor, as I guess you called
> it, has to be one of those things.
>
> DR. DICKINSON: That is what that shows.
>
> DR. BRASS: Yes, I think that is what that shows. I agree. I agree with
> Annette. I think that shows the relationship of causality and product
> precursor, and not the overlap.
>
> DR. DWYER: Does it imply Y always has to be before X?
>
> DR. BRASS: Because you have the arrow.
>
> DR. DWYER: There is directionality and there is temporality?
>
> DR. BLONZ: That is why Y came first.
>
> DR. CHILDS: I think what is happening is that we think of this as your
> starting diagram and your diagram as the concluding diagram.
>
> DR. BRASS: It will turn out that there is an overlap between but that
> area of overlap is not intrinsic to the definition.
>
> DR. BLONZ: One of the issues that I have with the definition is what
> would happen if you were to have an amino group as part of a reaction?
> Would the donation of that amino group then make that amino acid a
> precursor to the product?
>
> DR. BRASS: It would depend on the specific. The answer could be yes.
> Is an amino acid a precursor of urea?
>
> DR. BLONZ: Well, urea is a pretty uncomplicated substance.
>
> DR. BRASS: But that is the example.
>
> DR. BLONZ: One of the examples we have is an amino group from
> glutamine which then makes it glutamic that shovels that compound down
> the road. Are you saying it is the metabolite of both?
>
> DR. BRASS: Yes, conceivably that is true. I don\'t know for a fact\--I
> apologize\--whether adding glutamine increases the net flux through a
> set of reactions. I don\'t know which way it is limiting. So, again,
> both clauses have to be true under the functional definition I
> proposed but, yes, one metabolite might have more than one precursor,
> i.e., might be a metabolite of more than one molecule.
>
> DR. DWYER: One other question that might be asked is are there other
> ways, such as a structural definition rather than a functional
> definition, that might be thought of? It seems like there are some
> because they are in the paper. It has to be something that is an
> identifiable organic compound.
>
> DR. BRASS: No.
>
> DR. DICKINSON: It doesn\'t have to be organic.
>
> DR. DWYER: It doesn\'t have to be organic. It has to be an
> identifiable compound.
>
> DR. BRASS: You have to know what X is. X is a specific molecule so,
> yes, there has to be a specific molecule.
>
> DR. DWYER: Does it have to have any similarity to an amino acid,
> vitamin, mineral, herbal, botanical?
>
> DR. BRASS: In my opinion, the answer is no because we would argue all
> day whether molecule X and Y were similar, and we could go through
> 300,000 individual examples and develop 300,000 individual answers
> from the people on this committee but we wouldn\'t get insight into an
> extrapolatable definition.
>
> DR. CHILDS: But isn\'t that incorporated in your definition?
>
> DR. BRASS: Well, that is why I put structural element because that is
> different than similarity. Again, is an L-amino acid similar to a
> D-amino acid? It depends on whether or not you transfer RNA or not;
> one you recognize and one you don\'t. Again, I was trying to avoid
> that kind of discussion which I think would require individualization
> of every kind.
>
> DR. DWYER: Are there any other criteria? Do you have to know exactly?
>
> DR. BRASS: In my opinion, you do not. So, again, it terms of
> scientific principles, I do not think you need to know the pathway. I
> don\'t think you need to know the number of steps between. I don\'t
> think you need to know whether it is a good or bad molecule. I don\'t
> think any of those things are intrinsic to the definition of what a
> metabolite is or isn\'t. So, I tried to be reductionist. Again, I
> apologize that it is not clear and needs word-smithing but
> conceptually I have tried to incorporate what I think are the core
> concepts of a definition of metabolite that would apply to the maximum
> number of situations I can think of.
>
> DR. MEHENDALE: Would humans include also microflora in the gut?
>
> DR. BRASS: Well, I avoided that very carefully by saying ingestion by
> humans, and I think a reasonable interpretation of that would be
> ingestion by humans who have bugs in their gut, and acid in their
> stomach, and water in their blood and all the other non-enzymatic
> mammalian processes.
>
> DR. MEHENDALE: So, it is not intended to mean only by human cells,
> human tissues.
>
> DR. BRASS: I was impressed by the discussion both by you and Dr.
> Shannon this morning about other non-enzymatic pathways so I modified
> what I had originally scribbled on the airplane.
>
> DR. DWYER: Could I just ask one other clarifying thing? You called
> this a functional definition. I guess last night I was thinking about
> relationships and I guess it comes under function but, to me, they are
> a little different. One thing you might want to think about in the
> definition is what does it have to do with safety. Anything?
>
> DR. BRASS: Nothing. Other criteria apply. I mean, X may be safe, may
> be unsafe or may be safe at low doses or certain doses and not others.
> Those are all unrelated. They are not intrinsic to the definition of
> what a metabolite is.
>
> DR. DWYER: Essential function?
>
> DR. BRASS: Irrelevant.
>
> DR. DWYER: Bioaccumulation?
>
> DR. BRASS: Irrelevant.
>
> DR. DWYER: Stereoisomers; regulatory function?
>
> DR. BRASS: Irrelevant.
>
> DR. DICKINSON: Except that X may only be one isomer.
>
> DR. SHANNON: But that is not intrinsic to the definition.
>
> DR. BRASS: Yes, X is a molecule. That is why I clarified earlier that
> we acknowledge that stereoisomers are different molecules.
>
> DR. DWYER: Proximity?
>
> DR. BRASS: Irrelevant.
>
> DR. SCHIFF: Proximity\--you do have incorporating structural elements.
> There is certainly an element of proximity there.
>
> DR. DWYER: An element of proximity.
>
> DR. BRASS: Yes, but it is not numeric\--
>
> DR. SCHIFF: No.
>
> DR. BRASS: It is functional proximity.
>
> DR. DWYER: And then directionality, you said yes.
>
> DR. BRASS: Again, that is because X is a metabolite of Y.
>
> DR. SCHIFF: Eric, let me ask you, is not, to coin a term, the beauty
> of your definition that it more or less removes all of the mechanistic
> functionality involved, and it simply says we have this and somehow it
> is getting to this?
>
> DR. BRASS: Well, that was my intent. That was my intent because every
> time I tried to word-smith syntax I was arguing with myself the way I
> argued with Dr. Harris, and any time I tried to get specificity I
> could think of examples and I could think of no reason to pose those
> limitations on my functional definition in the context of what we are
> trying to do.
>
> DR. DWYER: Dr. Schiff, would you repeat what you said?
>
> DR. SCHIFF: I will try. I think I said that perhaps the beauty of the
> definition was that it tended to stress independence of mechanism, or
> as many of the other considerations dealt with a lot of functionality
> and a lot of mechanism.
>
> DR. DWYER: Are we about ready to go to questions?
>
> DR. BLONZ: Yes, let\'s go to questions.
>
> DR. DWYER: Question one, can we go around the table and try to answer
> this one? Maybe your best answer would be ditto if one person says it.
> Is there someone who would like to start?
>
> Is it possible to identify particular scientific criteria, principles,
> or conventions that enable a determination to be made about when a
> substance is or is not a metabolite of another substance?
>
> DR. DICKINSON: Yes, and Dr. Brass has outlined that for us very nicely
> I think.
>
> DR. SHANNON: Ditto.
>
> DR. SCHIFF: Ditto.
>
> MS. HARDY: Identify yourself.
>
> DR. SHANNON: Michael Shannon, ditto.
>
> DR. SCHIFF: Paul Schiff, ditto.
>
> DR. BLONZ: Ed Blonz. We were given a number of definitions from
> various sources, both biochemical and from dictionaries, and they were
> really all over the place. It is my opinion that we need to come up
> with something as it applies to DSHEA, not necessarily one that would
> be an English definition but one that would apply to a dietary
> supplement legislation.
>
> I also think that in the definition we have to have some means of
> stating that this reaction should be independent of any exogenous
> influences. So, the chemical reaction would take place only when there
> was a certain chemical agent in the body. That should be independent
> of the fact that this would happen when there were no outside
> influences. So, when an individual is under the influence, or they
> have liver problems and so forth and certain metabolites might be
> created, would those be metabolites? So, perhaps we could have under
> ideal conditions or in normal situations, some sort of caveat for
> that.
>
> DR. DWYER: Let me understand, you said in many ways you agree but it
> must apply to DSHEA. Then the second point was less clear to me. It
> must be independent of what?
>
> DR. BLONZ: Of any exogenous affecters.
>
> DR. BRASS: Otherwise unadulterated human.
>
> DR. BLONZ: Exactly.
>
> DR. BRASS: I agree with you about the exogenous thing. I am less
> sanguine about liver disease\--
>
> DR. DWYER: Let\'s go around the table. Hold your comments until then.
>
> DR. BLONZ: Well, liver disease might not have been the most ideal
> circumstance.
>
> DR. DWYER: Does everyone understand what is meant by exogenous
> affecters? Give one example.
>
> DR. BLONZ: Alcohol.
>
> DR. DWYER: Thank you. We will go around. Dr. Mehendale?
>
> DR. MEHENDALE: I have similar comments. Susceptible populations is
> another example. Aged populations is an example. Exposure to alcohol,
> smoke is another example. But I don\'t think we need to worry about
> that in this definition because those are safety issues and,
> hopefully, the safety issues will cover those aspects.
>
> So, I am a little ambivalent but I did want to bring my thought
> process into play at the table. My thinking is that those observations
> will be covered under safety regulations. I don\'t know that we need
> to worry about those in this definition.
>
> DR. DWYER: But the safety is determined after the fact rather than
> before. In one case you have a license to put something in and then
> you determine the safety by body counts, or whatever. In the other
> case you don\'t allow the thing in. I mean, isn\'t that the
> difference?
>
> DR. DICKINSON: It is a difference but it isn\'t a carte blanche. There
> are procedures to go through before you put a new ingredient on the
> market.
>
> DR. CHILDS: I am comfortable with the definition, and I agree with the
> fact that there are safety and other factors built into the larger
> Act.
>
> DR. DWYER: Eric?
>
> DR. BRASS: In response to question one, I would say yes, as I think we
> tried to articulate in our discussion.
>
> In response to the comments that have been made, I think intrinsic to
> the definition\--what I proposed is DSHEA specific in that it
> incorporates human ingestion and that is the relationship that is
> unique to DSHEA. This would not be a definition that would apply in
> any other context, other than DSHEA, because a metabolite need not
> occur after human ingestion in other contexts. If I give a drug IV it
> gets metabolized. A plant itself, as we have heard, metabolizes
> itself. Animals and bacteria have unique metabolic pathways. So, the
> DSHEA-ness of my definition, if you will, is the ingestion by humans
> because I agree with you, it is a very important differentiation.
>
> With respect to whether or not the definition has to incorporate
> special classes of endogenous conditions\--age, liver disease, renal
> disease, etc.\--I think that is really hard to try to do and would
> carry over, I think, to other safety concerns. If it requires an
> exogenous enzyme so you have to take Y and an enzyme that mix in your
> stomach, then I think the exogenous affecter clause might come into
> play.
>
> DR. DWYER: I think we are getting some place. My sticking points are,
> first, I don\'t think ingestion by humans is specific enough and, if
> you want it to be a definition that is meaningful under DSHEA it has
> to say specifically amino acids, vitamins, minerals, herbals,
> botanicals, or dietary substances produced by man.
>
> DR. BRASS: Well, that is what Y is.
>
> DR. DWYER: That is fine; let\'s say it in the definition.
>
> DR. DICKINSON: Or let\'s add a second sentence that says for purposes
> of this definition X is\--
>
> DR. BRASS: Y is, yes.
>
> DR. DICKINSON: Right.
>
> DR. DWYER: Then the second thing is again about the safety thing. I am
> not sure that I am satisfied about that.
>
> DR. BRASS: Well, believe me, I would love to put in a clause that says
> it has to be a safe molecule, but I don\'t think anybody would allow
> me to do that because to the degree safety is an issue, it is
> addressed in DSHEA itself, not in the definition of metabolite,
> unfortunately from some people\'s perspective.
>
> DR. SCHIFF: I agree.
>
> DR. DWYER: Okay, I still am not satisfied.
>
> DR. BRASS: Is there a way to deal with it?
>
> DR. CHILDS: Johanna, is that any different than the fact that herb or
> botanical is listed, and we know there are toxic herbs and botanicals
> that are automatically excluded by the prior language in the Act? So,
> how would this be different than that kind of generic reference to
> herbs and botanicals?
>
> DR. DWYER: I don\'t know.
>
> DR. SCHIFF: Johanna, the definition we are looking at, we seem to be
> reasonably close to agreeing on. When it comes to the nomenclature
> that is involved here, Eric\'s definition really refers to not a
> botanical but the individual constituents of the botanical, which
> makes it very different from a vitamin identifiable, a mineral
> identifiable, an amino acid identifiable, but for the an herb or other
> botanical really by direct implication he means the constituents, the
> individual constituents present in the herb or other botanical.
>
> DR. DWYER: Okay.
>
> DR. SCHIFF: I know we can\'t modify the law, but for the record, I
> think that is the intent of the definition.
>
> DR. DWYER: Well, for the record, we are defining metabolite and we
> don\'t intend to expunge the legislative history.
>
> DR. BRASS: But, again, he was trying to address your concern about
> what Y is.
>
> DR. DWYER: Okay, but I would like to see a definition of Y, and the
> definition of Y then also includes constituents of herbals and
> botanicals.
>
> DR. CHILDS: To support Johanna, it is in that herb and botanical area
> where we have had the issues in the past with DSHEA.
>
> DR. SHANNON: Excuse me, I didn\'t understand what you just said about
> constituents.
>
> DR. DWYER: That it isn\'t herbals and botanicals, as Dr. Schiff said,
> it is specific compounds in herbals and botanicals.
>
> DR. SCHIFF: This definition could not apply to a whole plant. It would
> apply to the individual chemical compounds that are present in the
> plant.
>
> DR. SHANNON: I see.
>
> DR. SCHIFF: As it could apply to a single vitamin or a single mineral.
> That is my point.
>
> DR. BRASS: And I appreciate that clarification\--
>
> DR. SHANNON: I am not trying to cloud that.
>
> DR. BRASS: No, it is critical. It is part of my trying to avoid
> defining what an herb or other botanical encompasses.
>
> DR. SHANNON: That is fine.
>
> DR. BRASS: And if herb or other botanical means all the constituents
> of that herb or botanical, then I agree. If there is some other
> interpretation of what those words mean that limit what would be the
> definition of Y, then I would accept those limits. But my
> understanding is what your understanding is.
>
> DR. DWYER: Yes, Dr. Dickinson?
>
> DR. DICKINSON: Herb or other botanical means whole herb or any of its
> parts, including the roots, the flowers, the seeds or whatever. But it
> isn\'t logical that there would be metabolites of the whole fruit.
> Their constituents are also covered in part d), e) or whatever it is
> that refers to the constituents or extracts or so forth. But for
> metabolites we are still talking about metabolites of single
> compounds.
>
> DR. BRASS: Again, I apologize because what it says is a concentrate,
> metabolite, constituent, extract or combination of any ingredient
> named above. Constituent is not above. Constituent is in the same
> clause. What is above is herb or other botanical. So, again, I have
> interpreted that to mean the herb, botanical, all its parts down to
> the molecular level. If there is some other interpretation of that
> that takes precedent, then that would be critical to know because that
> is what metabolite applies to. That is the universal Y.
>
> DR. DICKINSON: Well, an herb or botanical for purposes of normal
> products is some large piece of it or some extract of it, not a single
> compound of it. But we could use the word constituent or component as
> a foregoing word that applies to\--
>
> DR. BRASS: Again, it doesn\'t say metabolite of a constituent because
> constituent is not above. It says metabolite of an herb or other
> botanical. So, again, I was trying to avoid that in the definition of
> metabolite by saying Y is whatever Y is. If Y is an herb or botanical,
> I imply Paul\'s implication but if that violates some other
> interpretation I don\'t want to impose it.
>
> DR. DICKINSON: But we could add a sentence that says, you know,
> logically or biochemically speaking, a metabolite of an herb or
> botanical will be a metabolite of a particular constituent.
>
> DR. BRASS: I think that is very reasonable and common sense.
>
> DR. DWYER: Say that again.
>
> DR. DICKINSON: For purposes of an herb or other botanical, a
> metabolite is understood to be a metabolite of a particular
> constituent.
>
> DR. SCHIFF: Individual constituent.
>
> DR. DICKINSON: Individual constituent.
>
> DR. DWYER: Does everybody agree with that?
>
> DR. BRASS: Yes, as long as it doesn\'t violate any legal or regulatory
> interpretation that has already been made. Again, there may be some
> history that excludes constituents from that discussion that would
> make this re-interpreting the regulation. I just don\'t know.
>
> DR. DICKINSON: Would Dr. Moore be able to comment?
>
> DR. DWYER: Dr. Moore, are you able to comment on that? And would you
> also comment on the safety issue?
>
> DR. MOORE: I will do that one because it is straightforward
> relatively. The safety issue is separate because there are separate
> provisions of the Act to deal with safety. So, from a definitional
> point of view, it wouldn\'t need to be there.
>
> We haven\'t specifically addressed the issue of things that fit into
> dietary substances by man, herb or botanical, which may be an entity
> with lots of other smaller entities within it. Arguably, once
> something is used\--and, again, this isn\'t something in case law or
> policy, but arguably, once something is used, like an herb or
> botanical, it becomes a dietary substance because now it is part of
> the usual food or drink of man. We have interpreted that dietary
> substances include those things in it as dietary substances if those
> substances are the reason, in part or in whole, that someone would use
> that thing.
>
> So, I think while we don\'t have nice language that is cleared by our
> attorneys, the concept that has been articulated, while we haven\'t
> tried it in policy, in a practical sense is consistent with how we
> view it.
>
> DR. DWYER: Good.
>
> DR. BRASS: Paul, let me try another spin on your concern because I
> think it is very important. Another way to think about it is, okay,
> let\'s say you can\'t do it. Let\'s say you give Y as a complex plant
> part and you generate X. X may or may not be a metabolite of that herb
> because in order to meet the second clause, the structural
> relationship, you are, in fact, going to have to practically identify
> the molecular constituent in the herb to show the product-precursor
> relationship. So, whether you know it, when you define Y as an herb or
> not to show that, in fact, there is a molecular element that is a
> precursor for X you are going to have to identify the constituent and
> show the product-precursor relationship.
>
> DR. SCHIFF: I just think inherent in this is the big difference, when
> you say herb Y is a mixture, whereas when you say amino acid Y is a
> single\--
>
> DR. BRASS: Absolutely correct; absolutely correct.
>
> DR. DWYER: Have we settled on that one? We will go on and then at the
> end maybe we can play a little bit with this and try some compounds,
> if we can think of some compounds.
>
> DR. SHANNON: Can I just ask what kind of notes you took in terms of
> resolving the issue of the role of exogenous substances being required
> to produce the metabolite? I am not sure what kind of resolution we
> got on that issue.
>
> DR. DICKINSON: You thought that might be irrelevant.
>
> DR. BRASS: Well, I could think of no example but, again, Dr. Blonz\'
> point was a fair one, that implicit is that this is metabolism that is
> occurring by an otherwise unadulterated body. So, if one put an enzyme
> mix\--I can\'t think of an example.
>
> DR. SHANNON: But you could ingest a substance as well as another
> substance that is a foreign enzyme and now you have created a
> metabolite. The question is would we be satisfied with that product or
> not?
>
> DR. BRASS: No, because that is not a human metabolite and, again, that
> is the DSHEA-ness of the definition, in my opinion.
>
> DR. DWYER: Do you have some language there that would be helpful, Dr.
> Shannon?
>
> DR. SHANNON: Well, I think Dr. Brass kind of said it. We are talking
> about the ability of humans to create that metabolite rather than an
> exogenous substance that is creating that metabolite. I think we have
> accepted that we would include endogenous normal microflora but we
> would not include anything else that might be considered exogenous.
>
> The other issue I am not sure what kind of resolution we had about was
> humans and whether or not this definition would refer to a reference
> human or does it even have to be a healthy human. If so, is it age
> specific, gender specific, pediatric patients in terms of kind of
> breadth to give that term, humans, for the purposes of defining
> metabolite?
>
> DR. DWYER: Does anyone have an opinion around the table?
>
> DR. BRASS: I think it is a really valid question. Every time I tried
> to get around it I came up with 16 pages worth of, you know, verbiage
> that ended up creating more questions than it answered. So, I think it
> is a valid question. I just don\'t know how to address it, other than
> to say human. Again, I could imagine a supplement being differentially
> metabolized in different people, for better or for worse\--
>
> DR. SHANNON: Based on age, gender, disease.
>
> DR. BRASS: Yes, sure.
>
> DR. SHANNON: Perhaps we could say in normal, healthy adults.
>
> DR. BRASS: But that would exclude a unique metabolic pathway that
> existed in somebody who is sick who might generally benefit from the
> supplement.
>
> DR. SHANNON: Or a pediatric patient.
>
> DR. BRASS: Right, etc. As I say, I thought it hard to get more
> specific. From my perspective, if there were a group of people with a
> disease, healthy, male, female, you know, the phytoestrogens are going
> to be metabolized differently on a gender specific basis; children\--I
> think that would be okay with me but I see no way around it being
> okay.
>
> DR. DWYER: Weren\'t we saying that would all come under the safety?
> Dr. Moore, do you have an opinion on this? No?
>
> DR. BRASS: Again, if a metabolite were uniquely generated in women,
> should it be given to adolescent boys? That again becomes a safety
> issue, not a definition of metabolite issue, it seems to me.
>
> DR. DWYER: Is that, in fact, how the agency looks at that? Is that a
> safety issue? Is it an issue inherent in the definition? Or, are we
> asking you something you don\'t want to answer?
>
> DR. WALKER: This is Dr. Walker. Just inherently, I think we are
> interested really in the broader definition of metabolite. The safety
> issues generally are taken care of under a different rubric. So, I
> think if we can confine it really to the definition of metabolite it
> is a very helpful discussion for us.
>
> DR. DWYER: Let\'s go on to question two, which is very long. There is
> a shorter version up there. Consider and discuss the scientific
> strengths and weaknesses of the following concepts with respect to
> their usefulness in identifying whether a substance is or is not a
> metabolite of another dietary ingredient.
>
> So, we are talking about strengths and weaknesses and the first thing
> they ask you to talk about is direct or indirect participation in
> catabolic and/or anabolic sequences. Why don\'t we start here for a
> change and go around this way? Dr. Mehendale, do you have a comment on
> this one, participation in catabolic or anabolic sequences?
>
> DR. MEHENDALE: I have to think about it a little bit.
>
> DR. DWYER: Nancy, do you have any comments?
>
> DR. CHILDS: No comment.
>
> DR. DWYER: Eric?
>
> DR. BRASS: Irrelevant. Again, what specific kind of pathway is or
> isn\'t involved is not relevant to the definition.
>
> DR. DWYER: Annette?
>
> DR. DICKINSON: It seems to me that we have already been through these
> points under question two and have considered them and incorporated
> them into the shorter definition, have either considered them
> irrelevant to this definition or have included consideration of them,
> for example in specifying that structural elements must be
> incorporated.
>
> DR. DWYER: So, what is your answer?
>
> DR. DICKINSON: I that think a), b), c) and d) are all\--
>
> DR. DWYER: Irrelevant?
>
> DR. DICKINSON: Well, not necessarily irrelevant, but if they are
> relevant they are covered by our short definition.
>
> DR. DWYER: How about you, Dr. Shannon?
>
> DR. SHANNON: I agree, not irrelevant but I think they are encompassed
> by the short definition. I will say that in terms of a), I was a
> little confused by both the term participation and pathway. When I
> first read it I was assuming it to say that if the substance appears
> anywhere or occurs anywhere along the metabolic pathway, but it seems
> that is not really what it is saying. At any rate, I do think that the
> issues here are encompassed by this definition we are heading towards.
>
> DR. DWYER: So, you would put proximity, which is b), also in the same
> category?
>
> DR. SHANNON: Yes.
>
> DR. DWYER: Encompassed by the definition?
>
> DR. SHANNON: Yes.
>
> DR. DWYER: How about you, Dr. Schiff?
>
> DR. SCHIFF: I completely agree with Annette. I think what we have up
> there and what we have talked about literally covers most of these
> variables, although I have a hunch that probably we are dealing with
> \"metabolites\" as more than being catabolic but we don\'t need to go
> into that.
>
> DR. DWYER: Could you expand upon that because I found it difficult in
> just thinking about how I have always used the word in my own work.
>
> DR. SCHIFF: Break down, not build up.
>
> DR. DWYER: Correct, I have always thought of it as being catabolic
> rather than anabolic. I guess for the output of an anabolic process I
> have always used a different word than metabolite. I have used words
> like product for example. Maybe I am the only one but I am a little
> uncomfortable.
>
> DR. SCHIFF: I don\'t think it is relevant to the definition as we are
> looking at the definition.
>
> DR. BRASS: The definition of metabolite encompasses what you have
> described as products.
>
> DR. DWYER: Dr. Blonz?
>
> DR. BLONZ: The strengths and weaknesses of these four, I have both a)
> and b) as yes. They definitely play a role in the definition or
> metabolite and they are very well covered by our definition. For c), I
> do not consider a precursor to be a metabolite. So the preceding
> portion of c) is not there. Then, d), similarities to other
> ingredients, I don\'t think that analogous substances are metabolites
> as well.
>
> I had hoped that somewhere we might talk about biofunctionality but to
> get into that might be delving into more specifics than the simple
> definition that we are hoping to come out with. I also had some desire
> that we talk about metabolism vis-a-vis critical control points. If
> you would have a metabolite that would be past a critical control
> point and would be treated differently, it would under this definition
> be a metabolite but it would be treated differently in the body.
>
> DR. DICKINSON: I didn\'t understand that.
>
> DR. DWYER: I don\'t think I understand it.
>
> DR. BLONZ: There are a number of mechanisms whereby\--
>
> DR. DWYER: Well, wait, is it relevant to question two? We can discuss
> more at the end but really I would like to get question two nailed
> down because that is what we are supposed to be doing.
>
> DR. BLONZ: Well, let\'s postpone it until afterwards.
>
> DR. DWYER: Fine, bring it up at the end.
>
> DR. BLONZ: Yes.
>
> DR. DWYER: And your answer for d) was what?
>
> DR. BLONZ: I would place that as a weakness because I do not feel that
> analogous substances can be considered metabolites.
>
> DR. DWYER: And c)? Where did you put c)?
>
> DR. BLONZ: Precursors, a weakness because precursors are not
> metabolites unless, of course, there were some sort of loop as in a
> Cori cycle type arrangement where a precursor could become a
> metabolite and then it cycles around. So, if there was a cycle a
> precursor could be a metabolite but that would be that circumstance.
> Biochemistry is very complicated.
>
> DR. DWYER: I am still not sure we have answered this question. Am I
> right that the group feels that direct or indirect participation in
> catabolic and/or anabolic sequences or pathways is not useful in
> identifying whether a substance is or is not a metabolite? Is that
> correct?
>
> DR. DICKINSON: No.
>
> DR. BRASS: No. I do not find it useful, but I want to emphasize that
> the indirect clause is outright misleading and dangerous, and that
> goes to the allosteric regulation part or the hormone part, that a
> molecule can indirectly influence a pathway but have no structural
> particular precursor relationship. So, I think the indirect is
> absolutely inappropriate and the direct is unnecessary.
>
> DR. DICKINSON: But the direct is incorporated.
>
> DR. DWYER: Okay, that clarifies it a little bit. Anything else we want
> to suggest to the agency about direct or indirect participation? Back
> to the proximity, what are the strengths of proximity in terms of
> number of steps away?
>
> DR. DICKINSON: The number of steps I think we have said here are not
> relevant, but participation in the pathway is relevant because this
> definition requires that it result in an increase in the end product
> or in the X.
>
> DR. BRASS: Of the metabolite. It has to be a product-precursor
> relationship.
>
> DR. DWYER: So, the strength is that it is product-precursor
> relationship?
>
> DR. BRASS: Just to go back to some of the things Dr. Harris talked
> about, apparently when A goes to B goes to C goes to D, all those are
> metabolites of A, no matter how downstream they are, as long as they
> continue to be directly affected by the amount of A present.
>
> DR. DWYER: But is that true within this context now? We are talking
> about trying to provide some guidance to this agency that has to
> administer a law on dietary supplements. It is not to define
> metabolite for students in pharmacology.
>
> DR. BRASS: No, it is absolutely critical. Take a compound like a
> phytoestrogen, it may be sequentially metabolized to five different
> molecules. All of them are metabolites of the original phytoestrogen.
>
> DR. DWYER: And what is the weakness of proximity?
>
> DR. BRASS: Its vagueness. You can\'t define a number of reactions that
> are both necessary and sufficient.
>
> DR. MEHENDALE: I am trying to understand why the proximity was put
> here. So, in trying to understand the intent I wonder if proximity was
> thought of because certain metabolites can interfere with other
> pathways, and the proximity becomes an issue where in that pathway the
> interference might occur. To give an example, with porphyria you can
> have interference very early or sometimes later in the synthesis of
> heme, and the product preceding the step that is interfered is
> excessively accumulated, excessively excreted. In that sequence then,
> the later the interference, the lower the adverse effects. I don\'t
> know if I am making that clear. Therefore, if there are ten steps, if
> you are interfering with the first step the impact is enormous. If you
> are interfering with step number nine the impact may not be as
> enormous. And, I don\'t know if that proximity is because of such
> considerations.
>
> DR. BRASS: I think that is fair. My guess is that what the proximity
> was trying to differentiate is, again, net influence versus carbon
> tracing or atom tracing. Again the example I spoke of earlier, if you
> put a radiolabel in palmitate you will get a radiolabel in glucose but
> there is no net synthesis of glucose from palmitate. It represents
> just mixing in metabolic pools. So, in my mind, proximity means close
> enough to have a net influence on the \"metabolite\" not simply
> contributing an atom to it some place down the line. As Dr. Harris
> nicely illustrated, there are certain parts of metabolism where
> pathways pool. Acetyl CoA is a good example. So, anything that
> generates acetyl CoA will put carbons into a billion things even
> though it doesn\'t contribute to their net synthesis.
>
> DR. DWYER: Is the agency able to tell us why they asked the question?
> Just as a person who doesn\'t work with some of these pathways every
> day, I would think that it just would make sense to the common person
> that something closer to a thing, absent all of the knowledge around
> this table, would be more likely to be the thing, or close to the
> thing. If it walks like a duck and talks like a duck, it is a duck.
>
> DR. WALKER: I think you have done a good job of discussing issues
> related to proximity, and I think that those discussions are helpful
> for us. I don\'t think we need specific number of steps or that type
> of a discussion. On proximity, I think what might be helpful in the
> discussion of proximity relates a little bit to the structural
> elements. If you could discuss structural elements in the context of
> proximity, whether or not you think that the proximity is relevant to
> structural elements, that would be very helpful for us.
>
> DR. BLONZ: So, we are really talking about anabolic versus catabolic
> processes. If you are dealing with structural elements where you can
> get a contribution to acetyl CoA which would then be a structural
> element that would lead to steroid hormones, cholesterol and so forth,
> you do have a substance that ends up being\--can\'t physically be in
> there but it is a building block. So, do we want to say number of
> steps or are we talking about some sort of functionality issue as
> well? Can we separate catabolic from anabolic processes in this?
>
> DR. DWYER: Well, the people who administer the law or the people who
> write the law aren\'t necessarily chemists so the simpler one keeps
> it, the better.
>
> DR. BRASS: I agree with all the comments. This link between both net
> production and structural contribution\--I mean, originally I had the
> word significant in front of structural contribution but didn\'t want
> to answer what significant meant. It is easier to visualize for
> catabolic because most of the molecule can be traced through. For
> anabolic I think this net influence component is really key. There are
> a whole lot of things you can give that contribute carbons to acetyl
> CoA that don\'t affect the rate of cholesterol synthesis; that don\'t
> affect the rate of anything synthesis. They just mix into that pool
> because the regulation is different.
>
> I think your point earlier about are you proximally distal to
> regulatory steps that you put in also is intended to implicitly
> incorporate by this net concept. If you are proximal and you don\'t
> change the regulatory step you are not going to get any change in that
> flux.
>
> DR. DWYER: On this business of catabolic versus anabolic, is everybody
> satisfied? I am still uneasy about that.
>
> DR. SHANNON: I am too.
>
> DR. DWYER: You are satisfied?
>
> DR. SHANNON: I am uneasy.
>
> DR. BRASS: But think about amino acids contributing to the synthesis
> of glutathione. Think of N-acetyl cysteine. Is glutathione or the
> acetaminophen conjugate, are those metabolites of N-acetyl cysteine?
>
> DR. SHANNON: No, I wouldn\'t think of them as metabolites of N-acetyl
> cysteine. The analogy that comes to my mind is if you make
> catecholamine from an amino acid, is the catecholamine a metabolite?
>
> DR. BRASS: Yes, I think it is.
>
> DR. DWYER: Well, we don\'t.
>
> DR. BRASS: Because I think you are thinking narrowly catabolically.
>
> DR. DWYER: The problem is different scientific disciplines are looking
> at this differently, basically pharmacologists.
>
> DR. BRASS: Well, that would make it easy because thinking as a
> pharmacologist it is only catabolic.
>
> DR. DWYER: Ah!
>
> DR. BRASS: But I don\'t think that is right in the context of what
> dietary supplements, vitamins and minerals do. They are both building
> blocks and broken down too. I think any interpretation in the context
> of what has been posed has to recognize that putting two molecules
> together may generate a metabolite as well as breaking one molecule
> into two different ones.
>
> DR. DWYER: Okay, but the problem is that we are here as scientists so
> I am concerned that the shoemaker should be true to his last and, you
> know, that is how we use the term in our\--
>
> DR. BRASS: But this goes back to the DSHEA-ness of the definition. If
> you want be to put DSHEA aside and simply give a definition
> metabolite, I would give you something completely different. I
> wouldn\'t have written what I wrote on the board.
>
> DR. DWYER: I see your point. I am still uneasy about anabolic. Could
> we get another opinion from any one of the three of you in terms of
> how we can provide assistance to your quandaries? I am looking at the
> table in the back.
>
> DR. SCHIFF: Johanna, can I ask a question? If we accept the precepts
> of that definition with its provisos, is it mandatory that we open the
> catabolic/anabolic box? I don\'t mean to push it away or not do my
> duty, but I don\'t know that we need to do that. Am I the only one who
> thinks that from the definition, not from the duty standpoint?
>
> DR. MEHENDALE: I also agree. I don\'t know that we really need to
> concern ourselves with whether it is anabolic or catabolic. In the
> example that Eric was discussing with Dr. Shannon, you know, it was
> also referred to as a synthetic reaction and even by that definition
> it is a metabolite because structural elements are in the product. So,
> I am not sure we need to concern ourselves with anabolic or catabolic
> so I am falling in that column as well.
>
> DR. BRASS: Again, I don\'t want to pretend this definition solves all
> problems because you could take what I have put literally here and say
> superficially that every protein is a metabolite of lysing and,
> therefore, I can give any protein as a dietary supplement and that may
> or may not be a logical thing to say.
>
> DR. DWYER: You know, as a nutritionist, I am very uncomfortable with
> that.
>
> DR. BRASS: Again, that is why I originally had \"significant\" so that
> if you contribute one amino acid out of twenty no reasonable person
> could say that you are contributing to the net synthesis of.
>
> DR. DICKINSON: But, Johanna, I don\'t understand what you are
> uncomfortable with because as a nutritionist what you deal with all
> the time is nutrients going to build body parts basically.
>
> DR. SHANNON: Which she doesn\'t call metabolites.
>
> DR. DWYER: I don\'t call them metabolites; I call them products.
>
> DR. DICKINSON: Well, can you learn to call them metabolites?
>
> \[Laughter\]
>
> What is it that you are afraid of? What is it that you see coming that
> we don\'t see?
>
> DR. DWYER: As I said, you know, it makes the definition useless.
>
> DR. BRASS: I think you mis-extrapolated what I said. What I said is
> there are obvious limitations to any scrolled up definition and as
> part of the legislative record, I was saying, clearly that just
> because an amino acid is a precursor of a protein, that should not be
> construed as a metabolite by this definition because there is no way
> to construe that a single amino acid would change the rate of
> synthesis of a given protein, i.e., the net production clause or, two,
> that any single amino acid contributes significantly to the structure
> of any given protein. So, what I am saying is that it required common
> sense interpretation. I think it contains enough specificity that with
> the legislative record and the thousands of word-smiths that exist in
> the FDA they can turn it into an interpretable clause. I was, in fact,
> arguing not to get hung up on these points as long as the concepts are
> clear to the agency who will turn it, if they want, into a regulatory
> context that will resemble nothing I wrote.
>
> DR. DWYER: Well, that is their right I guess. What about possessing
> qualities or similarities to other dietary ingredients relative to
> speed/time, compartmentalization and fate?
>
> Oh, we skipped semblance. Are there any other things that would be
> helpful? I think we have gone about as far as we can get on the
> structural business. Is that correct? What about semblance to another
> dietary ingredient? Do we have any guidance there in terms of
> strengths, weaknesses or other comments for function, structure or
> combination? Dr. Mehendale?
>
> DR. MEHENDALE: Just to open it up, I might share a couple of thoughts.
> Semblance is similar but it can mean it actually participates in the
> pathway of another ingredient in this case. Or, sometimes it could
> also interfere with that pathway, antimetabolite. Metabolites and
> antimetabolites closely resemble each other. So, don\'t know if that
> was the intent there, semblance meaning either overload a pathway or
> interfere with a pathway.
>
> DR. DWYER: So, you are saying the strength is that structure sometimes
> is associated with function?
>
> DR. MEHENDALE: Yes.
>
> DR. DWYER: And structure sometimes isn\'t associated with function?
>
> DR. MEHENDALE: Yes, in that context those points could be relevant.
>
> DR. DWYER: Anybody else?
>
> DR. BRASS: No, other than, again, similarity is a trap. I think it is
> impossible to define and it can be misleading, as was just said.
>
> DR. DWYER: Nancy?
>
> DR. CHILDS: I have nothing to add.
>
> DR. DWYER: Annette?
>
> DR. DICKINSON: I just have a question. We talked a lot about enzymes.
> I am assuming enzymes might also be metabolites in that they are
> synthesized in the body from protein and other components and
> certainly an enzyme does not share the functional characteristics of
> the amino acids that went into it. So, function may, in fact, change
> in the metabolite as opposed to the precursor but I don\'t see that as
> a problem. I see that as just how the system works.
>
> DR. BRASS: There are a lot of examples with small molecules where the
> native molecule\--the ingested molecule is inactive; it gets
> metabolized; it is active, and the ingested molecule is active and the
> metabolite is inactive and the structural modifications can be very
> subtle, taking away double bond.
>
> DR. DWYER: I don\'t see how with that definition, with the caveats we
> have here, an enzyme could be regarded as a metabolite.
>
> DR. BRASS: That goes to the protein example that I spoke to earlier,
> that it would not be a reasonable extrapolation.
>
> DR. DWYER: Because of the clauses down there.
>
> DR. DICKINSON: It would not be what?
>
> DR. BRASS: A reasonable example because if you ingested an amino acid
> you would have a hard time showing the change in net synthesis of any
> given enzyme.
>
> DR. DWYER: Dr. Shannon?
>
> DR. SHANNON: Nothing to add.
>
> DR. DWYER: Dr. Schiff?
>
> DR. SCHIFF: No, nothing to add.
>
> DR. DWYER: Dr. Blonz?
>
> DR. BLONZ: I had said on c) that I did think it was helpful in helping
> define it because I didn\'t feel that a precursor was the equivalent
> to a metabolite
>
> DR. DWYER: Very good. Thank you very much.
>
> DR. DWYER: Let\'s go to d) and then we will be done with this one; d),
> is possessing qualities or similarities to another dietary ingredient
> relative to speed/time, and they got into reaction rates and so forth;
> compartmentalization; and fate? Shall we start with Dr. Blonz?
>
> DR. BLONZ: With this one, I had said I didn\'t think this is helpful
> because I didn\'t think that analogous substances would be equivalent
> to being a metabolite.
>
> DR. DWYER: Dr. Schiff?
>
> DR. SCHIFF: I think our definition handles this well. I wouldn\'t pick
> anything in particular out of here.
>
> DR. DWYER: Are there any strengths or weaknesses there?
>
> DR. SCHIFF: No.
>
> DR. SHANNON: I would agree with Dr. Blonz that a weakness would be the
> issue of analogs.
>
> DR. DWYER: Dr. Dickinson?
>
> DR. DICKINSON: No comment.
>
> DR. DWYER: Dr. Mehendale?
>
> DR. MEHENDALE: No comment.
>
> DR. DWYER: Dr. Childs?
>
> DR. CHILDS: No comment. I am assuming that we have reconciled the in
> and outside the body issue.
>
> DR. BRASS: Nothing further.
>
> DR. DWYER: No pros, cons, strengths, weaknesses?
>
> DR. BRASS: I think they are all a weakness to the point that they
> don\'t help intrinsically define what a metabolite is, can be
> misleading and to the degree anybody would think a chemically
> synthesized analog would be a metabolite would be very dangerous.
>
> DR. DWYER: And this goes for speed and time, compartmentalization and
> also fate? We are all agreed that those are not particularly helpful?
> Is there further guidance for the whole last issue? Is there further
> guidance that you would like with respect to this?
>
> DR. WALKER: I think you have covered it very well. I think what you
> are doing so far is very helpful to us.
>
> DR. DWYER: Any other comments? Shall we do question three first round,
> then take a break and come back and finish, hopefully?
>
> DR. BRASS: It depends on how long it is going to take. If it is quick,
> we might just as well finish.
>
> DR. DWYER: You never know. Okay, discuss the scientific validity and
> likely usefulness for identifying when a substance is or is not a
> metabolite of another dietary ingredient. If so, what characteristics
> associated with the criterion make it valid or useful? Why don\'t we
> go around and discuss a little more or at least jot down\--we think we
> have a definition but then what characteristics are associated with
> the criterion that make it valid or useful? We need some
> characteristics.
>
> DR. BRASS: It emphasizes the product-precursor relationship. It
> emphasizes that the formation of the metabolite is the result of human
> ingestion. It emphasizes that there has to be a product-precursor
> relationship in the form of net production of the product from the
> precursor, and that it has to incorporate structural elements, i.e.,
> it has to follow along the same processing metablic pathway whether it
> is enzymatic or non-enzymatic.
>
> DR. DWYER: Could you give them again?
>
> DR. BRASS: Could the transcriber read that back?
>
> \[The transcriber read back the record\]
>
> DR. DWYER: Anyone have any other suggestions? Annette?
>
> DR. DICKINSON: No, I think it is both valid from a science point of
> view and I think it is also very likely to be useful in terms of
> putting this human scope around it and limiting it in that fashion.
>
> DR. DWYER: Dr. Shannon?
>
> DR. SHANNON: No comment.
>
> DR. DWYER: Dr. Schiff?
>
> DR. SCHIFF: I like its functionality, its flexibility but, yet, with
> enough scientific rigor to put flesh on it.
>
> DR. BLONZ: My concerns have to do with the biofunctionality issue. I
> would like to see there be some sort of way of relating the
> originating substance, the Y, to the X in terms of biofunctionality.
>
> DR. DWYER: What do you mean by biofunctionality?
>
> DR. BLONZ: Well, when you are not dealing with a substance that all of
> a sudden is doing something different in the body, something that was
> nothing like the original substance\--
>
> DR. DICKINSON: But it is; it will be.
>
> DR. SHANNON: It doesn\'t have to be.
>
> DR. BRASS: Well, it may or may not be. Again, if Y is an inactive
> molecule and it is activated metabolically to an active X, would you
> like to exclude that from a definition of a metabolite? Their
> functionalities are completely different. One is no function; the
> other is very functional.
>
> DR. BLONZ: That is a good point where you could get activation of a
> substance. My concern, of course, is for the darker side of things.
>
> DR. BRASS: Yes.
>
> DR. BLONZ: I wouldn\'t want to see products on the marketplace that
> might start out as benign that would fit our definition of metabolite
> but would end up being precursors to other substances.
>
> DR. BRASS: I agree 10,000-fold but I don\'t think the definition of
> metabolite is a way to exclude those products from the market.
>
> DR. SCHIFF: If we consider a lot of the herbals the biofunctionality
> is, at best, only modestly defined if not ill-defined, and then the
> exact molecules responsible are rarely defined. So, that opens the
> door\--and I agree with these gentlemen that the dark side is a
> concern\--but that opens the door in the definition that I would
> rather not open.
>
> DR. BLONZ: Well, perhaps the important thing is to get it on the
> record then.
>
> DR. DWYER: Dr. Mehendale, do you have a comment?
>
> DR. MEHENDALE: I think the definition has scientific merit. I think it
> is going to be highly useful, likely to be highly useful. The agency
> asked us to provide some boundaries and I think in the definition we
> have pretty good boundaries actually. So, I like it. I think it is a
> good product.
>
> DR. DWYER: Dr. Childs?
>
> DR. CHILDS: Nothing. I think it is a useful and concise definition. I
> still have a little bit of a concern about it applying to all
> populations, particularly when it goes all the way down potentially to
> young children and to disease states, but I am not sure the definition
> is the place to address that. That might be elsewhere in the statute.
>
> DR. DWYER: Dr. Brass?
>
> DR. BRASS: No.
>
> DR. DWYER: If it worked, then we could go back to the marketplace
> examples which are in the back of Dr. Moore\'s presentation this
> morning. One was cholesterol to steroid hormones.
>
> DR. BLONZ: In each of those the first substance would have been a
> precursor, if you will, and the second one would not be the
> metabolite.
>
> DR. DWYER: Let\'s start with some vitamins. Anybody think of a
> precursor? I think of a provitamin beta carotene. Does the definition
> work for this?
>
> DR. SHANNON: I am sorry, what are you looking for?
>
> DR. DWYER: I am trying to see if we can go through these examples that
> he gave us and whether it works.
>
> DR. BRASS: You can eat a lot of cholesterol but you will not change
> your testosterone level.
>
> DR. DWYER: So, the steroid hormone would not be a metabolite of
> cholesterol.
>
> DR. BRASS: That is correct. That would be my interpretation. It
> falters at the second step because you don\'t get net production.
>
> DR. DWYER: No net production.
>
> DR. BRASS: I am sorry, you don\'t increase the amount of steroid
> hormone, that I know of.
>
> DR. DWYER: What about prostaglandins and arachidonic acid?
>
> DR. BRASS: That is a complicated one. I think the answer is probably
> prostaglandins are a metabolite of arachidonic acid. I don\'t know
> that much about the oral fate of arachidonic acid, whether it survives
> in the stomach, but even if it got into the mucosal cells of the
> stomach if you dump arachidonic acid on a mammalian cell it will make
> more prostaglandins.
>
> DR. SHANNON: Yes, it will.
>
> DR. BRASS: Now, whether that is the result of oral ingestion or
> not\--I have never given oral arachidonic acid and followed its fate,
> but in concept it very well might be, yes.
>
> DR. DWYER: Dr. Moore, did you give me your arachidonic to
> prostaglandin sequence? Thanks, Dr. Moore. Does everyone see this?
> Let\'s just look at this. Arachidonic is where?
>
> DR. BRASS: Right in the middle.
>
> DR. DWYER: So, we are right here and we are saying that prostaglandins
> are where? Down here.
>
> DR. BRASS: No, to the right; they are all over the place.
>
> DR. DWYER: And we are saying it is\--
>
> DR. BRASS: It may or may not be.
>
> DR. DWYER: PG2 is a metabolite.
>
> DR. BRASS: Here are the data I know, if you take a mammalian cell or a
> mammalian organ and provide it additional arachidonic acid it
> increases its prostaglandin production. Okay? So, that leads me to
> think the answer is yes. However, after oral ingestion of arachidonic
> acid, I don\'t know if it reaches enough cellular cyclooxygenase to
> change net prostaglandin production after oral ingestion. So, my
> answer is I don\'t know. I wouldn\'t be surprised if the answer was
> yes but I don\'t know that the answer is yes.
>
> DR. DWYER: Does anyone know around the table here?
>
> DR. DICKINSON: Yes.
>
> DR. DWYER: Yes, you do know and it will increase it?
>
> DR. DICKINSON: I know someone on the audience who I believe
> understands this pathway and he says it does. He says oral ingestion
> will increase it.
>
> DR. BLONZ: I think one of the connections is with heavy meat
> consumption too which requires arachidonic acid. It has been shown to
> increase, yes.
>
> DR. DWYER: Anything more on that particular one? What about
> catecholamines?
>
> DR. BRASS: Let me point out again this is an issue where the time
> factor and the proximity might be of interest to some people because
> if the mechanism is that arachidonic acid gets incorporated into
> cellular phospholipids and only later comes out and does it, or
> something like that but, again, I think it is conceivably a yes.
>
> DR. DWYER: What about catecholamines and amino acids?
>
> DR. BRASS: I assume you mean a specific amino acid.
>
> \[Laughter\]
>
> DR. DWYER: Yes, I will give you a specific amino acid, glycine.
>
> DR. BRASS: No.
>
> DR. DWYER: What about methionine?
>
> DR. BRASS: How about the precursor amino acid for catecholamines?
> Tyrosine?
>
> DR. DWYER: What about that?
>
> DR. BRASS: Yes.
>
> DR. DWYER: So, the answer is like the rabbi said, yes and no?
>
> DR. BRASS: Well, it depends. See, for tyrosine, I don\'t know the
> answer after oral tyrosine ingestion. I only know it for [in
> vitro]{.underline} and organ perfusion. I don\'t know if oral tyrosine
> changes catecholamine levels or not.
>
> DR. SHANNON: I don\'t think it does.
>
> DR. BRASS: I don\'t know. If it fails, it fails because of the oral
> ingestion clause.
>
> DR. DICKINSON: And because there are other regulatory steps.
>
> DR. BRASS: Yes, there are other regulatory steps but in some cases you
> can overwhelm those by giving enough, but I don\'t know; I don\'t
> know.
>
> DR. BLONZ: Let me add in here. I don\'t know what would happen with
> tyrosine as a supplement, but this is part of the rationale for having
> high protein breakfasts and having hefty levels of neurotransmitters
> during the day, it is primarily because of the tyrosine composition. I
> don\'t know what the effect would be if you were to take tyrosine on
> an empty stomach and whether that would affect neurotransmitters.
>
> DR. BRASS: As I said, I don\'t know either.
>
> DR. BLONZ: It would make a difference as to what we would decide as to
> how it fits our definition.
>
> DR. BRASS: I think the point is the definition would work because if
> it didn\'t, it wouldn\'t be and if it did, it would be.
>
> DR. DWYER: Any other comments on amino acids? Yes, Dr. Mehendale?
>
> DR. MEHENDALE: I think there are also examples with tryptophan.
> Everyone knows about the cheese and wine combination, and so on. So, I
> guess the answer would be yes.
>
> DR. BRASS: But also for serotonin.
>
> DR. DWYER: How about substrates, inosine-5 monophosphate?
>
> DR. BRASS: I just don\'t know what the regulation of that pathway is
> and whether ingesting would change it or not. I know the pathway, I
> don\'t know the regulation.
>
> DR. DWYER: Let\'s get some vitamin examples. I have been trying to
> think of some and I can\'t. Well, vitamin D, what do you think,
> hydroxy\--
>
> DR. BRASS: 125 is a metabolite.
>
> DR. DICKINSON: But it is also a prescription drug and so out of
> balance for this purpose.
>
> DR. BRASS: Yes, so are catecholamines.
>
> DR. DWYER: The metabolite would be what? Vitamin A, retinal?
>
> DR. DICKINSON: We don\'t make retinal but you could go from retinal to
> some of the vision compounds, rhodopsin.
>
> DR. DWYER: So, rhodopsin would be a metabolite? How about a mineral
> example just so that we work through all of them?
>
> DR. DICKINSON: We have all of a sudden become ignorant!
>
> DR. SHANNON: Calcium gluconate. I guess that is organic, isn\'t it?
>
> DR. DICKINSON: I mean, I can think of examples where deficiencies of
> minerals inhibit things, but I don\'t know to what degree extra
> minerals increase, say, some of the antioxidant enzymes.
>
> DR. BRASS: I don\'t know if, you know, superoxide dismutase is
> sensitive to copper exposure or magnesium exposure. I don\'t know. I
> can\'t think of any immediately. Iron and ferritin, ferritin as a
> metabolite of iron. There is not a lot of structural contribution
> there so it would be hard-pressed to do it. That is, again, where the
> oral ingestion in humans came in so that, for example plutonium is not
> a metabolite of uranium because you just can\'t do it.
>
> DR. DICKINSON: But if you give extra folic acid and B12 you change red
> cell synthesis. I don\'t know what all the intermediates are there but
> there are some metabolites that get created.
>
> DR. BRASS: It is not a product-precursor relationship.
>
> DR. DWYER: Any mineral example? How about herbal, botanical examples
> or constituents of those?
>
> DR. SCHIFF: Let\'s see, saw palmetto is loaded with long-chain fatty
> acids, straight-chain fatty acids and those get chopped down and
> metabolized. That would be an example, I suspect.
>
> DR. DWYER: I think we are pretty much toward the end of the end-game.
> Shall we just go around the table once more and try to conclude? I
> know, Dr. Blonz, you had a question.
>
> DR. BLONZ: Well, I think we have covered it. That had to do with the
> biofunctionality and also with the idea that a metabolite would end up
> past a critical control point and might have an undue influence on
> metabolism whereby the originating product would not. This is
> something that, hopefully, we would deal on the safety side of things,
> but it is still a possibility from a biochemical standpoint.
>
> DR. BRASS: An example of that, again, if you give methenolone you can
> increase cholesterol synthesis, unlike if you give the acetyl CoA
> precursor.
>
> DR. BLONZ: Right.
>
> DR. DWYER: Anyone have any comments on this for Dr. Blonz, a
> clarification? If not, I would just like to go around the table one
> last time to make sure we have any other additions or insights on all
> of this clarified for the record. I would also like to ask the agency
> to email us the final disposition of this, rather than just posting it
> on the web, if it is okay.
>
> DR. BRASS: You will see in the Congressional Record of the proposed
> rule.
>
> DR. DWYER: I doubt that, but if it is possible we would like to see
> it. Are there any other issues you wish to have us answer, Dr. Moore?
>
> DR. MOORE: No.
>
> DR. DWYER: Fine. Do you have other\--
>
> DR. BRASS: No, I don\'t. I think the discussion has been good. My
> final thought would be just to emphasize the concepts that have been
> discussed, not the specifics, because I think the concepts here are
> what is important, not any errors in word-smithing or
> mis-articulation.
>
> DR. CHILDS: I simply want to mention, as we had the agency reinforce
> for us earlier, that safety is outside of the context of this
> definition.
>
> DR. DICKINSON: But safety needs to be addressed.
>
> DR. DWYER: It may be outside the context of the definition but is
> truly very critical.
>
> DR. CHILDS: Yes, I agree completely. I was just simply trying to say
> we have addressed that. We have focused on it, and what has been
> brought to our attention is that that is elsewhere in the
> definition\--not in the definition, elsewhere in the language.
>
> DR. DWYER: Dr. Mehendale?
>
> DR. MEHENDALE: Yes, I also want to emphasize that the definition, as
> we have evolved it, is really in addition to other regulatory areas.
>
> DR. DWYER: Dr. Blonz?
>
> DR. BLONZ: I think that the definition is very silent but, again, we
> are talking about DSHEA and it opens the door and it really puts the
> onus on the agency in a post-regulatory environment to be able to
> police and check for those substances that may fit the definition of a
> metabolite but really might have a dubious place in the marketplace.
>
> DR. DWYER: Do you have suggestions for how best to protect the public?
>
> DR. BLONZ: Well, to my way of thinking the best way is improved
> surveillance. I think they are doing as good a job as their budget
> will allow them but, given the surveillance with MedWatch, and so
> forth, you really do need to keep in consult with biochemists,
> toxicologists and so forth, and find out what is going on and what
> people are taking. It is really do the best you can. That is all I can
> urge.
>
> DR. DWYER: Dr. Schiff?
>
> DR. SCHIFF: I am pleased with the definition. It is more than I
> thought we could do, to be honest with you. It is functional; it is
> broad-based; it is moderately cohesive. I think it gives the agency a
> good base from which to build.
>
> DR. DWYER: Dr. Shannon?
>
> DR. SHANNON: As others have said, I hope that today was useful to the
> agency in terms of finding ways to make these products safer.
>
> DR. DICKINSON: I share Dr. Schiff\'s feeling. I came into this meeting
> thinking we might stir around for quite a while and not come up with
> much, but I think we have come up with something that is useful and I
> think it has been a very productive discussion.
>
> DR. DWYER: Thank you for a very useful meeting. I too am concerned
> about the issue of surveillance being necessary and the safety issue.
> I think the resources that are being devoted to the Middle East rather
> then the East Coast, and I work on the East Coast and live on the East
> Coast\--I am a little concerned about the resources available to the
> agency to do the safety mandate. Nevertheless, we have made a lot more
> progress than I was afraid we were going to make with a green
> chairman.
>
> Can I urge you to fill out the questionnaires that the folks at the
> University of Maryland gave us? If you could do it today and drop it
> in the box, that would be great. If not, drop it in the box when you
> get back to your airport.
>
> We will look forward to getting together probably shortly for yet
> another session on these esoteric issues that are of such importance
> to the country. Dr. Walker, will you end the session?
>
> DR. WALKER: Yes, I would like to thank you very much on behalf of our
> office and the agency. I would like to thank Dr. Dwyer for leading a
> very interesting session. I think what has been said today will be
> very, very useful for us, and I would like to thank you all for the
> time and the interest that you have shown by coming here and joining
> us in this discussion. So, thank you all very much.
>
> \[Whereupon, at 2:25 p.m., the proceedings were adjourned.\]

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