From: altar@beaufort.sfu.ca (Ted Wayn Altar)
Subject: Well, I have a question for Ted. . .
Organization: Simon Fraser University, Burnaby, B.C., Canada
Date: Mon, 23 Nov 1992 02:37:03 GMT

I've tried three times to post a response to this thead,
over the last couple of days but for some reason
it simply doesn't seem to get posted, so I am instead
starting it as a new tread.  Sorry everyone for
any replications that might have occurred.
                                  ted


Melody Fend writes:

> . . . vitamin D was not necessarily the same type of
>steroid as (or even at all similar to) anabolic steroid hormone.


With respect to "vitamin D" being an anabolic steroid hormone, I
did provide a reference to Anthony Norman, Professor at the
Department of Biochemistry, U. of Calif., who is probably the
leading world authority on the biochemistry of vitamin D.  He has
written a number of books on the topic and has been the editor of
an important series of volumes specializing in vitamin D
research.

If that 1979 reference to A. Norman seems too "old", then
consider the 1992 book, NUTRITION BIOCHEMISTRY OF THE VITAMIN
(Cambridge U. Press) by D.A. Bender:

     Vitamin D is not strictly a vitamin, rather it is the
     precursor of one of the hormones involved in the maintenance
     of calcium homeostasis, and dietary sources are relatively
     unimportant compared with endogenous synthesis.
     . . .
     Vitamin D is a secosteroid -- i.e., a steroid in which the
     B-ring has undergone cleavage, followed by rotation of the
     A-ring

Professor D.A. Lawson back in 1978 also said,

     The term "vitamin D" refers to a group of seco-steroids with
     antirachtic properties, possessing in common a conjugated
     triene system of double bonds of which cholecaliciferol
     (vitamin D3) and egocalciferol (vitamin D2) are the best
     known examples" (from VITAMIN D, 1978)

Another stated in another recent advanced text on vitamins, THE
VITAMINS: FUNDAMENTAL ASPECTS IN NUTRITION AND HEALTH, 1992, by
Gerald Combs:

     At least some, if not all, of the mechanisms of action of
     1,25-(OH)2-vitaman D appears to fit the classical model of a
     STEROID HORMONE.  That is, it has specific cells in target
     organs with specific receptor proteins; the receptor-ligand
     complex moves to the nucleus where it binds to the chromatin
     and stimulates the transcription of particular genes to
     produce specific mRNAs which code for the synthesis of
     specific proteins.  Autoradiographic studies have
     demonstrated that 1,25-(OH)2-vitamin D is localized in
     intestinal mucosal epithelial cells (which contain the 1,25-
     (OH)2-vitamin D-receptor) exclusively in the nucleus.  the
     receptor has ben characterized and the cDNA for it has been
     cloned; it has been found to have substantial sequence
     homology with receptors for other steroids, thyroid hormone
     and retinoic acid.

Now, you may be getting confused about the various kinds of
vitamin D metabolites.  First, let us note that vitamin D refers
to a group of steroid hormones with the family name of calciferol
(due to their calcium-controlling functions).  There are many
different forms of calciferol, some of which are valuable
therapeutic agents.  It must also recognized, according to
Professor Moon, that poisoning by calciferol is characterized by
increased aging of the cardiovascular, renal, and skeletal
systems.  The question of concern that Dr. Moon raises is whether
or not such low level, long-term poisoning might not be occuring.

Both vitamin D2 (ergocalciferol) and vitamin D3 (cholecalciferol)
are the forms that are added to foods (or given to livestock
which in turn produces D-reinforced meat).  Once absorbed they in
turn are converted into a variety of hydroxylated products, some
of which are the metabolically active forms of the vitamin (hence
the lag time between administration of D and the first signs of a
biological response).  D2 or D3 is taken up by the liver and
converted (hydroxylated) to 25-OH (calcidol) and then transported
to the kidney where it is further hydroxylated to yield the
biologically active form, 1,25(OH)2 which most clearly look and
acts like steroid hormone produced by its endocrine gland, the
kidney, to act distally in a variety of target organs,
particularly the intestine and bone.

In animals vitamin D3 is formed by the action of ultraviolet
light on a pro-vitamin D sterol (7-dehydrocholesterol) in the
skin.  This is a product of (and can also be a precursor to)
cholesterol.

Permit me now to cite at some length from one of those volumes
where Professor Anthony Norman very straightforwardly explains at
length why vitamin D is a anabolic steroid (see Norman,  "1,20-
(OH)2-D3 as a Steroid Hormone" in VITAMIN D MOLECULAR BIOLOGY &
CLINICAL NUTRITION, 1980.).  The article is quite readable and I
would highly recommend that you take a quick look at it.  I'll
just cite a few paragraphs to give you a sense of its flavour and
to again document the fact that calciferol is an anabolic
steroid.  For brevity, I shall omit the many references that
Norman himself provides to back up his theoretical and empirical
points:

     "A formal definition of a "vitamin" is that it is a trace
     dietary constituent required to effect normal functioning of
     physiological processes.  Emphasis here is on TRACE and the
     fact that the vitamin must be supplied dietarily; this
     implies that the body has no formal biochemical mechanism to
     biosynthesize the vitamin in question.  Vitamins may be
     divided on the basis of their chemistry into either water-
     soluble or fat-soluble substances.  Many water-soluble
     vitamins are cofactors for enzymes and participate in a
     critical fashion to effect the catalytic event
     characteristic of a particular enzyme.  As yet there is no
     general statement of mode of action for the second class of
     vitamins, the fat-soluble substances, e.g., vitamins A, E,
     K, and D.  Chemically, vitamin is related to steroids, and
     in fact its formal chemical name is provided by the rules of
     nomenclature for steroids. (p. 201)
     
     It is largely due to an historical accident that calciferol
     has been classified as a vitamin rather than as a hormone.
     Physicians and scientists have known since at least the
     1600s of the correlation between the incidence of rickets
     and lack of sunshine.  These intuitive observations
     ultimately led to the brilliant studies of Mellanby who
     devised the first experimental diet capable of producing
     rickets in puppies.  However, an important, and at that
     time, unappreciated aspect of his experimental protocol was
     the fact that his puppies had no access to sunlight or
     ultraviolet light. . .  (p. 201)
     
     Once the connection between antirachitic activity,
     ultraviolet light, and delta5-7 unsaturated sterols such as
     7-dehydrocholesterol was appreciated, then it was possible
     for Askew et al. and Windaus et al. to carry out a formal
     chemical characterization of vitamin D.  The laboratory of
     Windaus, particularly, was engaged in many chemical
     isolation and characterization projects involving sterols.
     Professor Windaus certainly appreciated the strong
     structural similarity between vitamin D and other steroids.
     However, in the biological, clinical, and nutritional
     worlds, this correlation and similarity have never generally
     been appreciated, and most workers classified calciferol as
     a vitamin.  In a formalistic sense calciferol is only
     strictly a vitamin when the animal does not have access to
     sunlight or ultraviolet light.  All higher animals have a
     precursor of vitamin D present in their external epidermis;
     this is the steroid 7-dehydrocholesterol.  Upon appropriate
     irradiation with ultraviolet, the 9, 10-carbon-carbon bond
     is ruptured and the secosteroid cholecalciferol (vitamin D3)
     is generated.  Thus, biologists in general have tended to
     think of cholecalciferol as a vitamin, while chemists have
     approached their understanding of its structure knowing it
     is a member of the steroid family. (p. 201-2)
     
     While a recently as 1960 to 1965 little was known concerning
     either the absorption, tissue localization, or proposed mode
     of action of vitamin D, in the intervening period to time a
     new model of the mechanism of action of this nutritionally
     important secosteroid has emerged.  The model is based on
     the concept that in the terms of both structure and mode of
     action, vitamin D is similar to classic steroid hormones
     such as estradiol, testosterone, hydrocortisone,
     aldosterone, or ecdysone. (202)
     

     . . . vitamin D is officially a secosteroid.  Sterosteroids
     are those in which on the rings has undergone fission by
     breakage of a carbon-carbon bond.  In the instance of
     vitamin D this occurs in ring B, and this fact is indicted
     by the inclusion of 9,10-seco in its formal nomenclature."
     (p. 202)
     

Norman than argues that functionally calciferol acts like a
steroid hormone.  He first would classically define a HORMONE as:
     
     regulatory substances produced in small amounts in one organ
     or tissue which act distally in another tissue. (198)
     
He talks about 3 classes of hormones (p. 199):

     1.  peptide hormones (insulin, parathyroid hormone,
     glucagon)
     2.  steroid hormones (estradiol, testosterone, aldosterone)
     3. amino acid-derived hormones (thyroxine, epinephrine)
     
Then Norman proceeds to characterized steroids, one
characterization being that they are lipid-soluable hormones
derived from the 27-carbon nucleus of cholesterol.

Norman then notes that steroid hormones :

     "are believed to initiate biological responses in their
     characteristic target tissues and cells by virtue of their
     association with a receptor system that results in their
     transfer and localization into the nucleus or DNA-containing
     portion of the cell.  Then somehow, as a consequence of the
     presence of the steroid hormone-receptor complex in the
     nucleus of the cell, there ensures a cascade process
     resulting in the synthesis of specific messenger RNA
     molecules and protein molecules responsible for initiation
     of the biological response" (p. 200)
     
Norman then presents evidence as to how vitamin D is best
understood and classified as a "steroid hormone produced by the
endocrine organ, the kidney, and which a variety of other target
organs elicits the characteristic responses formally attributed
to vitamin D" (p. 205).

Norman then proceeds how vitamin D does indeed meet this
characterization and others of a steroid hormone.  Some 40 pages
later, Norman concludes:

     This chapter has attempted to summarize the current evidence
     that supports the steroid hormone concept for the mode of
     action of 1,25-(OH)2-D3 as a biologically active form of
     vitamin D.  The key element of data which supports this
     concept is the nuclear localization of 1,25-(OH)2-D3 in the
     target tissues, particularly the intestinal columnar
     epithelial cells vis-a-vis stimulation of intestinal calcium
     absorption.
     . . .
     While some attention has been directed toward models of
     posttranscriptional control for steroid hormone-induced
     protein synthesis, it now seems abundantly clear on the
     basis of data obtained from all steroid hormones that they
     exert their primary effects at the level of gene
     transcription.  Administration of aldosteroine,
     glucocorticoid, estrogen, progesterone, dihydrocortison,
     1,25-(OH)2-D3, or thyroid hormones, under conditions that
     permit localization of the hormones in vivo in their target
     tissues, results in measurable increases in RNA synthesis.