# Presentation: 137394

## Presented

**by Barry Shane, Ph.D.**
**at the **
**December 15, 2003**
**meeting of the**
**Advisory Committee for Reproductive Health**

## Folate nutrition and metabolism and

-                influence on NTDs

- Metabolic roles of folate and factors that influence its requirement

- Polymorphisms in folate genes and/or poor folate status are metabolic and genetic risk factors for disease (cancer, vascular disease, birth defects)

- Daily recommended intakes (DRIs) for folate may be
- influenced by individual genetic profiles

- Peri-conceptual folic acid reduces incidence of birth defects

## Slide 3

## Folate transport and retention in the body

- Dietary folates, primarily polyglutamates, are hydrolyzed by
- a brush border hydrolase, prior to absorption in the gut.
- Monoglutamate forms circulate in plasma and are transported
- into tissues via a membrane carrier (RFC) and/or by a receptor-
- mediated process (FBP).
- Folate retention by tissues requires their conversion to long
- chain length polyglutamate forms. Incomplete conversion to
- polyglutamates by tissues such as intestinal mucosa and liver leads to release of folate, mainly as methylfolate, into plasma.
- Tissue folates turn over primarily by catabolism to pterins and
- aminobenzoylpolyglutamates. The half life of whole body folate
- is approximately 100-200 days, depending on folate intake.

## Folate transport and retention in the body:

-         effect of high folate intake

- Plasma folate levels increase as folate intake increases while tissue folate levels saturate at high folate intakes.  Although folate absorption and tissue uptake are not limited,  a decreased ability to convert the entering folate in tissues to retainable polyglutamate forms leads to release of much of the transported folate back to the plasma.
- At high folate doses, the capacity of the intestinal mucosa and liver to metabolize the dose to methylfolate is exceeded and unmetabolized folate is released into the circulation.
- The half life of whole body folate decreases with increased
- folate intake. At very high intakes, the initial loss is due to exceeding the renal capacity for reabsorption.

## Slide 6

## Slide 7

## transmethylation

- serine

- glycine

- THF

- CH2-THF

- CH3-THF

- methionine

- AdoMet

- AdoHcy

- homocysteine

- X

- CH3-X

- MTHFR

- MATII

- MS

- SHMT

- PLP

- adenosine

- FAD

- B12

- SAHH

- remethylation

- cytosine

- CH3-cytosine

- export

## transmethylation

- serine

- glycine

- THF

- CH2-THF

- CH3-THF

- methionine

- AdoMet

- AdoHcy

- homocysteine

- cystathionine

- cysteine

- MTHFR

- CS

- MATI/III

- MS

- BHMT

- SHMT

- PLP

- adenosine

- FAD

- PLP

- PLP

- B12

- SAHH

- remethylation

- transsulfuration

- glycine

- sarcosine

- GNMT

- CH3-cytosine

- cytosine

## Consequences of impaired folate status or metabolism

**Metabolic Disruption**

**Biochemical Markers**

**Clinical Associations**

- S-adenosylmethionine (MTHFR, MS, B12 deficiency)
-  Thymidylate
-  Purines (A,G)

**Hypomethylated DNA**
**Elevated homocysteine**
**Reduced methylation**

**Decreased DNA synthesis & reduced cell division**

**Cancer****CVD****demyelination****NTDs**

**Cancer****NTDs****Anemia**

**Anemia**

**Increased uracil in DNA****Decreased DNA synthesis & reduced cell division**

## Neural tube defects (NTDs)

- The most common congenital abnormality at birth in US
- Neural tube closes during fourth week post conception
- Embryo nutrition dependent on yolk sac during this period
- Peri-conceptual folic acid decreases the incidence of NTDs
- Disruption of some folate genes in mice produces a NTD phenotype: in some cases preventable by additional folate

## Relationship of early pregnancy maternal red cell folate to risk of NTD

- Daly et al JAMA 1995; 274:1698-702

## Folate and the etiology of NTDs

- Mechanism(s) for protective effect of folate not established
- Etiology is both environmental and genetic
- Not all NTDs are preventable by additional folate
- Common polymorphisms in some folate genes influence NTD risk
**	****MTHFR     677 C->T  (case risk)**
**	****MTHFD1   R653Q      (maternal risk)**** **
- Folate fortification is the first nutritional intervention to expose the entire population to target distinct genetic populations

## A common polymorphism in the MTHFR gene

- ______________________________________________________
**Normal allele**
- Gene sequence           .....GCG  GGA  G**C**C  GAT..................
- Protein Sequence       ......Ala    Gly    **Ala****   **  Asp...................
**677 C->T allele**
- Gene Sequence          .....GCG  GGA  G**T**C  GAT...................
- Protein Sequence       ......Ala    Gly    **Val****   **  Asp ...................
- ______________________________________________________
- Associated with elevated homocysteine when folate (and
- riboflavin) status is poor, and decreased cancer risk.
- Elevated homocysteine is a risk factor for vascular disease.

## Common genetic variation may influence

**Increasing intake**

- UL

**Risk of inadequacy**

**Risk of excess**

**0.5**

**0.5**

- EAR1

- EAR2

**RDA****1**

**RDA****2**

-           the requirement for folate