![[Feedback]](/icons/banner/feedbackACT.gif){kind=icon}
![[For Subscribers]](/icons/banner/subscriberACT.gif){kind=icon}
![[Archive]](/icons/banner/archiveACT.gif){kind=icon}
![[Search]](/icons/banner/searchACT.gif){kind=icon}
![[Contents]](/icons/banner/tocACT.gif){kind=icon}
|
|
|
|
|
||
Food Science and Human Nutrition Department, University of Florida, Gainesville, FL 32611
3To whom correspondence and reprint requests should be addressed.
 |
ABSTRACT |
|---|
 TOP ABSTRACT INTRODUCTIONMetabolism.Metabolic Control Mechanisms.Metabolic and Clinical...Dietary Intake Recommendations.REFERENCES |
|---|
19 y, the Recommended Dietary Allowance (RDA) is
400 µg/d of dietary folate equivalents (DFE); for
lactating and pregnant women, the RDAs include an additional 100 and
200 µg of DFE/d, respectively.
KEY WORDS: • folate • one-carbon metabolism • requirements • dietary reference intakes
|
INTRODUCTION |
|---|
|
TOPABSTRACTINTRODUCTIONMetabolism.Metabolic Control Mechanisms.Metabolic and Clinical...Dietary Intake Recommendations.REFERENCES |
|---|
). The supply of
folate coenzymes in vivo depends primarily on the quantity and
bioavailability of ingested folate and the rate of loss by urinary and
fecal routes and through catabolism. During periods of inadequate
folate intake or malabsorption, biochemical changes associated with
inadequate folate status allow the onset of abnormalities in one-carbon
metabolism. These abnormalities (e.g., hyperhomocysteinemia orDNA
hypomethylation) may result in deleterious consequences, including
increased risk for certain types of chronic diseases (Boushey et al. 1995
, Mason 1995
) and developmental
disorders (e.g., neural tube defects)(Scott et al. 1995
). The long-term goal in defining folate requirements
involves identifying intakes that minimize deleterious processes
associated with inadequate intake and optimize folate-dependent
reactions in metabolism and cellular development.
Recently, new Dietary Reference Intakes
(DRI)4
for folate have been reported [Food and Nutrition Board (FNB)
1998
]. The DRIs include recommendations based primarily on
data from controlled metabolic studies in which blood folate
concentrations were measured, along with data from population-based
studies. Several newer functional status assessment methods have been
proposed to further define folate requirements. In addition, data from
whole-body folate kinetic studies will enhance understanding of how
changes in folate intake influence many phases of folate metabolism and
nutritional status (Gregory et al. 1998
).
|
Metabolism. |
|---|
|
TOPABSTRACTINTRODUCTIONMetabolism.Metabolic Control Mechanisms.Metabolic and Clinical...Dietary Intake Recommendations.REFERENCES |
|---|
). The central folate acceptor molecule in the one-carbon cycle is
a polyglutamyl form of tetrahydrofolate (THF) (Wagner 1995
). The principal function of folate coenzymes is to accept
or donate one-carbon units in key metabolic pathways (Fig. 1)
. The
conversion of THF to 5,10-methylene-THF is a crucial first step in the
cycle that employs the 3-carbon of serine as a major carbon source.
This one-carbon unit is transferred from serine to THF via pyridoxal
phosphate (PLP)-dependent serine hydroxymethyltransferase (SHMT) to
form 5,10-methylene-THF and glycine. A portion of the
5,10-methylenetetrahydrofolate thus produced undergoes irreversible
enzymatic reduction to the methyl oxidation state (as 5-methyl-THF) by
methylene tetrahydrofolate reductase (MTHFR). The N-5 methyl group of
5-methyl-THF can only be used metabolically for transfer to
homocysteine, which results in the (re)generation of methionine. MTHFR
serves a key role in one-carbon metabolism by converting methylene-THF
to 5-methyl-THF, thus irreversibly directing this one-carbon moiety to
methylation of homocysteine synthesis. Between 50 and 80% of the
homocysteine generated is remethylated, depending on the dietary
content of methionine and choline. In the methionine synthase reaction,
a methyl group is removed from 5-methyl-THF, which functions as a
substrate, and is sequentially transferred to the vitamin B-12 coenzyme
before homocysteine, thus forming methionine. In addition to protein
synthesis, methionine serves as a methyl group donor through conversion
to SAM, a key biological methylating agent involved in >100
methyltransferase reactions with a wide variety of acceptor molecules.
|
|
Metabolic Control Mechanisms. |
|---|
|
TOPABSTRACTINTRODUCTIONMetabolism.Metabolic Control Mechanisms.Metabolic and Clinical...Dietary Intake Recommendations.REFERENCES |
|---|
, Wagner 1995
). Folate coenzymes and relevant enzymes are
compartmentalized between the cytosol and the mitochondria. Metabolic
products are readily transported between compartments, but the folate
coenzymes are not. The cytosolic form of SHMT, although reversible, is
thought to function mainly in the transfer of carbons from serine to
THF, yielding 5,10-methylene-THF under most circumstances. A
mitochondrial form of SHMT also exists (Garcia-Martinez and
Appling, 1993
, Kastanos et al. 1997
).
Mitochondrial SHMT has been hypothesized to convert glycine to serine
and to serve as a source of mitochondrial THF. In contrast to
one-carbon metabolism in cytosol, mitochondrial one-carbon metabolism
appears to derive much of the one-carbon transfer from folate-mediated
serine oxidation (to formate) rather than via SHMT (Graham et al. 1997
). In cytosol, the carbon transfer from serine to THF
by SHMT is inhibited by 5-methyl-THF and by 5-formyl-THF (Stover and Schirch 1991
); 5-formyl-THF formation is a secondary
reaction catalyzed by SHMT (Stover and Schirch 1990
).
Regulation of this pathway also occurs by inhibition of MTHFR by SAM,
which suppresses the production of 5-methyl-THF. Thus, the
intracellular presence of excess methyl groups (i.e., increased
intracellular 5-methyl-THF and SAM as in periods of high intake of
methionine, choline and adequate supply of other relevant coenzymes)
curtails the further de novo biosynthesis of methyl groups.
Knowledge of nutritional regulation of one-carbon metabolism is
slowly evolving. The influence of intracellular folate concentration
(as governed largely by dietary intake) on the entry and processing of
substrate in one-carbon metabolism is uncertain. Because folates serve
as carbon acceptors, carriers and donors, inadequate folate status
would impair one-carbon metabolism during severe deficiency. However,
because of the role of 5-methyl and 5-formyl-THF as SHMT inhibitors,
marginal folate deficiency may (at least transiently) have little
adverse effect on carbon flux because the effects of these physiologic
inhibitors may be diminished. Flux through SHMT would be predicted to
be a function of PLP concentrations (Jones and Priest 1978
).
Regulation by SAM is disrupted in response to a folate deficiency
(Miller et al. 1994
). In poor folate status,
S-adenosylhomocysteine (SAH) concentration would tend to
increase due to impairment of methyl group synthesis and homocysteine
remethylation. Resulting product inhibition by SAH would suppress many
of the SAM-dependent methyltransferase reactions (Selhub and Miller 1992
), thus illustrating the far-reaching effects of
impaired one-carbon metabolism during such a nutritional deficiency.
Another aspect of nutritional influences on one-carbon metabolism
is the effect of cobalamin status on the activity and in vivo action of
methionine synthase. Methionine synthase catalyzes the
cobalamin-dependent transfer of a methyl group from 5-methyl-THF to
regenerate methionine from homocysteine. The co-dependence of
methionine synthase on folate and vitamin B-12 provides a biochemical
explanation of why a single deficiency of either vitamin leads to the
same hematological abnormalities. THF must be regenerated in the
methionine synthase reaction before conversion to 5–10-methylene-THF
required for thymidylate and, thus, DNA synthesis. Another aspect of
the interrelationship between folate and vitamin B-12 is the elevation
of plasma homocysteine concentrations by deficiencies of folate and/or
vitamin B-12. Thus hyperhomocystemia is not specific for folate
deficiency. Homocysteine has two primary metabolic fates as follows:
1) conversion to methionine, and 2)
catabolism via the transsulfuration pathway that involves PLP-dependent
enzymes cystathionine ß-synthase and 
-cystathionase. Vitamin B-6
deficiency inhibits homocysteine catabolism, which tends to increase
plasma homocysteine and intracellular SAH concentrations. In summary,
folate and vitamin B-12 function in the methylation of homocysteine,
whereas vitamin B-6 and folate act in the acquisition (and reduction to
methyl level) of one-carbon units from serine, and vitamin B-6 is
involved in homocysteine catabolism. Although other sources of
one-carbon units exist (e.g., choline, formate, glycine or betaine),
serine appears to be the primary carbon donor for the diverse processes
of one-carbon metabolism (Pasternack et al. 1996
,
Shane 1995
, Wagner 1995
).
|
Metabolic and Clinical Manifestations of Folate Deficiency. |
|---|
|
TOPABSTRACTINTRODUCTIONMetabolism.Metabolic Control Mechanisms.Metabolic and Clinical...Dietary Intake Recommendations.REFERENCES |
|---|
, Rimm et al. 1998
, Selhub et al. 1995
). The pathologic
mechanisms involved are still actively debated.
Clinically, severe folate deficiency yields a specific type of
anemia, a megaloblastic anemia (Lindenbaum and Allen 1995
). Megaloblasts are large, abnormal, nucleated cells that
are precursors of erythrocytes; in a folate deficiency, they accumulate
and are found in the bone marrow. These cells arise as a result of a
failure of the red cell precursors to divide normally. The resulting
anemia is not the only manifestation of diminished cell division. There
are also decreased numbers of white cells and platelets. There is
general impairment of cell division related to folate's role in
nucleic acid synthesis, which is more apparent in tissues that turn
over rapidly, such as the hematopoieitic system and the cells lining
the digestive tract (Lindenbaum and Allen 1995
).
Inadequate folate intake has been implicated in the development
or enhancement of certain types of cancer. Proposed hypotheses
regarding folate's role in carcinogenesis relate to DNA structure,
stability and transcriptional regulation;they include increased
susceptibility of DNA to strand breakage, uracil misincorporation in
DNA and hypomethylation of DNA. Misincorporation of uracil into DNA
with chronic folate deficiency is expected to stress the mechanism of
DNA repair and thus result in subsequent increases in DNA strand breaks
and chromosomal instability (Blount et al. 1997
). The
sensitivity of human thymidylate synthesis to a folate deficiency was
reported by Blount et al. (1997)
who observed increased
misincorporation of uracil into lymphocyte DNA. Folate-deficient humans
had elevated incorporation of uracil into DNA, accompanied by an
increased frequency of cellular micronuclei, a measure of DNA and
chromosome damage (Blount et al. 1997
). Uracil
misincorporation was markedly reduced by folate supplementation of
folate-deficient subjects, which restored thymidylate synthesis.
Methylation reactions are required for the biosynthesis of many
important products, but the methylation of DNA has been shown to
regulate the expression of genes in eukaryotic cells. Methyl groups are
transferred to the N-5 position of cytosine in DNA by a specific DNA
methylase. The extent of methylation of specific genes varies from
tissue to tissue and changes during development. It has been shown
that, in most cases, undermethylation favors gene expression, whereas
increased methylation is associated with gene silencing (Wagner 1995
).
The reduction in risk of neural tube defects by folic acid
supplementation has been definitively shown by controlled intervention
trials, as reviewed previously (Scott et al. 1995
). The
mechanism by which adequate folate intake reduces risk during the
crucial developmental phase of the embryonic neural tube is unknown.
Increasing folate intake, which increases the concentrations of folate
coenzymes in tissues, may overcome an unidentified metabolic defect in
the production of proteins and/or DNA or regulation of gene expression
at the time of neural tube development and closure (FNB
1998
).
Folate metabolism must adapt during pregnancy to multiple fetal and
maternal physiologic influences that change throughout gestation.
Adequate folate intake is essential throughout gestation to ensure
normal growth and development. Evidence associating impaired folate
status with reduced infant birth weight has been reported in the U.S.
(O'Scholl et al. 1996
).
|
Dietary Intake Recommendations. |
|---|
|
TOPABSTRACTINTRODUCTIONMetabolism.Metabolic Control Mechanisms.Metabolic and Clinical...Dietary Intake Recommendations.REFERENCES |
|---|
). More recently, the focus
has shifted to identifying intakes associated with maintenance of
normal one-carbon transfer reactions as described above. Inadequacies
identified by abnormalities in the metabolic pathways such as
hyperhomocysteinemia, hypomethylation of DNA (Jacob et al. 1998
) and uracil misincorporation (Blount et al. 1997
) are characterized as functional indicators of folate
status (Green and Jacobsen 1995
, Selhub et al. 1993
). In vivo kinetics, which are readily studied using stable
isotopically labeled tracers, also will aid in defining the folate
requirement more precisely (Gregory et al. 1998
). In
addition, a great deal of current research is focused on characterizing
optimum folate intake associated with risk reduction for chronic
disease (Boushey et al. 1995
) and developmental defects
(e.g., neural tube) (Daly et al. 1997
).
The FNB recently reported new DRI (Bailey 1998
,
FNB 1998
) that include a folate requirement estimate for
population groups referred to as the Estimated Average Requirement
(EAR). The EAR for folate is defined as the amount of folate that is
needed to meet the requirement of 50% of the population. This
requirement estimate was based primarily on the ability of specified
intakes of folate to maintain normal red cell folate concentration. Red
blood cell folate concentration was defined as the primary indicator of
adequacy because of its correlation with liver folate and thus tissue
stores (Wu et al. 1975
). Maintenance of normal
homocysteine concentration was also evaluated in relation to folate
intake and was considered an ancillary functional indicator of
adequacy. The Recommended Dietary Allowances (RDA) were estimated from
the EAR by correcting for population variance and were defined as the
average level of daily dietary intake sufficient to meet the nutrient
requirement of ~98% of the population.
As primary studies on which conclusions regarding the EAR were
drawn, the FNB committee considered those metabolic studies in which
folate status response to defined diets was determined. Other types of
supporting data were provided by epidemiologic studies in which folate
intake was estimated in conjunction with plasma folate and homocysteine
concentrations. The DRIs for folate are expressed as Dietary Folate
Equivalents (DFE), a term adopted by the National Academy of Sciences
to adjust for the generally higher bioavailability of synthetic folic
acid relative to most forms of naturally occurring folate in foods
(Bailey 1998
, Cuskelly et al. 1996
,
Peiffer et al. 1997
, Sauberlich et al. 1987
). An example of the type of study on which the EAR for
adults is based is that of O'Keefe et al. (1995)
; in that study, a
specified quantity of dietary folate was inadequate to maintain normal
indicators of folate adequacy in 50% of the experimental group.
Specifically, the consumption of 320 µg of DFE in a
long-term metabolic study in young adult women was inadequate to
maintain normal RBC folate concentrations (>140 ng/mL; 316
nmol/L) in 50% of the group. In addition, the ancillary
indicators, serum folate and plasma homocysteine concentrations, also
were abnormal in 50% of the group [<3 ng/mL (6.8 nmol/L) and
>14 µmol/L, respectively]. A complete description of
the entire database on which the new DRI are based is included in the
report (FNB 1998
). For male and female adults >19 y of
age, the folate EAR and RDA are 320 and 400 µg DFE/d,
respectively.
For pregnant women, the new EAR and RDA are 200
µg of DFE/d higher than for nonpregnant women (i.e.,
520 and 600 µg of DFE/d, respectively) (FNB
1998
). The increased requirements for folate during pregnancy
are associated with the rapid rate of maternal and fetal cellular
growth and development. The types of studies on which the NAS based the
EAR and RDA for pregnant women included population-based studies and
one controlled metabolic study (FNB, 1998
). Our research
group conducted the metabolic study in which folate status was
monitored for 12 wk in second trimester pregnant women and nonpregnant
controls who consumed one of two quantities of folate (Bonnette et al. 1998
, Caudill et al. 1997
and 1998
). A
folate intake of 600 µg of DFE/d was sufficient to
maintain both RBC folate concentration and serum folate in the normal
range in pregnant subjects and provided blood folate concentrations
that did not differ from those of nonpregnant controls. The conclusion
of this study was consistent with the findings from population studies
that ~600 µg of DFE/d is adequate to maintain normal
folate status in pregnant women.
An additional approach to estimating the folate requirements of
pregnant women is the measurement of urinary folate excretory products
(McPartlin et al. 1993
). This approach is based on the
assumption that urinary catabolic products are representative of folate
utilized daily because the major route of folate turnover is by
catabolism and cleavage of the C9-N10 bond, producing pteridines and
para-aminobenzoylglutamate (pABG), which is
N-acetylated before excretion (ApABG). McPartlin et al. (1993)
reported a twofold higher urinary ApABG excretion
by pregnant women during the second trimester relative to nonpregnant
controls. In contrast, data from our metabolic study in which dietary
folate intake was strictly controlled indicated no change in folate
catabolism due to pregnancy (Caudill et al. 1998
).
Folate requirements for lactating women are increased to replace the
quantity of folate secreted daily in breast milk plus the amount
necessary to maintain normal folate status (Bailey 1998
,
FNB 1998
). It is unclear whether the physiologic changes
associated with lactation increase maternal folate requirements. The
new EAR and RDA are 450 and 500 µg of DFE/d,
respectively (Bailey 1998
, FNB 1998
).
Folate DRI estimates for all age categories, including infants,
children and adolescents, are not based on data from controlled
metabolic studies. For infants, it was not possible to estimate an EAR
or RDA due to limitations in the database. A separate DRI, designated
the Adequate Intake (AI), was based on the quantity of folate consumed
daily by breast-fed infants (Bailey 1998
, FNB
1998
). For childhood and adolescence, data were extrapolated
from estimates for the EAR and RDA for adults (Bailey 1998
, FNB 1998
). Table 1
summarizes the AI and RDA estimates for all age and sex categories.
|
|
FOOTNOTES |
|---|
2 Manuscript received 19 January 1999.
3 Abbreviations used: AI, adequate intake; ApABG,
N-acylated para-aminobenzoylglutamate;
DFE, dietary folate equivalents; DRI, Dietary Reference Intakes; EAR,
estimated average requirement; FNB, Food and Nutrition Board; MTHFR,
methylene tetrahydrofolate reductase; pABG,
para-aminobenzoylglutamate; PLP, pyridoxal phosphate;
RDA, Recommended Dietary Allowance; SAH,
S-adenosylhomocysteine; SAM,
S-adenosylmethionine; SHMT, serine
hydroxymethyltransferase; THF, tetrahydrofolate.
|
REFERENCES |
|---|
|
TOPABSTRACTINTRODUCTIONMetabolism.Metabolic Control Mechanisms.Metabolic and Clinical...Dietary Intake Recommendations.REFERENCES |
|---|
1. Bailey L. B. Dietary reference intakes for folate: the debut of dietary folate equivalents. Nutr. Rev. 1998;56:294-299[Medline]
2.
Blount B. C., Mack M. M., Wehr C. M., MacGregor J. T., Hiatt R. A., Wang G., Wickramasinghe S. N., Everson R. B., Ames B. N. Folate deficiency causes uracil misincorporation into human DNA and chromosome breakage: implications for cancer and neuronal damage. Proc. Natl. Acad. Sci. U.S.A. 1997;94:3290-3295
3. Bonnette R. E., Caudill M. A., Boddie A. M., Hutson A. D., Kauwell G.P., A & Bailey L. B. Plasma homocysteine concentrations in pregnant and nonpregnant women with controlled folate intakes. Obstet. Gynecol. 1998;92:167-170[Medline]
4.
Boushey C. J., Beresford S.A.A, Omenn G. S., Motulsky A. G. A quantitative assessment of plasma homocysteine as a risk factor for vascular disease. Probable benefits of increasing folic acid intakes. J. Am. Med. Assoc. 1995;274:1049-1057
5.
Caudill M. A., Cruz A. C., Gregory J. F., III, Hutson A. D., Bailey L. B. Folate status response to controlled folate intake in pregnant women. J. Nutr. 1997;127:2363-2370
6.
Caudill M. A., Gregory J. F., III, Hutson A. D., Bailey L. B. Folate catabolism in pregnant and nonpregnant women with controlled folate intakes. J. Nutr. 1998;128:204-208
7. Cuskelly G. J., McNulty H., Scott J. M. Effect of increasing dietary folate on red cell folate: implications for prevention of neural tube defects. Lancet 1996;347:657-659[Medline]
8. Daly S., Mills J. L., Molloy A. M., Conley M., Lee Y. J., Kirke P. N., Weir D. G., Scott J. M. Minimum effective dose of folic acid for food fortification to prevent neural tube defects. Lancet 1997;350:1666-1669[Medline]
9. Food and Nutrition Board. National Academy of Sciences Recommended Dietary Allowances 10th ed. 1989 National Academy Press Washington, DC.
10. Food and Nutrition Board. Institute of Medicine. National Academy of Sciences, Subcommittee on Folate, Other B Vitamins, and Choline.(1998)Dietary Reference Intakes: Thiamin, Riboflavin, Niacin, Vitamin B-6, Folate, Vitamin B-12, Panthothenic Acid, Biotin and Choline (Pre-publication). National Academy Press, Washington, DC.
11. Garcia-Martinex L. F., Appling D. R. Characterization of the folate-dependent mitochondrial oxidation of carbon 3 of serine. Biochemistry 1993;32:4671-4676[Medline]
12.
Graham I. M., Daly L. E., Refsum H. M., Robinson K., Brattstrom L., Ueland P. M., PalmaReis R. J., Boers G.H.J., Sheahan R. G., Israelsson B., Uiterwaal C. S., Meleady R., McMaster D., Verhoef P., Witteman J., Rubba P., Bellet H., Wautrecht J. C., deValk H. W., Luis A.C.S., ParrotRoulaud F. M., Tan K. S., Higgins I., Garcon D., Medrano M. J., Candito M., Evans A. E., Andria G., The European Concerted Action Project Plasma homocysteine as a risk factor for vascular disease. J. Am. Med. Assoc. 1997;277:1775-1781
13. Green R., Jacobsen D. W. Clinical implications of hyperhomocysteinemia. Bailey L.B. eds. Folate in Health and Disease 1995:195-235 Marcel Dekker New York, NY.
14.
Gregory J. F., Williamson J., Liao J.-F., Bailey L. B., Toth J. P. Kinetic model of folate metabolism in nonpregnant women consuming [2H2] folic acid: isotropic labeling of urinary folate and the catabolite pABG indicates slow intake-dependent turnover of folate pools. J. Nutr. 1998;128:1896-1906
15.
Jacob R. A., Gretz D. M., Taylor P. C., James S. J., Pogribny I. P., Miller B. J., Henning S. M., Swendseid M. E. Moderate folate depletion increases plasma homocysteine and decreases lymphocyte DNA methylation in postmenopausal women. J. Nutr. 1998;128:1204-1212
16. Jones C. W., Priest D. G. Interaction of pyridoxal 5-phosphate with apo-serine hydroxymethyltransferase. Biochim. Biophys. Acta 1978;526:369-374[Medline]
17. Kastanos E. K., Woldman Y. Y., Appling D. R. Role of mitochondrial and cytoplasmic serine hydroxymethyltransferase isozymes de novo purine synthesis in Saccharomyces cerevisiae. Biochemistry 1997;36:14956-14964[Medline]
18. Lindenbaum J., Allen R. H. Clinical spectrum and diagnosis of folate deficiency. Bailey L. B. eds. Folate in Health and Disaese 1995 Marcel Dekker New York, NY.
19. Mason J. Folate status: effects on carcinogenesis. Bailey L. B. eds. Folate in Health and Disease 1995:329-361 Marcel. Dekker New York, NY.
20. McPartlin J., Halligan A., Scott J. M., Darling M., Weir D. G. Accelerated folate breakdown in pregnancy. Lancet 1993;341:148-149[Medline]
21. Miller J. W., Nadeau M. R., Smith J., Smith D., Selhub J. Folate-deficiency-induced homocysteinaemia in rats:disruption of S-adenosylmethionine's co-ordinate regulation of homocysteine metabolism. Biochem. J. 1994;298:415-419
22. O'Keefe C., Bailey L. B., Thomas E. A., Holfer S. A., Davis B. A., Cerda J. J., Gregory J. F. Controlled dietary folate affects folate status in nonpregnant women. J. Nutr. 1995;125:2717-2725
23.
O'Scholl T. O, Hediger M. L., Schall J. I., Khoo C. S., Fischer R. L. Dietary and serum folate: their influence on the outcome of pregnancy. Am J. Clin. Nutr. 1996;63:520-525
24. Pasternack L. B., Littlepage L. E., Laude D. A., Jr, Appling D. R. 13C NMR analysis of the use of alternative donors to the tetrahydrofolate-dependent one-carbon pools in Saccharomyces cerevisiae. Arch. Biochem. Biophys. 1996;326:158-165[Medline]
25.
Pfeiffer C. M., Rogers L. M., Bailey L. B., Gregory J. F. Absorption of folate from fortified cereal-grain products and of supplemental folates consumed with or without food determined using a dual-label stable-isotope protocol. Am J. Clin. Nutr. 1997;66:1388-1397
26.
Rimm E. B., Willett W. C., Hu F. B., Sampson L., Colditz G. A., Manson J. E., Hennekens C., Stampfer M. J. Folate and vitamin B-6 from diet and supplements in relation to risk of coronary heart disease among women. J. Am. Med. Assoc. 1998;279:359-364
27.
Sauberlich H. E., Kretsch M. J., Skala J. H., Johnson H. L., Taylor P. C. Folate requirement and metabolism in nonpregnant women. Am. J. Clin. Nutr. 1987;46:1016-1028
28. Scott J. M., Kirke P. N., Weir D. G. Folate and neural tube defects. Bailey L.B. eds. Folate in Health and Disease 1995:329-360 Marcel Dekker New York, NY.
29.
Selhub J., Jacques P. F., Wilson P. W., Rush D., Rosenberg I. H. Vitamin status and primary determinants of homocysteinemia in an elderly population. J. Am. Med. Assoc. 1993;270:2693-2698
30.
Selhub J., Miller J. W. The pathogenesis of homocysteinemia: interruption of the coordinate regulation of S-adenosylmethionine of the remethylation and transsulfuration of homocysteine. Am. J. Clin. Nutr. 1992;55:131-138
31.
Selhub J., Jacques P. F., Bostom A. G., D'Agostino R. B., Wilson P.W.F, Belanger A. J., O'Leary D. H., Wolf P. A., Schaefer E. J., Rosenberg I. H. Association between plasma homocysteine concentrations and extracranial carotid-artery stenosis. N. Engl. J. Med. 1995;332:286-291
32. Shane B. Folate chemistry and metabolism. Bailey L.B. eds. Folate in Health and Disease 1995:1-22 Marcel Dekker New York, NY.
33.
Stover P., Schirch V. Serine hydroxymethyltransferase catalyzes the hydrolysis of 5,10-methenyltetrahydrofolate to 5-formyl-tetrahydrofolate. J. Biol. Chem. 1990;265:14227-14233
34.
Stover P., Schirch V. 5-Formyltetrahydrofolate polyglutamates are slow tight binding inhibitors of serine hydroxymethyltransferase. J. Biol. Chem. 1991;266:1543-1550
35. Wagner C. Biochemical role of folate in cellular metabolism. Bailey L.B. eds. Folate in Health and Disease 1995:23-42 Marcel Dekker New York, NY.
36. Wu A., Chanarin I., Slavin G., Levi A. J. Folate deficiency in the alcoholic: its relationship to clinical and haematological abnormalities, liver disease, and folate stores. Br. J. Haematol 1975;29:269-278
This article has been cited by other articles:
|
|
 |
|
  M. E. Platek, P. G. Shields, C. Marian, S. E. McCann, M. R. Bonner, J. Nie, C. B. Ambrosone, A. E. Millen, H. M. Ochs-Balcom, S. K. Quick, et al. Alcohol Consumption and Genetic Variation in Methylenetetrahydrofolate Reductase and 5-Methyltetrahydrofolate-Homocysteine Methyltransferase in Relation to Breast Cancer Risk Cancer Epidemiol. Biomarkers Prev., September 1, 2009; 18(9): 2453 - 2459. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M.P. GALLEGOS-ARREOLA, J.E. GARCIA-ORTIZ, L.E. FIGUERA, A.M. PUEBLA-PEREZ, G. MORGAN-VILLELA, and G.M. ZUNIGA-GONZALEZ Association of the 677C ->T Polymorphism in the MTHFR Gene with Colorectal Cancer in Mexican Patients Cancer Genomics Proteomics, May 1, 2009; 6(3): 183 - 188. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. Lamers, J. Williamson, D. W. Theriaque, J. J. Shuster, L. R. Gilbert, C. Keeling, P. W. Stacpoole, and J. F. Gregory III Production of 1-Carbon Units from Glycine Is Extensive in Healthy Men and Women J. Nutr., April 1, 2009; 139(4): 666 - 671. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. J. Weinstein, D. Albanes, J. Selhub, B. Graubard, U. Lim, P. R. Taylor, J. Virtamo, and R. Stolzenberg-Solomon One-Carbon Metabolism Biomarkers and Risk of Colon and Rectal Cancers Cancer Epidemiol. Biomarkers Prev., November 1, 2008; 17(11): 3233 - 3240. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Lamers, J. Williamson, L. R. Gilbert, P. W. Stacpoole, and J. F. Gregory III Glycine Turnover and Decarboxylation Rate Quantified in Healthy Men and Women Using Primed, Constant Infusions of [1,2-13C2]Glycine and [2H3]Leucine J. Nutr., December 1, 2007; 137(12): 2647 - 2652. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. Graulet, J. J. Matte, A. Desrochers, L. Doepel, M.-F. Palin, and C. L. Girard Effects of Dietary Supplements of Folic Acid and Vitamin B12 on Metabolism of Dairy Cows in Early Lactation J Dairy Sci, July 1, 2007; 90(7): 3442 - 3455. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. I. Diaz de la Garza, J. F. Gregory III, and A. D. Hanson From the Cover: Folate biofortification of tomato fruit PNAS, March 6, 2007; 104(10): 4218 - 4222. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. DellaPenna Biofortification of plant-based food: Enhancing folate levels by metabolic engineering PNAS, March 6, 2007; 104(10): 3675 - 3676. [Full Text] [PDF]
|
|
|
|
|
|
F. F. Zhang, M. B. Terry, L. Hou, J. Chen, J. Lissowska, M. Yeager, W. Zatonski, S. Chanock, A. Morabia, and W.-H. Chow Genetic Polymorphisms in Folate Metabolism and the Risk of Stomach Cancer Cancer Epidemiol. Biomarkers Prev., January 1, 2007; 16(1): 115 - 121. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. J Weinstein, R. Stolzenberg-Solomon, P. Pietinen, P. R Taylor, J. Virtamo, and D. Albanes Dietary factors of one-carbon metabolism and prostate cancer risk. Am. J. Clinical Nutrition, October 1, 2006; 84(4): 929 - 935. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Kohlmeier, K.-A. da Costa, L. M. Fischer, and S. H. Zeisel Genetic variation of folate-mediated one-carbon transfer pathway predicts susceptibility to choline deficiency in humans PNAS, November 1, 2005; 102(44): 16025 - 16030. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Chanson, T. Sayd, E. Rock, C. Chambon, V. Sante-Lhoutellier, G. Potier de Courcy, and P. Brachet Proteomic Analysis Reveals Changes in the Liver Protein Pattern of Rats Exposed to Dietary Folate Deficiency J. Nutr., November 1, 2005; 135(11): 2524 - 2529. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J.-I. Lee, J.-A Lee, and H.-S. Lim Effect of time of initiation and dose of prenatal iron and folic acid supplementation on iron and folate nutriture of Korean women during pregnancy Am. J. Clinical Nutrition, October 1, 2005; 82(4): 843 - 849. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. L Tucker, N. Qiao, T. Scott, I. Rosenberg, and A. Spiro III High homocysteine and low B vitamins predict cognitive decline in aging men: the Veterans Affairs Normative Aging Study Am. J. Clinical Nutrition, September 1, 2005; 82(3): 627 - 635. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. A. Orjuela, L. Titievsky, X. Liu, M. Ramirez-Ortiz, V. Ponce-Castaneda, E. Lecona, E. Molina, K. Beaverson, D. H. Abramson, and N. E. Mueller Fruit and Vegetable Intake during Pregnancy and Risk for Development of Sporadic Retinoblastoma Cancer Epidemiol. Biomarkers Prev., June 1, 2005; 14(6): 1433 - 1440. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. L. Girard, H. Lapierre, J. J. Matte, and G. E. Lobley Effects of Dietary Supplements of Folic Acid and Rumen-Protected Methionine on Lactational Performance and Folate Metabolism of Dairy Cows J Dairy Sci, February 1, 2005; 88(2): 660 - 670. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. J. Moat, S. N. Doshi, D. Lang, I. F. W. McDowell, M. J. Lewis, and J. Goodfellow Treatment of coronary heart disease with folic acid: is there a future? Am J Physiol Heart Circ Physiol, July 1, 2004; 287(1): H1 - H7. [Full Text] [PDF]
|
|
|
|
|
|
M. J. Shrubsole, Y.-T. Gao, Q. Cai, X. O. Shu, Q. Dai, J. R. Hebert, F. Jin, and W. Zheng MTHFR Polymorphisms, Dietary Folate Intake, and Breast Cancer Risk: Results from the Shanghai Breast Cancer Study Cancer Epidemiol. Biomarkers Prev., February 1, 2004; 13(2): 190 - 196. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. N. Craciunescu, E. C. Brown, M.-H. Mar, C. D. Albright, M. R. Nadeau, and S. H. Zeisel Folic Acid Deficiency During Late Gestation Decreases Progenitor Cell Proliferation and Increases Apoptosis in Fetal Mouse Brain J. Nutr., January 1, 2004; 134(1): 162 - 166. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. T. Merchant, F. B. Hu, D. Spiegelman, W. C. Willett, E. B. Rimm, and A. Ascherio The Use of B Vitamin Supplements and Peripheral Arterial Disease Risk in Men Are Inversely Related J. Nutr., September 1, 2003; 133(9): 2863 - 2867. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. C. Anguera, J. R. Suh, H. Ghandour, I. M. Nasrallah, J. Selhub, and P. J. Stover Methenyltetrahydrofolate Synthetase Regulates Folate Turnover and Accumulation J. Biol. Chem., August 8, 2003; 278(32): 29856 - 29862. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. V. Oleinik and S. A. Krupenko Ectopic Expression of 10-Formyltetrahydrofolate Dehydrogenase in A549 Cells Induces G1 Cell Cycle Arrest and Apoptosis Mol. Cancer Res., June 1, 2003; 1(8): 577 - 588. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. P. Quinlivan, S. Roje, G. Basset, Y. Shachar-Hill, J. F. Gregory III, and A. D. Hanson The Folate Precursor p-Aminobenzoate Is Reversibly Converted to Its Glucose Ester in the Plant Cytosol J. Biol. Chem., May 30, 2003; 278(23): 20731 - 20737. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Herbig, E.-P. Chiang, L.-R. Lee, J. Hills, B. Shane, and P. J. Stover Cytoplasmic Serine Hydroxymethyltransferase Mediates Competition between Folate-dependent Deoxyribonucleotide and S-Adenosylmethionine Biosyntheses J. Biol. Chem., October 4, 2002; 277(41): 38381 - 38389. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. F. Choumenkovitch, J. Selhub, P. W. F. Wilson, J. I. Rader, I. H. Rosenberg, and P. F. Jacques Folic Acid Intake from Fortification in United States Exceeds Predictions J. Nutr., September 1, 2002; 132(9): 2792 - 2798. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. Buccianti, S. Raselli, I. Baragetti, F. Bamonti, E. Corghi, C. Novembrino, C. Patrosso, F. M. Maggi, and A. L. Catapano 5-methyltetrahydrofolate restores endothelial function in uraemic patients on convective haemodialysis Nephrol. Dial. Transplant., May 1, 2002; 17(5): 857 - 864. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. Ducloux, A. Aboubakr, G. Motte, G. Toubin, V. Fournier, J.-M. Chalopin, T. Drueke, and Z. A. Massy Hyperhomocysteinaemia therapy in haemodialysis patients: folinic versus folic acid in combination with vitamin B6 and B12 Nephrol. Dial. Transplant., May 1, 2002; 17(5): 865 - 870. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. A. Krupenko and N. V. Oleinik 10-Formyltetrahydrofolate Dehydrogenase, One of the Major Folate Enzymes, Is Down-Regulated in Tumor Tissues and Possesses Suppressor Effects on Cancer Cells Cell Growth Differ., May 1, 2002; 13(5): 227 - 236. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. L. Sedjo, P. Inserra, M. Abrahamsen, R. B. Harris, D. J. Roe, S. Baldwin, and A. R. Giuliano Human Papillomavirus Persistence and Nutrients Involved in the Methylation Pathway among a Cohort of Young Women Cancer Epidemiol. Biomarkers Prev., April 1, 2002; 11(4): 353 - 359. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. J. Weinstein, G. Gridley, L. C. Harty, S. R. Diehl, L. M. Brown, D. M. Winn, E. Bravo-Otero, and R. B. Hayes Folate Intake, Serum Homocysteine and Methylenetetrahydrofolate Reductase (MTHFR) C677T Genotype Are Not Associated with Oral Cancer Risk in Puerto Rico J. Nutr., April 1, 2002; 132(4): 762 - 767. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. F. Choumenkovitch, P. F. Jacques, M. R. Nadeau, P. W. F. Wilson, I. H. Rosenberg, and J. Selhub Folic Acid Fortification Increases Red Blood Cell Folate Concentrations in the Framingham Study J. Nutr., December 1, 2001; 131(12): 3277 - 3280. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. Calvaresi and J. Bryan B Vitamins, Cognition, and Aging: A Review J. Gerontol. B. Psychol. Sci. Soc. Sci., November 1, 2001; 56(6): P327 - 339. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. A. Caudill, J. C. Wang, S. Melnyk, I. P. Pogribny, S. Jernigan, M. D. Collins, J. Santos-Guzman, M. E. Swendseid, E. A. Cogger, and S. J. James Intracellular S-Adenosylhomocysteine Concentrations Predict Global DNA Hypomethylation in Tissues of Methyl-Deficient Cystathionine {beta}-Synthase Heterozygous Mice J. Nutr., November 1, 2001; 131(11): 2811 - 2818. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. J. Hartman, K. Woodson, R. Stolzenberg-Solomon, J. Virtamo, J. Selhub, M. J. Barrett, and D. Albanes Association of the B-Vitamins Pyridoxal 5'-Phosphate (B6), B12, and Folate with Lung Cancer Risk in Older Men Am. J. Epidemiol., April 1, 2001; 153(7): 688 - 693. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Z. A. Massy Reversal of hyperhomocyst(e)inaemia in chronic renal failure--is folic or folinic acid the answer? Nephrol. Dial. Transplant., December 1, 1999; 14(12): 2810 - 2812. [Full Text] [PDF]
|
|
|
|
|
|
L. B. Bailey and J. F. Gregory III Polymorphisms of Methylenetetrahydrofolate Reductase and Other Enzymes: Metabolic Significance, Risks and Impact on Folate Requirement J. Nutr., May 1, 1999; 129(5): 919 - 922. [Abstract] [Full Text]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
