Moderate folate depletion increases plasma homocysteine and decreases lymphocyte DNA methylation in postmenopausal women.

To determine the human folate requirement on the basis of changes in biochemical pathways, we studied the effect of controlled folate intakes on plasma homocysteine and lymphocyte DNA methylation and deoxynucleotide content in healthy postmenopausal women. Eight women (49-63 y of age) were housed in a metabolic unit and fed a low folate diet containing 56 microg/d of folate for 91 d. Folate intake was varied by supplementing 55-460 microg/d of folic acid (pteroylglutamic acid) to the diet to provide total folate intake periods of 5 wk at 56 microg/d, 4 wk at 111 microg/d and 3 wk at 286-516 microg/d. A subclinical folate deficiency with decreased plasma folate was created during the first two periods. This resulted in significantly elevated plasma homocysteine and urinary malondialdehyde, and lymphocyte DNA hypomethylation. The folate depletion also resulted in an increased ratio of dUTP/dTTP in mitogen-stimulated lymphocyte DNA and decreased lymphocyte NAD, changes suggesting misincorporation of uracil into DNA and increased DNA repair activity. The DNA hypomethylation was reversed with 286-516 microg/d of folate repletion, whereas the elevated homocysteine decreased with 516 but not 286 microg/d of folate. The results indicate that marginal folate deficiency may alter DNA composition and that the current RDA of 180 microg/d may not be sufficient to maintain low plasma homocysteine concentrations of some postmenopausal women.

[1]  B. P. Eynon,et al.  'Spontaneous' genetic damage in man: evaluation of interindividual variability, relationship among markers of damage, and influence of nutritional status. , 1997, Mutation research.

[2]  B. Ames,et al.  Folate deficiency causes uracil misincorporation into human DNA and chromosome breakage: implications for cancer and neuronal damage. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[3]  I. Pogribny,et al.  Apoptosis and proliferation under conditions of deoxynucleotide pool imbalance in liver of folate/methyl deficient rats. , 1997, Carcinogenesis.

[4]  R. Jacob,et al.  Food Folate Assay with Protease, α-Amylase, and Folate Conjugase Treatments , 1997 .

[5]  W. Coulson,et al.  Male rats fed methyl- and folate-deficient diets with or without niacin develop hepatic carcinomas associated with decreased tissue NAD concentrations and altered poly(ADP-ribose) polymerase activity. , 1997, The Journal of nutrition.

[6]  L. Bailey,et al.  Kinetic modeling of folate metabolism through use of chronic administration of deuterium-labeled folic acid in men. , 1997, The American journal of clinical nutrition.

[7]  I. Pogribny,et al.  Folate deficiency in rats induces DNA strand breaks and hypomethylation within the p53 tumor suppressor gene. , 1997, The American journal of clinical nutrition.

[8]  P. Durand,et al.  Pro-thrombotic effects of a folic acid deficient diet in rat platelets and macrophages related to elevated homocysteine and decreased n-3 polyunsaturated fatty acids. , 1996, Atherosclerosis.

[9]  K. Rasmussen,et al.  Age- and gender-specific reference intervals for total homocysteine and methylmalonic acid in plasma before and after vitamin supplementation. , 1996, Clinical chemistry.

[10]  A. Basnakian,et al.  Quantification of 3'OH DNA breaks by random oligonucleotide-primed synthesis (ROPS) assay. , 1996, DNA and cell biology.

[11]  G. Omenn,et al.  A quantitative assessment of plasma homocysteine as a risk factor for vascular disease. Probable benefits of increasing folic acid intakes. , 1995, JAMA.

[12]  L. Bailey,et al.  Controlled dietary folate affects folate status in nonpregnant women. , 1995, The Journal of nutrition.

[13]  S. Henning,et al.  In vivo methylation capacity is not impaired in healthy men during short-term dietary folate and methyl group restriction. , 1995, Journal of NutriLife.

[14]  J. Mason,et al.  Moderate folate deficiency does not cause global hypomethylation of hepatic and colonic DNA or c-myc-specific hypomethylation of colonic DNA in rats. , 1995, The American journal of clinical nutrition.

[15]  L. Poirier,et al.  Breaks in genomic DNA and within the p53 gene are associated with hypomethylation in livers of folate/methyl-deficient rats. , 1995, Cancer research.

[16]  A. Basnakian,et al.  In vitro folate deficiency induces deoxynucleotide pool imbalance, apoptosis, and mutagenesis in Chinese hamster ovary cells. , 1994, Cancer research.

[17]  S. Morris,et al.  The effect of folic acid and/or methionine deficiency on deoxyribonucleotide pools and cell cycle distribution in mitogen‐stimulated rat lymphocytes , 1994 .

[18]  S. Henning,et al.  Homocysteine increases as folate decreases in plasma of healthy men during short-term dietary folate and methyl group restriction. , 1994, The Journal of nutrition.

[19]  B. Jones,et al.  Lipid peroxidation and homocysteine induced toxicity. , 1994, Atherosclerosis.

[20]  D. Albanes,et al.  Folate and cancer: a review of the literature. , 1994, Nutrition and cancer.

[21]  S. Chirico,et al.  High-performance liquid chromatography-based thiobarbituric acid tests. , 1994, Methods in enzymology.

[22]  P. Wilson,et al.  Vitamin status and intake as primary determinants of homocysteinemia in an elderly population. , 1993, JAMA.

[23]  S. Morris,et al.  The essentiality of folate for the maintenance of deoxynucleotide precursor pools, DNA synthesis, and cell cycle progression in PHA-stimulated lymphocytes. , 1993, Environmental health perspectives.

[24]  J Olszewski,et al.  Cellular oxidation of low density lipoprotein is caused by thiol production in media containing transition metal ions. , 1993, Journal of lipid research.

[25]  C. Wagner,et al.  DNA methylation in folate deficiency: use of CpG methylase. , 1993, Biochemical and biophysical research communications.

[26]  K. Mccully,et al.  Homocysteine metabolism and the oxidative modification of proteins and lipids. , 1993, Free radical biology & medicine.

[27]  B. Halliwell,et al.  Lipid peroxidation: its mechanism, measurement, and significance. , 1993, The American journal of clinical nutrition.

[28]  D. Wilcken,et al.  Circulating lipid hydroperoxide levels in human hyperhomocysteinemia. Relevance to development of arteriosclerosis. , 1993, Arteriosclerosis and thrombosis : a journal of vascular biology.

[29]  S. J. James,et al.  Alterations in nucleotide pools in rats fed diets deficient in choline, methionine and/or folic acid. , 1992, Carcinogenesis.

[30]  G. Block,et al.  Folate intake and food sources in the US population. , 1989, The American journal of clinical nutrition.

[31]  S. J. James,et al.  Diet-induced DNA damage and altered nucleotide metabolism in lymphocytes from methyl-donor-deficient rats. , 1989, Carcinogenesis.

[32]  P. Taylor,et al.  Folate requirement and metabolism in nonpregnant women. , 1987, The American journal of clinical nutrition.

[33]  Y. Sako,et al.  Determination of free and total homocysteine in human plasma by high-performance liquid chromatography with fluorescence detection. , 1987, Journal of chromatography.

[34]  C. Hagengruber,et al.  Automated determination of urinary creatinine without sample dilution: theory and practice. , 1986, Clinical Chemistry.

[35]  V. Herbert Megaloblastic anemias. , 1985, Laboratory investigation; a journal of technical methods and pathology.

[36]  N. Tietz Clinical guide to laboratory tests , 1983 .

[37]  Stanton A. Glantz,et al.  Primer of biostatistics : statistical software program version 6.0 , 1981 .

[38]  D. Jenden,et al.  PLASMA CHOLINE: ITS TURNOVER AND EXCHANGE WITH BRAIN CHOLINE 1 , 1975, Journal of neurochemistry.

[39]  J. Murphy Influence of temperature and method of centrifugation on the separation of erythrocytes. , 1973, The Journal of laboratory and clinical medicine.

[40]  Raymond L. Blakley The biochemistry of folic acid and related pteridines , 1969 .

[41]  A. Bøyum,et al.  Isolation of mononuclear cells and granulocytes from human blood. , 1968 .

[42]  A. Böyum,et al.  Isolation of mononuclear cells and granulocytes from human blood. Isolation of monuclear cells by one centrifugation, and of granulocytes by combining centrifugation and sedimentation at 1 g. , 1968, Scandinavian journal of clinical and laboratory investigation. Supplementum.

[43]  Nutrition Board,et al.  RECOMMENDED DIETARY ALLOWANCES. , 1964, Clinical pediatrics.