Folate catabolite excretion is responsive to changes in dietary folate intake in elderly women

BACKGROUND: The major route of folate turnover is by catabolic cleavage of the C9-N10 bond producing p-aminobenzoylglutamate (pABG) and its primary excretory form, p-acetamidobenzoylglutamate (ApABG). We hypothesize that total pABG (ApABG + pABG) excretion parallels both the mass of body folate pools from which these catabolites originate and the folate-status indicators. OBJECTIVE: The objective was to determine whether urinary folate catabolite excretion reflects body pool size and parallels the static and functional measures of folate status. DESIGN: Urinary folate catabolite excretion was measured in women (aged 60-85 y) consuming controlled amounts of folate for 14 wk. A low-folate diet (120 microg/d) was consumed (n = 33) for 7 wk, and then subjects were randomly assigned to consume either 200 (n = 14) or 400 (n = 16) microg folate/d. Urinary pABG and ApABG concentrations were measured by HPLC at 0, 7, and 14 wk. RESULTS: Urinary excretion of total pABG was significantly lower (P = 0.001) after depletion (73.9 +/- 4.7 nmol/d) than at baseline (115 +/- 12.7 nmol/d). This rate of decline (approximately 0.7% per day) is consistent with the kinetically measured rate of turnover of total body folate at moderate folate intakes. The average percentage increase in total pABG in response to folate repletion with 400 microg/d (75%) was significant (P = 0.02). Folate catabolite excretion was significantly (P = 0.0001) associated with serum and red blood cell folate, plasma homocysteine, and DNA hypomethylation after depletion and with serum folate (P = 0.001) and plasma homocysteine (P = 0.0002) after repletion with 400 microg folate/d. CONCLUSIONS: Total urinary pABG excretion reflects total body folate pool size and is a long-term indicator that parallels functional measures of folate status.     

Ethnicity and race influence the folate status response to controlled folate intakes in young women

Population-based studies report differences in folate status indicators among Mexican American (MA), African American (AA) and Caucasian (CA) women. It is unclear, however, whether these differences are due to variations in dietary folate intake. The present study was designed to investigate the influence of ethnicity/race on folate status parameters in MA, AA, and CA women (18-45 y; n = 14 in each group) under conditions of strictly controlled folate intake. In addition, the adequacy of the 1998 folate U.S. recommended dietary allowance (RDA), 400 micro g/d as dietary folate equivalents (DFE), for non-Caucasian women was assessed. Subjects (n = 42) with the methylenetetrahydrofolate reductase 677 CC genotype consumed a low-folate diet (135 micro g DFE/d) for 7 wk followed by repletion with 400 (7 MA, 7 AA, 7 CA) or 800 micro g DFE/d (7 MA, 7 AA, 7 CA) for 7 wk. AA women had lower (P 相似文献   

Folate status response to controlled folate intake is affected by the methylenetetrahydrofolate reductase 677C-->T polymorphism in young women

This study was designed to evaluate the effect of the methylenetetrahydrofolate reductase (MTHFR) 677C-->T polymorphism on folate and homocysteine response in non-Hispanic women consuming a low folate diet followed by a diet providing the Recommended Dietary Allowance (RDA) for folate. Women (aged 20-30 y old) with either the TT (n = 19) or CC (n = 22) MTHFR 677C-->T genotype participated in a folate depletion-repletion study (7 wk, 115 microg dietary folate equivalents (DFE)/d; 7 wk, 400 microg DFE/d). Overall serum folate decreased (P < 0.0001) during depletion and increased (P < 0.0001) during repletion with lower (P = 0.03) postdepletion serum folate in women with the TT versus CC genotype. Folate status was low (serum folate < 13.6 nmol/L) in more women with the TT (59%) compared with the CC genotype (15%) postdepletion. Red blood cell folate for all subjects decreased during depletion (P < 0.0001) and repletion (P = 0.02) with lower (P = 0.04) red blood cell folate in women with the TT compared with the CC genotype postrepletion. Homocysteine increased (P < 0.0001) for both genotype groups postdepletion and decreased (P = 0.02) postrepletion for the CC genotype group only. Homocysteine concentrations tended to be higher (P = 0.09) in the TT versus CC genotype group postdepletion and postrepletion. These data suggest that the MTHFR 677C-->T polymorphism negatively affects the folate and homocysteine response in women consuming low folate diets followed by repletion with the RDA. These results may be important when evaluating the impact of the MTHFR 677C-->T polymorphism in countries in which low folate diets are chronically consumed.     

Genomic DNA methylation decreases in response to moderate folate depletion in elderly women

BACKGROUND: Methylation of genomic DNA is dependent on an adequate supply of folate coenzymes. Previous data support the hypothesis that abnormal DNA methylation plays an integral role in carcinogenesis. To date, no studies assessing the effect of inadequate folate status on DNA methylation in older women (aged >63 y) have been reported. OBJECTIVE: The effect of moderate folate depletion followed by folate repletion on leukocyte genomic DNA methylation was investigated in elderly women (aged 60-85 y) to evaluate whether DNA methylation could be used as a functional indicator of folate status. DESIGN: Healthy, postmenopausal women (n = 33) consumed a moderately folate-depleted diet (118 microg folate/d) for 7 wk, followed by 7 wk of folate repletion with 200 or 415 microg/d, each provided as 2 different dietary treatments for a total of 4 treatment groups (n = 30). Leukocyte DNA methylation was determined on the basis of the ability of DNA to incorporate [(3)H]methyl groups from labeled S:-adenosylmethionine in an in vitro assay. RESULTS: Incorporation of [(3)H]methyl groups increased significantly (P: = 0.0025) in response to folate depletion, suggesting undermethylation of DNA. No significant changes were detected in [(3)H]methyl incorporation in any group over the 7-wk repletion period compared with postdepletion values. CONCLUSIONS: DNA methylation status may be used as a functional indicator of moderately depleted folate status. The slow response to the repletion diets observed suggests that normalization of DNA methylation after moderate folate depletion may be delayed in older women.     

Low-dose vitamin B-6 effectively lowers fasting plasma homocysteine in healthy elderly persons who are folate and riboflavin replete

BACKGROUND: Current data suggest that physiologic doses of vitamin B-6 have no significant homocysteine-lowering effect. It is possible that an effect of vitamin B-6 was missed in previous trials because of a much greater effect of folic acid, vitamin B-12, or both. OBJECTIVE: The aim of this study was to investigate the effect of low-dose vitamin B-6 supplementation on fasting total homocysteine (tHcy) concentrations in healthy elderly persons who were made replete with folate and riboflavin. DESIGN: Twenty-two healthy elderly persons aged 63-80 y were supplemented with a low dose of vitamin B-6 (1.6 mg/d) for 12 wk in a randomized, double-blind, placebo-controlled trial after repletion with folic acid (400 microg/d for 6 wk) and riboflavin (1.6 mg/d for 18 wk); none of the subjects had a vitamin B-12 deficiency. RESULTS: Folic acid supplementation lowered fasting tHcy by 19.6% (P < 0.001). After folic acid supplementation, baseline tHcy concentrations ranged from 6.22 to 23.52 micromol/L and 10 subjects had suboptimal vitamin B-6 status (plasma pyridoxal-P < 20 nmol/L). Two-way analysis of variance showed that the significant improvement in vitamin B-6 status in response to vitamin B-6 supplementation (on the basis of both pyridoxal-P: and the erythrocyte aspartate aminotransferase activation coefficient) was reflected in a significant reduction in plasma tHcy of 7.5%. CONCLUSIONS: Low-dose vitamin B-6 effectively lowers fasting plasma tHcy in healthy subjects who are both folate and riboflavin replete. This suggests that any program aimed at the treatment or prevention of hyperhomocysteinemia should include vitamin B-6 supplementation.     

Methylenetetrahydrofolate reductase 677C-->T variant modulates folate status response to controlled folate intakes in young women

A common genetic variant in the methylenetetrahydrofolate reductase (MTHFR) gene involving a cytosine to thymidine (C-->T) transition at nucleotide 677 is associated with reduced enzyme activity, altered folate status and potentially higher folate requirements. The objectives of this study were to investigate the effect of the MTHFR 677 T allele on folate status variables in Mexican women (n = 43; 18-45 y) and to assess the adequacy of the 1998 folate U.S. Recommended Dietary Allowance (RDA), 400 micro g/d as dietary folate equivalents (DFE). Subjects (14 CC, 12 CT, 17 TT genotypes) consumed a low folate diet (135 micro g/d DFE) for 7 wk followed by repletion with 400 micro g/d DFE (7 CC, 6 CT, 9 TT) or 800 micro g/d DFE (7 CC, 6 CT, 8 TT) for 7 wk. Throughout repletion with 400 micro g/d DFE, the TT genotype had lower (P 0.05) in their response relative to the CC genotype. Throughout repletion with 800 micro g/d DFE, the CT genotype had lower (P 0.05) in the measured variables between the TT and CC genotypes. Repletion with 400 micro g/d DFE led to normal blood folate and desirable plasma tHcy concentrations, regardless of MTHFR C677T genotype. Collectively, these data demonstrate that the MTHFR C-->T variant modulates folate status response to controlled folate intakes and support the adequacy of the 1998 folate U.S. RDA for all three MTHFR C677T genotypes.     

Methylenetetrahydrofolate reductase 677C-->T genotype modulates homocysteine responses to a folate-rich diet or a low-dose folic acid supplement: a randomized controlled trial

BACKGROUND: Low folate status and elevated plasma homocysteine are associated with increased risk of neural tube defects and cardiovascular disease. Homocysteine responses to folate may be influenced by genetic variants in folate metabolism. OBJECTIVE: We determined the effect of folate-enhancing dietary interventions on plasma folate and plasma total homocysteine (tHcy) with respect to the methylenetetrahydrofolate reductase 677C-->T genotype. DESIGN: A total of 126 healthy subjects (42 TT, 42 CT, and 42 CC genotypes) completed 3 dietary interventions (4 mo each) in random order: 1) exclusion diet (avoidance of folic acid-fortified foods and ingestion of a placebo daily), 2) folate-rich diet (increased intake of fortified and naturally folate-rich foods to achieve 400 microg folate/d), and 3) supplement (exclusion diet plus a folate supplement of 400 microg/d). RESULTS: Plasma folate was higher (P < or = 0.001) and plasma tHcy lower (P < or = 0.001) after the folate-rich and supplement interventions than after the exclusion diet. Plasma folate was significantly greater after supplementation than after the folate-rich diet, but there was no significant difference in tHcy concentration (P = 0.72). TT homozygotes had higher plasma tHcy (14.5 compared with 8.9 micromol/L, P < or = 0.001) and lower plasma folate (14.8 compared with 19.0 nmol/L, P < or = 0.01) than did subjects with the CC genotype after the exclusion diet. CT heterozygotes had intermediate concentrations. The trend toward higher tHcy in TT homozygotes persisted throughout the study but was less marked with increasing folate intake (TT compared with CC after supplementation, P = 0.097). CONCLUSIONS: A folate-rich diet including folic acid-fortified foods or low-dose supplements effectively increases folate status. TT homozygotes require higher folate intakes than do individuals with the CT or CC genotype to achieve similar tHcy concentrations but are responsive to folate intervention.     

Effect of the methylenetetrahydrofolate reductase 677C-->T mutation on the relations among folate intake and plasma folate and homocysteine concentrations in a general population sample

BACKGROUND: Methylenetetrahydrofolate reductase (MTHFR) is a key enzyme in folate and homocysteine metabolism. The common MTHFR 677C-->T polymorphism decreases the enzyme's activity. OBJECTIVE: The objective of the study was to assess the effect of the polymorphism on the relations among folate intake, plasma folate concentration, and total plasma homocysteine (tHcy) concentration. DESIGN: The design was a cross-sectional analysis in a random sample (n = 2051) of a Dutch cohort (aged 20-65 y). RESULTS: At a low folate intake (166 micro g/d), folate concentrations differed significantly among the genotypes (7.1, 6.2, and 5.4 nmol/L for the CC, CT, and TT genotypes, respectively; P for all comparisons < 0.05). At a high folate intake (250 microg/d), folate concentrations in CT and CC subjects did not differ significantly (8.3 and 8.6 nmol/L, respectively, but were significantly higher (P = 0.2) than those in TT subjects (7.3 nmol/L; P = 0.04). At a low folate concentration (4.6 nmol/L), TT subjects had a significantly higher (P = 0.0001) tHcy concentration than did CC and CT subjects (20.3 compared with 15.0 and 14.1 micromol/L, respectively), whereas at a high folate concentration (11.9 nmol/L), the tHcy concentration did not differ significantly between genotypes (P > 0.2; <13.1 for all genotypes). The relation between folate intake and tHcy concentration had a pattern similar to that of the relation between plasma folate and tHcy concentrations. CONCLUSIONS: At any folate intake level, TT subjects have lower plasma folate concentrations than do CT and CC subjects. Yet, at high plasma folate concentrations, tHcy concentrations in TT subjects are as low as those in CT and CC subjects.     

Effects of short-term folic acid and/or riboflavin supplementation on serum folate and plasma total homocysteine concentrations in young Japanese male subjects

OBJECTIVE: To investigate the effects of short-term folic acid and/or riboflavin supplementation on serum folate and plasma plasma total homocysteine (tHcy) concentrations in young Japanese male subjects. DESIGN: In a double blind, randomized controlled trial. INTERVENTION: Subjects were randomly assigned to one of four groups and received a placebo (control group), 800 microg/day folic acid (FA group), 8.4 mg/day riboflavin (R group), or both (FAR group) for 2 weeks. SETTING: Tokyo, Japan. SUBJECTS: In total, 32 healthy male volunteers aged 20-29 years. RESULTS: At the end of the 2 week supplementation period, the tHcy concentration decreased significantly in the FA group. Serum folate concentrations had increased between 2.7 and 2.0-fold in the FA and FAR groups, respectively, but the mean within-group changes in serum folate and plasma tHcy concentrations did not differ between these two groups. At the end of the study, alanine amino transferase was decreased in the R and FAR groups, while alanine amino transferase was increased in the FA group. CONCLUSION: Supplementation with folic acid, 800 microg/day, for 2 weeks, increased the serum and red blood cell folate concentrations and decreased the plasma tHcy concentrations in healthy young male subjects. Riboflavin supplementation may have blunted the effect of folic acid, which resulted in a diminished reduction of tHcy in our subjects.     

Plasma, liver and kidney folate and plasma homocysteine concentrations are poor response variables at very low dietary folate intakes, in a folate depletion/repletion rat model

Folate depletion/repletion rat models are popular protocols for assessing the bioavailability of folate. Much of the early work carried out on folate bioavailability concentrated on foods naturally high in folate. However, foods low in folate often contribute significantly to folate intake because of their high consumption in the general population. Therefore, the assessment of the bioavailability of foods low in folate is essential to properly estimate folate intake. The present study investigated plasma, liver and kidney folate and plasma homocysteine concentrations as appropriate response variables for measuring folate bioavailability in the rat at very low dietary folate intakes. One hundred and one weanling male rats (Wistar strain) were fed a folate-deficient diet containing 1% succinyl sulfathiazole for 28 d. Following depletion, six rats were randomly assigned to each of 16 repletion diets containing folic acid, fortified white bread, unfortified wholemeal bread or unfortified rye bread calculated to provide 6.25, 12.5, 18.75 and 25 micrograms folate/kg of each diet. After a further 28 d, plasma, liver and kidney folate concentrations were determined by microbiological assay. Plasma homocysteine was measured by HPLC as a functional indicator of folate status. Only a weak correlation was found between the response variables measured and dietary folate intake, indicating that this folate depletion/repletion rat model is not suitable for testing the response of rats fed diets containing very low levels of folate.     

Dietary folate intake, blood folate status, and urinary folate catabolite excretion in Korean women of childbearing age

This study assessed folate intake, folate concentrations in plasma and erythrocytes, plasma total homocysteine (tHcy) concentrations, and urinary excretion of folate metabolites in Korean women of childbearing age. A total of 36 women voluntarily participated in this study. Precise dietary intake for 3 consecutive days was determined by weighing all foods consumed, and folate intake was calculated with a computer-aided dietary analysis system. Folate concentrations in plasma and erythrocytes were determined via microbiological methods and in plasma by HPLC. Urine excreted over the same period of time was collected and assayed for folate catabolites, para-aminobenzoylglutamate (pABG) and para-acetamidobenzoylglutamate (ApABG) by reverse-phase HPLC after affinity chromatography. The mean folate intake was 206.9+/-90.8 mug DFE/d, and the mean concentrations in plasma and erythrocytes were 10.5+/-3.7 and 249.9+/-77.8 ng/mL, respectively. Erythrocyte folate concentration was low in 2.8% of the subjects (<140 ng/mL) and was marginal in 5.5% (140-156 ng/mL). The mean plasma tHcy concentration was 12.7+/-0.2 nmol/mL, and 11% of the subjects evidenced hyperhomocysteinemia (>/=15 nmol/mL). The mean urinary excretion levels of pABG and ApABG were 10.7+/-3.8 and 89.1+/-19.5 nmol/d, respectively. The means of folate reserve and folate turnover rate were 26.2+/-11.6 and 10.5+/-3.9, respectively. We noted positive relationships between folate intake and the folate concentrations in plasma and erythrocytes, as well as the urinary excretions of ApABG and total folate catabolites. In addition, the erythrocytic folate concentrations were positively associated with the urinary excretions of ApABG and total folate catabolites. In conclusion, the folate status of Korean women of childbearing age was marginally deficient with inadequate concentrations of erythrocyte folate and elevated plasma tHcy, largely due to insufficient folate intake. The marginally deficient folate status was confirmed by the low excretion of folate catabolites in urine.     

Racial differences in prevalence of cobalamin and folate deficiencies in disabled elderly women.

BACKGROUND: Many previous investigations of cobalamin and folate status were performed in white populations. OBJECTIVE: Our objective was to determine whether there are racial differences in the prevalence of cobalamin and folate deficiency. DESIGN: The study was a cross-sectional comparison of baseline serum cobalamin, folate, methylmalonic acid (MMA), total homocysteine (tHcy), and creatinine concentrations, complete blood count, and vitamin supplementation in 550 white and 212 African American subjects from a cohort of physically disabled older women. RESULTS: The mean (+/-SD) serum MMA concentration was significantly higher in whites than in African Americans: 284 +/- 229 compared with 218 +/- 158 nmol/L (P = 0.0001). tHcy concentration was higher in African Americans than in whites: 12.4 +/- 7.0 compared with 10.9 +/- 4.6 micromol/L (P = 0.001). Serum cobalamin was lower in whites (P = 0.0002). Cobalamin deficiency (serum cobalamin <258 pmol/L and MMA >271 nmol/L) was more frequent in the white women (19% compared with 8%; P < 0.0003). Folate deficiency (serum folate <11.4 nmol/L, tHcy >13.9 micromol/L, and MMA <271 nmol/L) was more prevalent in African Americans than in whites (5% compared with 2%; P = 0.01). Multivitamin use was associated with lower tHcy but not with MMA concentrations. Regression models showed that age >85 y, African American race, serum creatinine >90 micromol/L, and high MMA concentration were all significantly correlated with higher tHcy. Creatinine > 90 micromol/L, white race, and folate concentration were positively associated with MMA concentration. CONCLUSIONS: Cobalamin deficiency with elevated serum MMA concentration is more prevalent in elderly white than in African American women and elevated serum tHcy and folate deficiency are more prevalent in elderly African American than in white women.     

Unmetabolized folic acid in plasma is associated with reduced natural killer cell cytotoxicity among postmenopausal women

Folic acid (FA) supplements and food fortification are used to prevent neural tube defects and to lower plasma homocysteine. Through exposure to food fortification and vitamin supplement use, large populations in the United States and elsewhere have an unprecedented high FA intake. We evaluated dietary and supplemental intakes of folate and FA in relation to an index of immune function, natural killer cell (NK) cytotoxicity, among 105 healthy, postmenopausal women. Among women with a diet low in folate (<233 microg/d), those who used FA-containing supplements had significantly greater NK cytotoxicity (P = 0.01). However, those who consumed a folate-rich diet and in addition used FA supplements > 400 microg/d had reduced NK cytotoxicity compared with those consuming a low-folate diet and no supplements (P = 0.02). Prompted by this observation, we assessed the presence of unmetabolized FA in plasma as a biochemical marker of excess FA. Unmetabolized folic acid was detected in 78% of plasma samples from fasting participants. We found an inverse relation between the presence of unmetabolized FA in plasma and NK cytotoxicity. NK cytotoxicity was approximately 23% lower among women with detectable folic acid (P = 0.04). This inverse relation was stronger among women >or= 60 y old and more pronounced with increasing unmetabolized FA concentrations (P-trend = 0.002). Because of the increased intake of FA in many countries, our findings highlight the need for further studies on the effect of long-term high FA intake on immune function and health.     

Effect of increased vegetable and fruit consumption on plasma folate and homocysteine concentrations

OBJECTIVE: We assessed the effects of an intervention aimed at increasing the consumption of fruits and vegetables on plasma folate and homocysteine concentrations. METHODS: Seventy-one healthy non-smoking women (mean +/- SD 41 +/- 4 y of age) were randomized to an intervention or a control group. Participants in the intervention group (n = 36) received weekly packets containing fruits and vegetables free of charge and were asked to consume a daily amount of >or=200 g of vegetables and two pieces of fruit (the Dutch recommended intake level) over a period of 1 mo. Control subjects did not receive any intervention. RESULTS: Compared with the control group, reported fruit and vegetable intakes in the intervention group increased by 133 g/d (95% confidence interval [CI] 87-179, P < 0.001) for fruits and juice and 64 g/d (95% CI 37-91, P < 0.001) for vegetables and estimated folate intake from fruits and vegetables increased by 40 microg/d (95% CI 22-58, P < 0.001). However, no effect was observed on plasma folate concentrations (intervention effect 0.3 nmol/L, 95% CI -1.8 to 2.8, P = 0.77) or homocysteine concentrations (intervention effect 0.26 micromol/L, 95% CI -0.34 to 0.87, P = 0.39). CONCLUSION: The results suggest that 4 wk of increased fruit and vegetable consumption to the recommended amounts may be insufficient to change plasma folate and homocysteine concentrations.     

Homocysteine and folate as risk factors for dementia and Alzheimer disease

BACKGROUND: In cross-sectional studies, elevated plasma total homocysteine (tHcy) concentrations have been associated with cognitive impairment and dementia. Incidence studies of this issue are few and have produced conflicting results. OBJECTIVE: We investigated the relation between high plasma tHcy concentrations and risk of dementia and Alzheimer disease (AD) in an elderly population. DESIGN: A dementia-free cohort of 816 subjects (434 women and 382 men; mean age: 74 y) from an Italian population-based study constituted our study sample. The relation of baseline plasma tHcy to the risk of newly diagnosed dementia and AD on follow-up was examined. A proportional hazards regression model was used to adjust for age, sex, education, apolipoprotein E genotype, vascular risk factors, and serum concentrations of folate and vitamin B-12. RESULTS: Over an average follow-up of 4 y, dementia developed in 112 subjects, including 70 who received a diagnosis of AD. In the subjects with hyperhomocysteinemia (plasma tHcy > 15 micromol/L), the hazard ratio for dementia was 2.08 (95% CI: 1.31, 3.30; P = 0.002). The corresponding hazard ratio for AD was 2.11 (95% CI: 1.19, 3.76; P = 0.011). Independently of hyperhomocysteinemia and other confounders, low folate concentrations (< or = 11.8 nmol/L) were also associated with an increased risk of both dementia (1.87; 95% CI: 1.21, 2.89; P = 0.005) and AD (1.98; 95% CI: 1.15, 3.40; P = 0.014), whereas the association was not significant for vitamin B-12. CONCLUSIONS: Elevated plasma tHcy concentrations and low serum folate concentrations are independent predictors of the development of dementia and AD.     

Influence of folic acid-fortified foods on folate status in a folate depletion-repletion rat model

An increasing number of foods fortified with varying levels of folic acid are appearing in the market place, targeted either at the general population or at specific consumer groups. Although it is assumed that the folate in these products should be highly bioavailable, there is a need to carry out studies to ascertain that this is, in fact, the case. The present study investigated the ability of selected folic acid-fortified foods (targeted at different types of consumer) to increase the folate status of folate-deficient rats. Forty-two weanling male rats (Wistar strain) were fed a folate-deficient diet containing 1 % succinyl sulfathiazole (w/w) for 28 d. Following depletion, seven rats were randomly assigned to each of five repletion diets containing folic acid, Complan, Slim Fast, Opti-Fuel2 or Cola Coa calculated to provide 200 microg folate/kg of each diet. Calculations were based on folate information from the product labels. After a further 28 d, plasma, liver and kidney folate concentrations were determined by microbiological assay. Plasma homocysteine was measured by HPLC as a functional indicator of folate status. The folate content of the foods was measured by tri-enzyme extraction followed by microbiological assay. Our analyses suggest that there may be considerable inaccuracies on the part of the manufacturers in relation to the folate declarations on the product labels. Despite this, the four foods evaluated were highly effective in elevating plasma, liver and kidney folate and lowering plasma homocysteine concentrations in rats. These results lend support to the policy of food fortification with folic acid as a means of raising the folate status of the population, and in particular to the fortification of specific foods which may target areas of the population where increased folate status is most needed.     

Folate nutriture alters choline status of women and men fed low choline diets

Choline and folate share methylation pathways and, in studies of rats, were shown to be metabolically inter-related. To determine whether choline status is related to folate intake in humans, we measured the effect of controlled folate depletion and repletion on the plasma choline and phosphatidylcholine concentrations of 11 healthy men (33-46 y) and 10 healthy women (49-63 y) fed low-choline diets in two separate metabolic unit studies. Total folate intake was varied by supplementing low folate (25 and 56 microg/d for men and women, respectively) and low choline (238 and 147 mg/d for men and women, respectively) diets with pteroylglutamic acid for 2-6 wk following folate-depletion periods of 4-5 wk. The low folate/choline intakes resulted in subclinical folate deficiencies; mean plasma choline decreases of 28 and 25% in the men and women, respectively; and a plasma phosphatidylcholine decrease of 26% in the men (P < 0. 05). No functional choline deficiency occurred, as measured by serum transaminase and lipid concentrations. The decreases in choline status measures returned to baseline or higher upon moderate folate repletion and were more responsive to folate repletion than plasma folate and homocysteine. Feeding methionine supplements to the men did not prevent plasma choline depletion, indicating that folate is a more limiting nutrient for these methylation pathways. The results indicate that 1) choline is utilized as a methyl donor when folate intake is low, 2) the de novo synthesis of phosphatidylcholine is insufficient to maintain choline status when intakes of folate and choline are low, and 3) dietary choline is required by adults in an amount > 250 mg/d to maintain plasma choline and phosphatidylcholine when folate intake is low.     

Polymorphisms of key enzymes in homocysteine metabolism affect diet responsiveness of plasma homocysteine in healthy women

High plasma total homocysteine (tHcy), low dietary intake of folate and other B vitamins, and genetic polymorphisms related to metabolism of homocysteine may interactively contribute to the risk of cardiovascular disease. We investigated whether known mutations in genes regulating homocysteine metabolism affect the responsiveness of serum folate and plasma tHcy to high intake of natural folate from food. Healthy females (n = 37) aged 22-57 y volunteered to participate in a crossover dietary intervention with two 5-wk diet periods (low and high folate diets). Concentrations of serum and RBC folate, serum vitamin B-12 and plasma tHcy were measured at baseline and at the end of each diet period. The prevalences of C677T transition of methylenetetrahydrofolate reductase (MTHFR) gene, 844ins68 of cystathionine beta-synthase (CBS) gene and A2756G mutation of methionine synthase (MS) gene were determined. Compared with the low folate diet, the high folate diet increased the serum folate concentration by 85% (P < 0.001), 77% (P < 0.001) and 55% (P < 0.05) in the subjects with the genotypes C/C (n = 19), C/T (n = 13) and T/T (n = 5), respectively, of the MTHFR gene. Also, the plasma tHcy of the subjects with the genotypes C/C, C/T and T/T was decreased by 11% (P < 0.001), 15% (P < 0.01) and 18% (P < 0.05), respectively, during the high folate diet period. The subjects carrying the G2756 allele of the MS gene (n = 15) had a more extensive reduction (P < 0.05) of plasma tHcy during the high folate diet period than the subjects with the genotype A/A (n = 22). The 844ins68 of CBS gene did not affect plasma tHcy concentrations or diet responsiveness. In conclusion, diet responsiveness of plasma homocysteine may be genetically regulated.     

Oxidative stress in mothers who have conceived fetus with neural tube defects: the role of aminothiols and selenium

BACKGROUND & AIMS: Methionine metabolic impairment and selenium deficit have been associated to neural tube defects. The relationship between thiol metabolism and selenium is not well known. We assessed the status of aminothiols and selenium, as well as thiolic status and the amino acids involved in arginine synthesis in the case of selenium depletion and repletion, studying their relationship to neural tube defects. METHODS: We studied 44 women of 37 +/- 8 years (mean +/- SD) who had conceived fetuses with neural tube defects as cases; and 181 women of 39 +/- 7 years (mean +/- SD) with healthy children as controls. We determined selenium, vitamin B12, serum folates, plasma thiol compounds and amino acids. Homocysteine transsulfuration was assessed using total cysteine/total homocysteine ratio (tCys/tHcy), and selenium repletion cut-off value was 1.06 micromol/l (84 microg/l). RESULTS: Cases showed significantly lower levels (median) than controls of total homocysteine (P = 0.001), total cysteinylglycine (P < 0.001), selenium (P < 0.001) and tryptophane (P = 0.002); and higher tCys/tHcy levels (P < 0.001), glutathione (P = 0.008) and L-arginine (P = 0.001). Cases with selenium depletion (selenium < or = 1.06 micromol/l) had significantly higher levels than controls of cysteine (P = 0.010), glutathione (P = 0.005), tCys/tHcy (P < 0.001), and arginine (P = 0.004), but significantly lower levels than controls of tryptophane (P = 0.027), cysteinylglycine (P < 0.001) and folates (P < 0.001). Only cysteinylglycine was lower than controls (P < 0.001) when selenium > 1.06 micromol/l. Methionine levels were higher in cases with selenium depletion than in repletion (P = 0.029). CONCLUSIONS: According to our data, a diet deficient in selenium and folates or their absorption impairment, and/or other mechanisms related to polyamines and nitric oxide can lead to oxidant/antioxidant imbalance and to a higher occurrence of these malformations.     

Alcohol intake and methylenetetrahydrofolate reductase polymorphism modify the relation of folate intake to plasma homocysteine

BACKGROUND: Folate intake increases plasma folate and reduces total homocysteine (tHcy) concentrations, which may lower coronary artery disease (CAD) and cancer risks. Folate metabolism may be altered by alcohol intake and 2 common polymorphisms in the methylenetetrahydrofolate reductase (MTHFR) gene, 677C-->T and 1298A-->C. OBJECTIVE: We examined whether the associations between folate intake and plasma folate and tHcy concentrations were modified by alcohol intake or variations in the MTHFR gene. DESIGN: We conducted a cross-sectional analysis among 988 women by using multivariate linear regression models to estimate mean plasma tHcy and folate concentrations. Folate intake was the sum of food and supplemental sources. RESULTS: We observed an inverse association between folate intake and tHcy, which was modified by alcohol intake (P for interaction = 0.04) and MTHFR677 genotype (P for interaction = 0.05) but not by MTHFR1298 genotype (P for interaction = 0.97). In the lowest quintile of folate intake, moderate drinkers (>/=15 g alcohol/d) had significantly higher tHcy concentrations (15.2 +/- 2.9 nmol/mL) than did light drinkers (11.3 +/- 0.7 nmol/mL) and nondrinkers (11.0 +/- 0.8 nmol/mL). However, the reduction in tHcy between the highest and lowest quintiles of folate intake was significantly greater in moderate drinkers (-6.6 nmol/mL) than in light drinkers (-2.3 nmol/mL) and nondrinkers (-2.1 nmol/mL). The elevated tHcy in women with low folate intake who also consumed moderate amounts of alcohol was even higher (22.4 +/- 4.8 nmol/mL) in the presence of the variant MTHFR677 allele. The positive association between folate intake and plasma folate was somewhat modified by alcohol intake (P for interaction = 0.08) but not by either MTHFR genotype. CONCLUSIONS: Moderate alcohol intake and low MTHFR activity have adverse effects on tHcy, but those effects may be overcome by sufficient folate intake.