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Folic acid improves arterial endothelial function in adults with hyperhomocystinemia.

OBJECTIVES: To evaluate whether oral folic acid supplementation might improve endothelial function in the arteries of asymptomatic adults with hyperhomocystinemia. BACKGROUND: Hyperhomocystinemia is an independent risk factor for endothelial dysfunction and occlusive vascular disease. Folic acid supplementation can lower homocystine levels in subjects with hyperhomocystinemia; however, the effect of this on arterial physiology is not known. METHODS: Adults subjects were recruited from a community-based atherosclerosis study on healthy volunteers aged 40 to 70 years who had no history of hypertension, diabetes mellitus, hyperlipidemia, ischemic heart disease or family history of premature atherosclerosis (n = 89). Seventeen subjects (aged 54 +/- 10 years, 15 male) with fasting total homocystine levels above 75th percentile (mean, 9.8 +/- 2.8 micromol/liter) consented to participate in a double-blind, randomized, placebo-controlled and crossover trial; each subject received oral folic acid (10 mg/day) and placebo for 8 weeks, each separated by a washout period of four weeks. Flow-mediated endothelium-dependent dilation (percent increase in diameter) of the brachial artery was assessed by high resolution ultrasound, before and after folic acid or placebo supplementation. RESULTS: Compared with placebo, folic acid supplementation resulted in higher serum folate levels (66.2 +/- 7.0 vs. 29.7 +/- 14.8 nmol/liter; p < 0.001), lower total plasma homocystine levels (8.1 +/- 3.1 vs. 9.5 +/- 2.5 micromol/liter, p = 0.03) and significant improvement in endothelium-dependent dilation (8.2 +/- 1.6% vs. 6 +/- 1.3%, p < 0.001). Endothelium-independent responses to nitroglycerin were unchanged. No adverse events were observed. CONCLUSION: Folic acid supplementation improves arterial endothelial function in adults with relative hyperhomocystinemia, with potentially beneficial effects on the atherosclerotic process.

Administration, Oral↗

Endothelial function in post-menopausal women: effect of folic acid supplementation.

BACKGROUND: Higher than normal homocysteine levels are associated with an increased incidence of adverse cardiovascular events in post-menopausal women, perhaps via hyperhomocysteinaemia-induced vascular endothelial damage. Because folic acid supplementation reduces homocysteine levels, we attempted to evaluate whether folic acid supplementation may affect endothelial function in post-menopausal women. METHODS: Brachial artery flow-mediated dilatation (endothelium-dependent) and nitroglycerin-induced dilatation (endothelium-independent) before and after a methionine load were analysed in 15 healthy post-menopausal women. Plasma levels of folate, homocysteine, glucose, insulin and lipids were measured, as was blood pressure. All studies were repeated after 1 month supplementation with 7.5 mg/day of folic acid. RESULTS: After folate, endothelial function rose 37% over pre-folic acid supplementation value (P < 0.001), and flow-mediated dilation before folic acid was reduced by 62% subsequent to methionine loading (P < 0.0001); this reduction was still present after folic acid, but was only 19% (P < 0.001). Nitroglycerin-induced dilatation did not change in response to methionine loading before or after folic acid supplementation. Among the other cardiovascular risk factors studied, only high-density lipoprotein (HDL)-cholesterol and low-density lipoprotein (LDL)-cholesterol showed significant changes after folic acid supplementation, with a 6% increase (P < 0.03) and a 9% decrease (P < 0.03) respectively. CONCLUSIONS: Although preliminary, these results indicate that folic acid supplementation may improve endothelial function and lipid profile in post-menopausal women, thus contributing to reduce their cardiovascular risk.

Brachial Artery↗

Knowledge, use, and education regarding folic acid supplementation: continuation study of women in Colorado who had a pregnancy affected by a neural tube defect.

BACKGROUND: This study was conducted to: (1) determine whether women who have had a neural tube defect (NTD) affected pregnancy know about recommendations for NTD recurrence prevention; (2) educate them about the recommendations; and (3) ensure that they have access to folic acid prior to another pregnancy. METHODS: Colorado women who had an NTD affected pregnancy in 1999 or later were interviewed about their knowledge and use of folic acid, provided with verbal information about folic acid and NTD prevention, and offered written information and a voucher for free folic acid. RESULTS: Thirty-two of 68 women who had an NTD affected pregnancy were interviewed. Of these, 22 (69%) were aware of the 0.4 mg. folic acid recommendation for women of child bearing age who have not had an NTD affected pregnancy (MMWR, '91). Only 15 (47%) of the women knew about the U.S. Public Health Service recommendation (MMWR, '92) to consume 4.0 mg of folic acid prior to another pregnancy for NTD recurrence prevention. Twenty-five (78%) of the women reported taking a multivitamin or folic acid daily. CONCLUSIONS: Nine years after national folic acid recommendations, a majority of interviewed women (53%) with NTD affected pregnancies did not know about the recommendation to consume 4.0 mg of folic acid for NTD recurrence prevention. This sample of women are receptive to information about folic acid. Health care providers and public health officials should ensure that education about folic acid is provided in an effective and timely manner to women with NTD-affected pregnancies.

Colorado↗

Sparing effect of folic acid deficiency on the development of vitamin B12 deficiency in baboons fed a vitamin B12 deficient diet.

The effect of a vitamin B12 and folic acid deficient diet on juvenile and adolescent baboons (Papio cynocephalus anubis) was studied. The baboons developed clinical and hematological signs characteristics of folacin deficiency, although they were less severe in juvenile baboons. The signs disappeared when folic acid was replaced in the diet. The serum vitamin B12 levels increased in all baboons fed the vitamin B12 and folic acid deficient diet. When folic acid was added to the diet, the levels gradually decreased in adolescent baboons, liver vitamin B12 levels decreased to a lesser extent when fed a vitamin B12 and folic acid deficient diet than when fed a vitamin B12 deficient diet. In juvenile baboons fed a vitamin B12 and folic acid deficient diet, for 7 months and a vitamin B12 deficient diet for a further 11 months, liver vitamin B12 levels did not decrease at any time but were similar to those in baboons fed a vitamin B12 and folic acid supplemented diet.

Aging↗

Folic acid knowledge and use among expectant mothers in 1997: a comparison with 1996.

This study examined changes in folic acid knowledge and use among antenatal women in Dublin maternity hospitals between 1996 and 1997, following a campaign to improve the very low uptake of peri-conceptional folic acid. The results showed significant improvements between the two years. Almost 76% of respondents had heard of folic acid in 1997 compared with 54% in 1996 (p < 0.01), with a shift in the proportion of people hearing of folic acid from hospital doctors to general practitioners (GP). Almost 43% of respondents in 1997 knew that folic acid can prevent spina bifida compared with 21% in 1996 (p < 0.01). A higher proportion was taking folic acid prior to conception in 1997 (16% vs 6%, p < 0.01). We conclude that the improvements may have been in part due to the promotional campaign among health professionals, women's groups and the media. However, less than a fifth of women were taking folic acid peri-conceptionally in 1997 and there is still scope for much improvement.

Adult↗

[Radioimmunological determination of the serum level of folic acid in healthy persons and patients treated by periodic hemodialysis].

Folic acid serum level was assayed in 31 patients with chronic renal insufficiency, hemodialysis-treated. Decreased level was established in 9 patients (30%). The average value of serum folic acid was 5.24 ng/ml (11.8 nmol/l) with a norm of 5.79 ng/ml (13.1 nmol/l) in the control group. No statistically significant difference was found between the healthy subjects and the patients. A low correlation dependence was found between serum folic acid level and the duration of hemodialysis treatment and diuresis. No statistically significant difference was established in the value of the folic acid in the patients on dialysis two or three times weekly. The irrational nutrition was concluded by the authors, to play a more significant role in the present disturbed folic homeostasis than the hemodialysis treatment per se.

Diuresis↗

Bioavailability of heptaglutamyl relative to monoglutamyl folic acid in healthy adults.

BACKGROUND: The bioavailability of dietary folate has been estimated to be approximately 50% of that of synthetic folic acid. Folate in the diet is linked to a polyglutamate chain that may restrict folate absorption. OBJECTIVE: Our goal was to quantify the bioavailability and bioefficacy of low doses of polyglutamyl folic acid relative to that of monoglutamyl folic acid. DESIGN: In total, 180 men and women aged 50-75 y ingested capsules containing 323 nmol heptaglutamyl folic acid/d or 262 nmol monoglutamyl folic acid/d or placebo in a randomized parallel trial. Serum and erythrocyte folate and plasma homocysteine concentrations were measured after an overnight fast at baseline and after 12 wk of intervention. RESULTS: Mean serum and erythrocyte folate concentrations increased less in the polyglutamyl folic acid group [6.1 (95% CI: 5.3, 7.0) and 155 (122, 188) nmol/L, respectively] than in the monoglutamyl folic acid group [11.8 (10.3, 13.3) and 282 (246, 318) nmol/L, respectively]. Differences remained statistically significant (P < 0.05) after correction for the difference in the amount of folic acid administered. The decrease in plasma homocysteine concentrations did not differ significantly between treatment groups [polyglutamyl: -12.1% (-14.8%, -9.3%); monoglutamyl: -14.1% (-16.3%, -11.9%)]. The relative bioavailability of polyglutamyl folic acid was 64% (52%, 75%) on the basis of serum folate and was 68% (51%, 84%) on the basis of erythrocyte folate concentrations. Bioefficacy, determined by changes in plasma homocysteine concentrations, was 106% (77%, 134%). CONCLUSION: The polyglutamate chain of folates in the diet reduces their bioavailability.

Administration, Oral↗

Are women with recent live births aware of the benefits of folic acid?

Each year, approximately 4,000 pregnancies result in spina bifida or anencephaly, serious and often fatal conditions for the newborn. The B vitamin folic acid can reduce the incidence of these conditions by 50%-70%. To examine folic acid awareness among women who had recently delivered a live-born infant, CDC analyzed Pregnancy Risk Assessment Monitoring System (PRAMS) data for 1995-1998. The question used to measure awareness was, "Have you ever heard or read that taking the vitamin folic acid can help prevent some birth defects?" During the study period, overall folic acid awareness increased 15%, from 64% in 1996 to 73% in 1998, although changes varied by state. Despite this increase, differences in folic acid awareness were observed among different groups of women. Women who obtained a high school education or less; who were black, Hispanic, or from other racial/ethnic groups; who entered prenatal care after the first trimester; and whose pregnancies were unintended were less aware of folic acid. This study indicates that gaps persist among women in low socioeconomic groups. Overall, PRAMS data indicated an increase in folic acid awareness among women with recent deliveries. However, this awareness might be too late for the pregnancy that has occurred, indicating a continued need to educate all reproductive-aged women regarding the need to take folic acid before they become pregnant.

Dietary Supplements↗

The effect of folic acid deficiency and MTHFR C677T polymorphism on chromosome damage in human lymphocytes in vitro.

We performed a comprehensive study on the genotoxic and cytotoxic effects of in vitro folic acid deficiency on primary human lymphocytes. Lymphocytes were cultured in medium containing 12-120 nM folic acid for 9 days in a novel cytokinesis-block micronucleus (CBMN) assay system (n = 20). Besides identifying optimal folic acid concentrations for in vitro genomic stability, we tested the hypothesis that lymphocytes from individuals homozygous for the C677T methylenetetrahydrofolate reductase (MTHFR) polymorphism (TTs, n = 10) are protected against chromosome damage relative to controls (CCs, n = 10) under conditions of folic acid deficiency. This hypothesis is based on the assumption that reduced MTHFR activity in TT lymphocytes causes a diversion of 5,10-methylene tetrahydrofolate toward thymidine synthesis, which minimizes uracil-induced double-stranded DNA breakage. Cells were scored for micronuclei, apoptosis, necrosis, nucleoplasmic bridges, and nuclear budding. The latter two endpoints are indicative of chromosome rearrangements and gene amplification, respectively, and to the best of our knowledge, this is the first report of their association with folic acid concentration. Folic acid concentration correlated significantly (P < 0.0001) and negatively (r, -0.63 to -0.74) with all markers of chromosome damage, which were minimized at 60-120 nM folic acid, much greater than concentrations assumed "normal," but not necessarily optimal in plasma. Two-way ANOVA revealed no effect of the MTHFR genotype on any of the endpoints. Results show that the C677T polymorphism does not affect the ability of a cell to resist chromosome damage induced by folic acid deficiency in this in vitro system.

Analysis of Variance↗

Folic acid supplementation diminishes diabetes- and glucose-induced dysmorphogenesis in rat embryos in vivo and in vitro.

Maternal administration of folic acid diminishes the risk of neural tube defects (NTDs) in offspring, but whether folic acid exerts a similar effect in diabetic pregnancy is unknown. The aim was to investigate whether maldevelopment in rat embryos caused by exposure to diabetes in vivo or high-glucose concentrations in vitro is affected by subcutaneous administration of folic acid to the pregnant mother or by adding the compound to the culture medium, respectively. Exposure of embryos to maternal diabetes in vivo or 30 mmol/l glucose in vitro yielded an increased malformation rate (71 and 88% NTD, respectively) and lowered somite number and crown-rump length compared with control embryos. When we injected folic acid into the diabetic pregnant rat, or added 2 mmol/l folic acid to the culture medium with high glucose, the embryonic parameters improved (3 and 5% NTD, respectively). The present work shows that administration of folic acid can diminish diabetes-induced maldevelopment. This suggests that folic acid supplementation may have a role in the prevention of malformations in diabetic pregnancy.

Animals↗

Does the use of folic acid increase the risk of twinning?

The increased rates of twinning and the increased consumption of folic acid are two parallel processes described in recent years. However, the possible association between an increased incidence of twin pregnancies and periconceptional folic acid supplementation remains controversial. Whereas the data indicating that when folic acid levels are increased to the range required for reducing the incidence of neural tube defects, the data pertaining to the increase in twinning rate are significantly incoherent and are flawed by serious confounders, such as fertility treatments and maternal age. The only plausible theory connecting methyltetrahydrofolate reductase mutation, folic acid, and twinning has not been confirmed. In addition, temporal and dose-effect relationships have not been established. Because of the lack of coherence, questionable plausibility, and no clear dose-effect and temporal relationships, a cause (folic acid supplementation) and effect (increased twinning rate) association cannot be, at present, accepted. Thus, the established policy of peri-conceptional folic acid supplementation to reduce the incidence of neural tube defects should be continued.

Adult↗

Chemopreventive effects of rofecoxib and folic acid on gastric carcinogenesis induced by N-methyl-N'-nitro-N-nitrosoguanidine in rats.

OBJECTIVES: Epidemiological and experimental studies indicate that non-steroidal anti-inflammatory drugs (NSAIDs) are chemopreventive agents of gastrointestinal cancers, but few studies on gastric cancer have been carried out. A decrease in folic acid supplement and subsequent DNA hypomethylation are related to gastrointestinal cancers, and it has been shown that high-dose folic acid may interfere with gastric carcinogenesis in dogs. The objective of this study was to investigate the effects of rofecoxib, a selective cyclooxygenase-2 (COX-2) inhibitor, and folic acid on the chemoprevention of gastric cancer induced by N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) in Wistar rats, and to evaluate the cell proliferation of gastric mucosa in different experimental groups. METHODS: Eighty male Wistar rats were randomly divided into five groups (16 rats in each group). In the control group, the rats were given pure water and basal diet. In the MNNG group, the rats received MNNG in drinking water (100 mg/L) and basal diet. In the MNNG + low-dose rofecoxib group, the rats were given MNNG and rofecoxib 5 mg/kg per day with basal diet. In the MNNG + high-dose rofecoxib group, the rats were given MNNG and rofecoxib 15 mg/kg per day with basal diet. In the MNNG + folic acid group, the rats were given MNNG and folic acid 5 mg/kg per day with basal diet. The experiment was terminated at 50 weeks, and all rats were killed. Blood samples of 3 mL were obtained for measurement of serum folic acid concentrations in the control group, the MNNG group and the MNNG + folic acid group by using chemiluminescent method. The stomach was removed from all rats for histopathological examination and immunohistochemical study. Proliferating cell nuclear antigen (PCNA) expression in gastric epithelial cells was also determined. RESULTS: In the MNNG group, five of 11 rats (45.5%) developed gastric cancer, while in all other four groups no gastric cancer was found (P < 0.05). The positivity rate of PCNA expression in the cancerous tissues was significantly higher than that in the non-cancerous tissues (80.0%vs 14.1%, P < 0.05). The positivity rate of PCNA expression in the gastric mucosal cells of the MNNG group was significantly higher than that in the other four groups. The mean serum folic acid concentration of rats was significantly higher in the MNNG + folic acid group (193.70 +/- 60.73 ng/mL) than those in the control group (84.21 +/- 25.26 ng/mL) and the MNNG group (72.27 +/- 16.70 ng/mL, P < 0.05). It was shown that both low- and high-dose rofecoxib as well as folic acid interfered with the development of gastric cancer induced by MNNG in Wistar rats. CONCLUSIONS: The results indicate that rofecoxib as well as folic acid interferes with gastric carcinogenesis induced by MNNG in Wistar rats, and the suppression of gastric cell proliferation may play a crucial role in the chemoprevention of gastric cancer by rofecoxib and folic acid. The higher serum folic acid concentration of rats may play an important role in the prevention of gastric cancer.

Adenocarcinoma↗

Comparative effects of intestinal absorption of folic acid and methyltetrahydrofolic acid in chronic ethanol-fed rats.

This study concerns in vivo folic acid and methyltetrahydrofolic acid (MTHF) absorption by the whole intestinal surface after 20 weeks of 30% ethanol ingestion in drinking water. The results were compared with control rats fed ad libitum. The total intestinal serosal areas were similar in ethanol-fed and control rats. Significant increases in intestinal length, and decreases in tissue wet and dry weights were found in ethanol-fed rats. Serum folic acid concentrations were significantly less in the animals which had ingested ethanol than in the control rats. Intestinal folic acid absorption was significantly increased at lower substrate concentrations (0.5 and 1 microM), while no difference was observed at 2.5 microM in the ethanol-fed rats. Folic acid absorption relative to tissue wet weight showed significant increases at all tested concentrations in the ethanol-fed rats. Intestinal MTHF absorption showed no significant changes at 0.5 microM MTHF concentration, and an increase was observed in the absorption values at 1 and 2.5 microM concentrations in the ethanol-fed rats. When expressed as tissue wet weight, MTHF absorption values in ethanol-fed rats increased at 1 and 2.5 microM but did not differ at 0.5 microM substrate concentrations. The above results indicate compensatory responses in the folic acid and MTHF intestinal absorption after chronic ethanol ingestion. These effects are observed when the whole intestinal surface is evaluated.

Animals↗