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PubMedDate not supplied

Hyperhomocysteinemia in children with juvenile idiopathic arthritis is not influenced by methotrexate treatment and folic acid supplementation: a pilot study.

OBJECTIVE: Our first objective was to compare plasma total homocysteine (tHcy) concentrations in juvenile idiopathic arthritis (JIA) patients requiring methotrexate (MTX) treatment and healthy children. Our second aim was to evaluate the influence of low-dose (10-15 mg/m2/week) MTX treatment combined with folic acid supplementation (1 mg/d) or placebo on tHcy concentrations in JIA patients. METHODS: In 17 JIA patients and 17 age- and sex-matched healthy children, baseline tHcy concentrations were measured. When MTX treatment was initiated, JIA patients were randomly assigned to folic acid 1 mg/d/p.o. followed by placebo (8 weeks each) or vice versa. Blood samples for measurement of tHcy, vitamin B6, B12 and folate were taken after 4 weeks, 12 weeks and 20 weeks of treatment. RESULTS: 1) In the healthy children the mean tHcy concentration was 6.3 +/- 1.68 mumol/l as compared to 9.99 +/- 5.17 mumol/l in JIA patients (p < 0.04). At baseline, 5/17 JIA patients had tHcy concentrations > 10.5 mumol/l, the 99th percentile for teenagers. 3/5 patients even exceeded the upper normal level for adults (tHcy > or = 15 mumol/l). MTX treatment did not result in a significant increase of tHcy and folic acid supplementation had no significant impact on tHcy levels. CONCLUSION: This pilot study shows that patients with JIA requiring MTX treatment have significantly elevated baseline plasma tHcy concentrations compared to age- and sex-matched healthy controls. No significant impact of MTX and folate supplementation on tHcy concentration was found.

Adolescent↗
PubMed1983

Folic acid and chromosome breakage. I. Implications for genotoxicity studies.

Chromosome breakage is significantly lower in culture medium containing folic acid than in medium that does not. This effect is similar to that observed in studies of chromosome fragile sites and suggests that fragile sites and some types of chromosome breakage may share a common mechanism. It also suggests that high non-physiological levels of folic acid in many commonly used culture media may artifactually decrease chromosome breakage.

Cells, Cultured↗
PubMed2004

Inhibition of the rat breast cytosolic bioactivation of ethanol to acetaldehyde by some plant polyphenols and folic acid.

There is a well-established association between alcohol consumption and breast cancer risk. About 4% of the breast cancers in developed countries are estimated to be attributable to drinking alcohol. The mechanism of tumor promotion by alcohol remains unknown. Recent studies from our laboratory and others showed the ability of mammary tissue to bioactivate ethanol to mutagenic/carcinogenic acetaldehyde and free radicals. Xanthine oxidoreductase (XOR) is an enzyme involved in those biotransformation processes. In the present study, we provide evidence of the ability of different natural polyphenols and of folic acid derivatives to inhibit the biotransformation of alcohol to acetaldehyde by rat breast cytosolic XOR. Folic acid and dihydrofolic acid, at concentrations of 10 microM, inhibited 100% and 84%, respectively, of the cytosolic acetaldehyde formation. Thirty-five polyphenols were tested in these initial experiments: ellagic acid, myricetin, quercetin, luteolin, and apigenin inhibited 79-95% at 10 microM concentrations. The remaining polyphenols were either less potent or noninhibitory of acetaldehyde formation at similar concentrations in these screening tests. Results are relevant to the known preventive effects of folic acid against alcohol-induced breast cancer and to their potential preventive actions if added to foods or alcoholic beverages.

Acetaldehyde↗
PubMed2005

Role of vitamins B6, B12 and folic acid on hyperhomocysteinemia in a Pakistani population of patients with acute myocardial infarction.

BACKGROUND AND AIM: Pakistani people belong to an ethnic group which has the highest rate of coronary artery disease (CAD). We investigated the possible correlation between deficiency of vitamins B6, B12 or folic acid and hyperhomocysteinemia in Pakistani patients with acute myocardial infarction (AMI). A case-control study was carried out involving 224 AMI patients (age 30-70 years; 55 females and 169 males) and 126 normal healthy subjects (age 31-70 years; 35 females and 91 males). METHODS AND RESULTS: Fasting venous blood was obtained from cases and controls. Serum was analyzed for folic acid and B12 using radioassays. Plasma was analyzed for pyridoxal phosphate (PLP; coenzymic form of B6) using a radioenzymatic assay and for total homocysteine using a fluorescence polarization immunoassay. Mean serum B12 concentration in AMI patients was found to be significantly lower than the mean for controls (241+/-185 pg/ml vs 608+/-341 pg/ml; p < 0.001). Mean serum folate level in patients was also found to be lower than controls (3.35+/-3.78 ng/ml vs 4.93+/-2.93 ng/ml), however, the differences were not statistically significant. Similarly, mean PLP concentration in plasma of cases (19.4+/-24.4 nmol/l) was lower than the concentration in controls (23.2+/-17.6 nmol/l), but the difference was not statistically significant. Mean plasma homocysteine level in AMI cases (18+/-8.36 micromol/l) was higher than the mean level in controls (16.4+/-4.9 micromol/l), but not to a significant extent. However, this mean homocysteine concentration in normal healthy subjects was among the highest reported in the literature and was significantly more than mean values reported in most Eastern and Western studies. Compared to controls, there was significantly greater deficiency of folate (32.5% vs 67.1%), B12 (3.2% vs 63.4%) and PLP (49.2% vs 74.1%) in AMI patients. Deficiencies of folate, B12 and PLP were defined as serum folate levels less than 3.5 ng/ml, serum levels of B12 less than 200 pg/ml and plasma PLP levels less than 20 nmol/l. Mean plasma homocysteine levels in smokers were found to be significantly higher in both cases and controls. Similarly, mean serum folate levels in smokers (compared to nonsmokers) were significantly lower in both cases and controls. CONCLUSIONS: Substantial nutritional deficiencies of these three vitamins along with mild hyperhomocysteinemia, perhaps through an interplay with the classical cardiovascular risk factors (highly prevalent in this population), could be further aggravating the risk of CAD in the Pakistani population.

Adult↗
PubMed2006

Rationale, design and baseline characteristics of a large, simple, randomized trial of combined folic acid and vitamins B6 and B12 in high-risk patients: the Heart Outcomes Prevention Evaluation (HOPE)-2 trial.

BACKGROUND: Epidemiological studies suggest that mild to moderate elevation in plasma homocysteine concentration is associated with increased risk of atherothrombotic cardiovascular (CV) disease. Simple, inexpensive and nontoxic therapy with folic acid and vitamins B6 and B12 reduces plasma homocysteine levels by approximately 25% to 30% and may reduce CV events. Therefore, a large, randomized clinical trial--the Heart Outcomes Prevention Evaluation (HOPE)-2 study--is being conducted to evaluate this therapy in patients at high risk for CV events. OBJECTIVES: To evaluate whether long-term therapy with folic acid and vitamins B6 and B12 reduces the risk of major CV events in a high-risk population. The primary study outcome is the composite of death from CV causes, myocardial infarction and stroke. METHODS: A total of 5522 patients aged 55 years or older with pre-existing CV disease or with diabetes and additional risk factor(s) at 145 centres in 13 countries were randomly assigned to daily therapy with combined folic acid 2.5 mg, vitamin B6 50 mg and vitamin B12 1 mg, or to placebo. Follow-up will average five years, to be completed by the end of 2005. RESULTS: The patients' baseline characteristics confirmed their high-risk status. Baseline homocysteine levels varied between countries and regions. HOPE-2 is one of the largest trials of folate and vitamins B6 and B12 and is expected to significantly contribute to the evaluation of the role of homocysteine lowering in CV prevention.

Aged↗
PubMedDate not supplied

Folic acid: nutritional biochemistry, molecular biology, and role in disease processes.

This paper reviews the chemistry, metabolism, and molecular biology of folic acid, with a particular emphasis on how it is, or may be, involved in many disease processes. Folic acid prevents neural tube defects like spina bifida, while its ability to lower homocysteine suggests it might have a positive influence on cardiovascular disease. A role for this B vitamin in maintaining good health may, in fact, extend beyond these clinical conditions to encompass other birth defects, several types of cancer, dementia, affective disorders, Down's syndrome, and serious conditions affecting pregnancy outcome. The effect of folate in these conditions can be explained largely within the context of folate-dependent pathways leading to methionine and nucleotide biosynthesis, and genetic variability resulting from a number of common polymorphisms of folate-dependent enzymes involved in the homocysteine remethylation cycle. Allelic variants of folate genes that have a high frequency in the population, and that may play a role in disease formation include 677C --> T-MTHFR, 1298A --> C-MTHFR, 2756A --> G-MetSyn, and 66A --> G-MSR. Future work will probably uncover further polymorphisms of folate metabolism, and lead to a wider understanding of the interaction between this essential nutrient and the many genes which underpin its enzymatic utilization in a plethora of critical biosynthetic reactions, and which, under adverse nutritional conditions, may promote disease.

Biological Transport, Active↗
PubMed1983

[Effect of folic acid on 35S-methionine transport in vitro].

The experiments were carried out with 4-week-old broiler birds given a ration that was balanced in terms of basic nutrients. Following decapitation inverted intestinal sacs were prepared from the proximal part of the jejunum the incubation of which lasted 40 min. To elucidate the effect of folic acid on the transport of 35S-methionine the acid was used in a conc. of 4 X 10(-6). Studied was also the effect of replacing the sodium ion (148 mEq/l) in the incubation solution with equivalent amount of the potassium ion, and the incorporation into the same solution of monoiodine-acetic acid (10(-3)M) as it affects the transmembrane transport of methionine. The flasks with the sacs of each group of birds contained 10microCi 35S-methionine each. The content of cyclic 3', 5'-adenosine-monophosphate (cAMP), the SH-groups, and the activity of alkaline phosphatase in the jejunal mucosa were determined. Results showed that folic acid at 4 X 10(-6)M stimulated dependably both the transport and the incorporation of 35S-methionine into the erythrocytes. These processes were inhibited when monoiodine-acetic acid at 10(-3)M was added to the incubation solution. Identic negative effect was produced also when K+ was used instead of Na+. Folic acid was said to raise the content of cAMP, SH-groups, and the activity of alkaline phosphatase in the jejunal mucosa.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed2006

Effect of folic acid treatment on carotid intima-media thickness of patients with coronary disease.

BACKGROUND: Carotid intima-media thickness (CIMT) is a surrogate marker of cardiovascular morbility. Hyperhomocysteinemia, which is an independent cardiovascular risk factor, is associated with low folate levels. The aim of this study was to evaluate the effect of folic acid treatment on the evolution of CIMT in patients with coronary disease and homocysteinemia > or =9 micromol/l. METHODS: In 137 consecutive patients with coronary disease treated with statins and normal vitamin B12 values, a randomized treatment with open-label folic acid 2.5 mg/day (group A) or not (group B) was performed during 3 years. CIMT was evaluated by two-dimensional ultrasonography baseline and at the final of the study. RESULTS: Clinical, biochemical parameters and CIMT were similar in both groups of patients. Homocysteine levels decreased (12.4+/-3.4 vs. 10.3+/-2.4 micromol/l; p<0.001) in group A, but not in group B. CIMT did not change neither in group A (0.71+/-0.23 vs. 0.69+/-0.20 mm; p=0.34) nor in group B (0.74+/-0.23 vs. 0.72+/-0.29 mm; p=0.39). In 12 patients of group A with methylenetetrahydrofolate reductase (MTHFR) 677TT mutation a decrease of CIMT was found (0.83+/-0.35 vs. 0.72+/-0.27 mm; p=0.02), but a multiple linear regression only showed a trend to the association between CIMT changes and MTHFR 677TT (p=0.051), probably due to the small number of patients with this mutation. CONCLUSIONS: Long-time treatment with folic acid in patients with coronary disease and normal values of vitamin B12 decreases homocysteine levels. A CIMT decrease is observed in treated patients with MTHFR 677TT mutation.

Aged↗
PubMed1996

[Folic acid and cervix dysplasia].

The localized folate deficiency, which is sometimes misdiagnosed as cervical dysplasia, because of morphological similarities between the cytologic features of megaloblastosis seen with folate deficiency and the changes associated with dysplasia, could be a component of the dysplastic process. In this study we attempted the effect of oral folic in women with cervical dysplasia. A total of 154 subjects with grade 1 or 2 CIN were randomly assigned either 10 mg of folic acid or a placebo daily for 6 months. Clinical status, human papillomavirus type 16 infection and blood folate levels were monitored at 2 month intervals. After 6-months no significant differences were observed between supplemented and unsupplemented subjects regarding dysplasia status, biopsy results, or prevalence of human papillomavirus type 16 infection. Folate deficiency the initiation of cervical dysplasia, but folic acid supplements do not alter the course of established disease.

Administration, Oral↗
PubMed1992

Alterations in nucleotide pools in rats fed diets deficient in choline, methionine and/or folic acid.

The fidelity of DNA synthesis is critically dependent on the correct balance and availability of the deoxynucleoside triphosphate (dNTP) precursors for the polymerases involved in replication and repair. Since folate-derived one-carbon groups are essential for the de novo synthesis of both purines and pyrimidines, the purpose of the present investigation was to determine whether diet-induced depletion of folates would alter intracellular dNTP pools. Fischer 344 rats were fed one of four semi-purified diets for a period of 8 weeks: (i) supplemented control; (ii) deficient in folic acid; (iii) deficient in methionine and choline; and (iv) deficient in methionine, choline and folic acid. In contrast to natural diets, semi-purified diets are nucleotide-free and consequently lack substrates for salvage pathway synthesis. This omission may place unusual stress on folate-dependent de novo nucleotide synthesis especially under conditions of dietary methyl-donor deficiency. Reversed-phase HPLC analysis of dNTP in spleen cell extracts indicated that both the thymidylate monophosphate and thymidylate triphosphate pools were decreased in spleen cells from the deficient rats consistent with a decrease in folate-dependent de novo synthesis. In addition, purine biosynthesis appeared to be negatively affect by methyl-donor deficiency as evidenced by a reduction in dGTP and dATP pools. These data indicate that deoxynucleotide pool imbalance, well known to produce cytogenetic and mutagenic events in vitro, can also be induced in this in vivo model of diet-induced carcinogenesis.

Animals↗
PubMed2006

Efficacy of folic acid therapy for prevention of in-stent restenosis: a randomized clinical trial.

BACKGROUND: It is known that there is an association between elevated total plasma homocysteine level and restenosis after percutaneous coronary angioplasty. OBJECTIVE: To evaluate the effect of lowering plasma homocysteine levels on the rate of restenosis after stent-percutaneous coronary angioplasty. METHODS: Folic acid (1 mg) or placebo was administered to 200 patients (mean +/- SD age of 54 +/- 9 years) for 3 months, after successful coronary angioplasty in a double-blind randomized clinical trial. The primary end point was restenosis within six months, as assessed by quantitative coronary angiography after positive exercise tolerance test. The secondary end point was a composite of major cardiac events. RESULTS: Base line characteristics and initial angiographic results after stent-percutaneous coronary angioplasty were similar in the two study groups. The rate of restenosis showed no significant difference in the two groups (5% in placebo vs. 10% in folic acid groups; P = 0.141), as there was the need for revascularization of the target lesion (4% in both groups; P = 0.766). CONCLUSION: Treatment with folic acid does not decrease the rate of restenosis and need for revascularization of the target lesion after stent-percutaneous coronary angioplasty.

Coronary Angiography↗
PubMed1996

The effect of folic acid on the homocysteine metabolism in human umbilical vein endothelial cells (HUVECs).

Mild hyperhomocysteinaemia is associated with increased risk for vascular disease. We studied homocysteine export from human umbilical vein endothelial cells (HUVECs) by measuring total homocysteine (tHcy) concentrations in the culture medium. Under standard culture conditions tHcy concentrations in the HUVEC culture medium increased by constant amounts after 24, 48 and 72 h [mean = 2.5 (SD +/- 0.7) mumol L-1 homocysteine every 24 h]. As the cells are the only source of homocysteine increase in the culture medium, we designate this as homocysteine export from HUVEC. Folic acid supplementation to the culture medium lowered the homocysteine export in a dose-dependent manner. Methyl-tetrahydrofolate (MeTHF) and folinic acid (a stable precursor of MeTHF) were in this respect about 10 times more effective than folic acid. A 50% reduction in the homocysteine export was seen with 10-30 nmol L-1 MeTHF supplementation; reduction to almost zero was seen with 100-300 nmol L-1 MeTHF. Additions to the culture medium of the other vitamins involved in the homocysteine metabolism, such as vitamin B12, vitamin B6 and flavin adenine dinucleotide, did not show any effect on homocysteine export. Because homocysteine export reflects an imbalance in the homocysteine metabolism, our observations showed a susceptible dependency of this metabolism on folic acid in endothelial cells.

Cells, Cultured↗
PubMedDate not supplied

Folic acid--the scientific debate as a base for public health policy.

Randomized controlled trials have proven that periconceptional folic acid intake reduces the risk of neural tube defects (NTDs). This lead to different public health policies: fortification of foods in many countries and supplementation in some others. We concentrate here on pro's and con's of fortification policies. Meanwhile, new beneficial but also potential adverse effects are being hypothesized. Highest level evidence is available for the protective effect of folic acid on NTDs. Lower level evidence suggests other protective effects, but also some potential adverse effects, such as masking Vitamin B-12 deficiency, increasing twinning rates and an 'acceleration phenomenon' in pre-existing malignant neoplasms. While observational studies show lower cancer rates associated with increased folate intake, some case reports and animal experiments suggest opposite effects. Thus, public health policy makers are facing the question of balancing beneficial and potential adverse effects repeatedly. We propose that the scientific debate no longer focuses on NTDs alone, but that a comprehensive evaluation be undertaken by a public health authority with experience in complex meta-analyses and technology assessment.

Adult↗
PubMed2000

Effects of supplementation with folic acid and antioxidant vitamins on homocysteine levels and LDL oxidation in coronary patients.

Hyperhomocysteinemia is an important cardiovascular risk factor. Serum homocysteine levels are specially dependent on folate nutritional status. In addition, the oxidative modification of low-density lipoproteins (LDLs) in the endothelial microenvironment is a damaging factor that can be modified with fat-soluble antioxidant vitamins. The present study was done to assess the effect of a supplementation of folic acid and antioxidant vitamins on homocysteine levels and in vitro LDL oxidation in patients with coronary artery disease. Twenty-three patients with angiographically proven coronary artery disease were given supplements for 15 d consisting of one capsule twice a day of a multivitamin preparation containing 0.65 mg folic acid, 150 mg alpha-tocopherol, 150 mg ascorbic acid, 12.5 mg beta-carotene, and 0.4 microgram vitamin B12. Serum lipids, vitamin and homocysteine levels, and in vitro LDL oxidation were measured before and after the supplementation period. During the supplementation period, serum folate levels increased from 5.0 +/- 1.5 to 10.8 +/- 3.8 ng/mL (P < 0.001), vitamin B12 increased from 317.4 +/- 130.4 to 334.5 +/- 123.8 pg/mL (P < 0.05), and alpha-tocopherol increased from 8.2 +/- 5.1 to 13.7 +/- 7.9 mg/L (P < 0.001). Serum homocysteine levels decreased from 8.7 +/- 4.3 to 6.3 +/- 2.2 mumol/L (P < 0.001). In vitro LDL oxidation decreased from 2.6 +/- 1.1 to 1.6 +/- 1.1 nmol malondialdehyde/mg protein (P < 0.001). In comparing patients with healthy controls, basal levels of folate were lower in the patients, whereas vitamin B12, alpha-tocopherol, and homocysteine levels were similar. No changes in serum lipid levels or body weight were observed. In conclusion, a short-term supplementation with folic acid and antioxidant vitamins can reduce serum homocysteine levels and in vitro LDL oxidation in patients with coronary artery disease.

Antioxidants↗
PubMed1990

Time dependent inhibition of xanthine oxidase in irradiated solutions of folic acid, aminopterin and methotrexate.

The xanthine oxidase catalyzed oxidation of hypoxanthine was followed by monitoring the formation of uric acid at 290 nm. Inhibition of xanthine oxidase occurs in aqueous solutions of folic acid methotrexate and aminopterin. These compounds are known to dissociate upon exposure to ultraviolet light resulting in the formation of their respective 6-formylpteridine derivatives. The relative rates of dissociation were monitored spectrophotometrically by determining the absorbance of their 2,4-dinitrophenylhydrazine derivatives at 500 nm. When aqueous solutions of folic acid, aminopterin and methotrexate were exposed to uv light, a direct correlation was observed between the concentrations of the 6-formylpteridine derivatives existing in solution and the ability of these solutions to inhibit xanthine oxidase. The relative potency of the respective photolysis products were estimated.

Aminopterin↗
PubMedDate not supplied

Analysis of milk-based infant formula. Phase V. Vitamins A and E, folic acid, and pantothenic acid: Food and Drug Administration-Infant Formula Council: collaborative study.

In 1982, the U.S. Food and Drug Administration, the Infant Formula Council and its member companies, contract laboratories, and other government laboratories began a study of analytical methods for the nutrients listed in the Infant Formula Act of 1980 (P.L. 96-359). Four phases of the study have been completed and are discussed in earlier reports. The present report provides data on Phase V, in which 13 laboratories collaboratively studied individual methods for folic acid, pantothenic acid, and vitamin E, in addition to 2 methods for vitamin A. Vitamins A and E are determined by liquid chromatography. Folic acid and pantothenic acid are determined by microbiological methods using acidimetric and/or turbidimetric assays as the determinative step. In most cases, relative standard deviations for repeatability, RSDr, and reproducibility, RSDR, are as good as those that would be predicted from other collaborative studies. RSDr and RSDR values obtained for the 5 methods are 9.35 and 25.44% for folic acid, 4.59 and 10.23% for pantothenic acid, 8.46 and 11.69% for vitamin E, 3.62 and 9.72% for vitamin A (retinol isomers), and 4.9 and 10.5% for vitamin A (retinol). The 5 methods have been adopted first action by AOAC International.

Animals↗
PubMed2003

Folic acid and 5-methyltetrahydrofolate in fortified milk are bioaccessible as determined in a dynamic in vitro gastrointestinal model.

Dairy products are a potential matrix for folate fortification to enhance folate consumption in the Western world. Milk folate-binding proteins (FBP) are especially interesting because they seem to be involved in folate bioavailability. In this study, folate bioaccessibility was investigated using a dynamic computer-controlled gastrointestinal model [TNO gastrointestinal model (TIM)]. We used both ultrahigh temperature (UHT)-processed milk and pasteurized milk, differing in endogenous FBP concentrations and fortified with folic acid or 5-methyltetrahydrofolate (5-CH(3)-H(4)folate). To study FBP stability during gastrointestinal passage and the effect of additional FBP on folate bioaccessibility, FBP-fortified UHT and pasteurized milk products were also tested. Folate bioaccessibility and FBP stability were measured by taking samples along the compartments of the gastrointestinal model and measuring their folate and FBP concentrations. Folate bioaccessibility from folic acid-fortified milk products without additional FBP was 58-61%. This was lower (P < 0.05) than that of the 5-CH(3)-H(4)folate-fortified milk products (71%). Addition of FBP reduced (P < 0.05) folate bioaccessibility from folic acid-fortified milk (44-51%) but not from 5-CH(3)-H(4)folate-fortified milk products (72%). The residual FBP levels in the folic acid- and 5-CH(3)-H(4)folate-fortified milk products after gastrointestinal passage were 13-16% and 0-1%, respectively, of the starting amounts subjected to TIM. In conclusion, milk seems to be a suitable carrier for folate, because both folic acid and 5-CH(3)-H(4)folate are easily released from the matrix and available for absorption. However, our results suggest that folic acid remains partly bound to FBP during passage through the small intestine, which reduces the bioaccessibility of folic acid from milk in this model.

Animals↗