Homocysteine, iron and cardiovascular disease: a hypothesis.

Elevated circulating total homocysteine (tHcy) concentrations (hyperhomocysteinemia) have been regarded as an independent risk factor for cardiovascular disease (CVD). However, several large clinical trials to correct hyperhomocysteinemia using B-vitamin supplements (particularly folic acid) have largely failed to reduce the risk of CVD. There is no doubt that a large segment of patients with CVD have hyperhomocysteinemia; therefore, it is reasonable to postulate that circulating tHcy concentrations are in part a surrogate marker for another, yet-to-be-identified risk factor(s) for CVD. We found that iron catalyzes the formation of Hcy from methionine, S-adenosylhomocysteine and cystathionine. Based on these findings, we propose that an elevated amount of non-protein-bound iron (free Fe) increases circulating tHcy. Free Fe catalyzes the formation of oxygen free radicals, and oxidized low-density lipoprotein is a well-established risk factor for vascular damage. In this review, we discuss our findings on iron-catalyzed formation of Hcy from thioethers as well as recent findings by other investigators on this issue. Collectively, these support our hypothesis that circulating tHcy is in part a surrogate marker for free Fe, which is one of the independent risk factors for CVD.

Meta-analysis of cancer risk in folic acid supplementation trials.

Several reports suggest that folate has a procarcinogenic effect. Folate has a unique role because its coenzymes are needed for de novo purine and thymine nucleotide biosynthesis. Antifolates, such as methotrexate, are used in cancer treatment. Using a meta-analysis weighted for the duration of folic acid (pteroylglutamic acid) supplementation, we analyzed the cancer incidence of six previously published large prospective folic acid-supplementation trials in men and women. These articles were carefully selected from over 1100 identified using PubMed search. Our analyses suggest that cancer incidences were higher in the folic acid-supplemented groups than the non-folic acid-supplemented groups (relative risk=1.21 [95% confidence interval: 1.05-1.39]). Folic acid-supplementation trials should be performed with careful monitoring of cancer incidence. Solid monitoring systems to detect side effects, including increase in cancer risk, should be established before the initiation of folic acid supplementation trials.

Effect of paternal folate deficiency on placental folate content and folate receptor α expression in rats.

We investigated the effect of paternal folate status on folate content and expression of the folate transporter folate receptor α (FRα) in rat placental tissues. Rats were mated after males were fed a diet containing 0 mg of folic acid/kg of diet (paternal folate-deficient, PD) or 8 mg folic acid/kg of diet (paternal folate-supplemented, PS) for 4 weeks. At 20 days of gestation, the litter size, placental weight, and fetal weight were measured, and placental folate content (n = 8/group) and expression of FRα (n = 10/group) were analyzed by microbiological assay and Western blot analysis, respectively. Although there was no difference observed in litter size or fetal weight, but significant reduction (10%) in the weight of the placenta was observed in the PD group compared to that in the PS group. In the PD group, placental folate content was significantly lower (by 35%), whereas FRα expression was higher (by 130%) compared to the PS group. Our results suggest that paternal folate status plays a critical role in regulating placental folate metabolism and transport.

Zinc status of women with low bone mineral density who receive calcium supplements.

We evaluated whether a daily high-dose calcium supplement perturbs the zinc status in 23 postmenopausal women (mean age: 63 yr) with low bone mineral density. Plasma and erythrocyte zinc concentrations, plasma bone-specific alkaline phosphatase (BSAP) and 5'-nucleotidase activities, and urinary zinc and calcium excretion were determined first at the end of 4 wk of daily oral calcium (1200 mg) and were measured again at the end of the subsequent 4 wk of daily cosupplementation with calcium (1200 mg) and zinc (30 mg). Mean plasma and erythrocyte zinc concentrations after 4 wk of calcium alone were not significantly different from concentrations after cosupplementation of calcium and zinc. Mean plasma BSAP activities before cosupplementation with zinc was significantly higher than that after zinc (p < 0.02), whereas plasma 5'-nucleotidase activities were not affected by zinc supplementation. Urinary zinc excretion slightly, but significantly, increased after the supplementation of zinc (p < 0.05), whereas calcium excretion remained similar. Our data indicate that a 4-wk zinc supplementation did not significantly improve zinc status. Although limited by the small sample size and short study duration, our data suggest that a daily calcium dose of 1200 mg had no effect on the zinc status of our subjects.

Folate and human reproduction.

The influence of folate nutritional status on various pregnancy outcomes has long been recognized. Studies conducted in the 1950s and 1960s led to the recognition of prenatal folic acid supplementation as a means to prevent pregnancy-induced megaloblastic anemia. In the 1990s, the utility of periconceptional folic acid supplementation and folic acid food fortification emerged when they were proven to prevent the occurrence of neural tube defects. These distinctively different uses of folic acid may well be ranked among the most significant public health measures for the prevention of pregnancy-related disorders. Folate is now viewed not only as a nutrient needed to prevent megaloblastic anemia in pregnancy but also as a vitamin essential for reproductive health. This review focuses on the relation between various outcomes of human reproduction (ie, pregnancy, lactation, and male reproduction) and folate nutrition and metabolism, homocysteine metabolism, and polymorphisms of genes that encode folate-related enzymes or proteins, and we identify issues for future research.

Folate status of mothers during pregnancy and mental and psychomotor development of their children at five years of age.

OBJECTIVE: There are limited data relating folate nutritional status of mothers during pregnancy to mental and psychomotor development of their offspring. Using an existing data set from a study on the effect of prenatal zinc supplementation on child neurodevelopment, we evaluated the association between folate nutritional status of mothers during pregnancy and neurodevelopment of their children. METHODS: Maternal blood folate and total homocysteine (tHcy) concentrations were measured at 19, 26, and 37 weeks of gestation. At a mean of 5.3 years of age, 355 black children with low-socioeconomic background were given 6 tests: Differential Ability Scales, Visual and Auditory Sequential Memory, Knox Cube Test, Gross Motor Scale, and Grooved Pegboard. The scores of the tests between the 2 groups of mothers with poor versus adequate folate nutritional status classified by blood folate or tHcy concentrations were compared. RESULTS: There were no differences in the test scores of neurodevelopment between the 2 groups. CONCLUSION: Folate nutritional status of mothers in the later half of pregnancy assessed by plasma and erythrocyte folate and plasma tHcy concentrations had no impact on neurodevelopment of their children at age 5. It is unknown whether our findings in a low-socioeconomic population can be readily extrapolated to other populations.

Folate content in commercial white and whole wheat sandwich breads.

After the U.S. mandate of folic acid fortification of enriched grain products, a report indicated higher than expected fortification. Limited information is available on folic acid in enriched products. We measured the folate content in 92 sandwich breads (46 white breads and 46 whole wheat breads) in Birmingham, Alabama, during 2001-2003. The mean folate content in white bread declined significantly from 2001 to 2002 or 2003, whereas the decline in folate content in whole wheat bread containing enriched flour was not significant. White bread contained significantly more folate than whole wheat bread containing enriched flour in 2001 and 2003. In 2002 and 2003, >40% of breads made of enriched flour contained <115 microg of folate/100 g and >70% contained <160 microg/100 g. These percentages were markedly higher than those in 2001. Our data suggest that folic acid in breads containing enriched flour declined after 2001 and monitoring of fortification may be necessary.

Effect of long-term, high-copper intake on the concentrations of plasma homocysteine and B vitamins in young men.

OBJECTIVE: We evaluated the effect of a long-term, high-copper intake on plasma total homocysteine, folate, vitamin B12, and pyridoxal-5'-phosphate concentrations in humans. METHODS: Nine healthy young men were confined in a metabolic research unit for 18 d and fed 3-d rotation diets supplying an average of 1.6 mg of copper per day followed by 129 d of free-living conditions when they received 7 mg of copper per day in addition to their usual diets. The subjects returned to the metabolic research unit for the second 18-d period and were given the same diets as during the first 18 d with the exception that the copper intake was 7.8 mg/d. There was no apparent biochemical indication that the subjects were deficient in copper before the large-dose copper intake. Blood samples were obtained at the end of the first and second 18-d periods at the metabolic research unit, and plasma concentrations of total homocysteine, folate, vitamin B12, and pyridoxal-5'-phosphate were measured. RESULTS: The long-term, high-copper intake resulted in small but significant decreases in plasma concentrations of total homocysteine and folate. There was no effect of the high-copper intake on plasma concentrations of vitamin B12 and pyridoxal-5'-phosphate. CONCLUSIONS: These findings can be explained by our previous observation in rats suggesting that methionine synthase is copper dependent and that the metabolism of homocysteine and folate is regulated in part by copper nutriture. It may be necessary to consider copper nutriture for the interpretation of plasma concentrations of total homocysteine in humans.

Effect of zinc supplementation of pregnant women on the mental and psychomotor development of their children at 5 y of age.

BACKGROUND: A negative effect of prenatal zinc deficiency on brain function has been well established in experimental animals, but this association in humans is controversial. OBJECTIVE: We evaluated the effect of prenatal zinc supplementation on the mental and psychomotor development of 355 children whose mothers participated in a double-blind trial of zinc supplementation that resulted in increased head circumference and birth weight. DESIGN: The children took 6 tests-the Differential Ability Scales, Visual Sequential Memory, Auditory Sequential Memory, Knox Cube, Gross Motor Scale, and Grooved Pegboard tests-at a mean age of 5.3 y. The scores were compared between the children of women who received a daily oral dose of 25 mg Zn during the second half of pregnancy and the children of women who received placebo. RESULTS: There were no differences in the test scores of neurologic development between the 2 groups. We analyzed the scores in 4 subgroups on the basis of maternal body mass index, because the increases in birth weight and head circumference due to the supplementation occurred only in the children of women with a body mass index (in kg/m(2)) < 26.0 in the original trial. No differences in the scores were found between these subgroups. CONCLUSIONS: Zinc supplementation of women in the latter half of pregnancy had no effect on the neurologic development of their children at age 5 y. It is not known whether our findings of no positive effect in the population with apparently inadequate zinc nutriture can be readily extrapolated to other populations.