| Summary: | The aim of this study was to investigate the influence of folate on DNA stability and DNA methylation in three different systems. (i) Folate deficiency significantly increased DNA strand breakage and uracil misincorporation in human colon epithelial cells and lymphocytes in vitro. DNA methylation was decreased in both cell types when depleted of folate. (ii) Rats fed a folate-free diet for 10 weeks were moderately folate deficient measured as a 25-50% decrease in plasma, red blood cell or hepatic folate concentrations and a 20% rise in plasma homocysteine, a functional marker for folate status. Folate deficiency specifically increased DNA strand breakage in isolated rat lymphocytes and colonocytes and misincorporated uracil in lymphocytes. (iii) In a human colorectal cancer case-control study, no significant associations were observed between plasma or red blood cell folate, plasma vitamin B12 or homocysteine and lymphocyte DNA strand breakage, misincorporated uracil or DNA methylation. Homozygosity for the C677T polymorphism in the methylenetetrahydrofolate reductase gene was associated with a decreased risk of colorectal cancer, increased plasma homocysteine levels and decreased plasma folate levels compared with heterozygous or wild-type individuals. Plasma vitamin B12 level was associated with a reduction in cancer risk, whereas homocysteine was associated with increased risk of colorectal cancer. DNA strand breakage was associated with increased risk, whereas uracil misincorporation was protective. Red blood cell folate concentrations were not associated with risk. Old age (>65 years) and male gender were associated with increased risk of colorectal cancer.
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