One-Carbon Metabolism, Colorectal Carcinogenesis, Chemoprevention--with Caution

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One-carbon metabolism comprises a network of integrated biochemical pathways that donate, and regenerate, the one-carbon moieties needed for physiologic processes. Efficient one-carbon metabolism is required for the biosynthesis of the purines, adenine and guanine, and the conversion of uridylate to thymidylate, which prevents the misincorporation of uracil into DNA ( 1 ). By donating a methyl group to homocysteine to create methionine, one-carbon metabolism also generates S -adenosylmethionine, the universal methyl donor, which is required for DNA methylation ( 1 ). Disruption of one-carbon metabolism can, therefore, interfere with DNA replication, DNA repair, and regulation of gene expression through methylation, each of which could promote carcinogenesis. One-carbon metabolism requires optimal activity of 25 or more enzymes, some of which depend on not only folate, a B vitamin, but also vitamins B-12, B-6, and B-2 (riboflavin) as coenzymes. Over the past 15 years, one-carbon metabolism has received increasing attention as a process whereby diet and genetic variation could modulate cancer risk. Based on the biochemistry, hypotheses were generated about the influence on cancer risk of folate and B-vitamin intake; folate and B-vitamin status; alcohol use, which interferes with folate bioavailability ( 2 ); and altered enzyme activity related to common genetic polymorphisms — hypotheses that could be tested in animal experiments, epidemiologic studies, and randomized clinical trials. In epidemiologic studies, low folate intake has been linked to increased risks of several cancers, including cancers of the breast, ovary, cervix, esophagus, stomach, pancreas, and lymphoid tissues, but the evidence is most extensive for colorectal cancer and its precursor, colorectal adenoma. In both men and women, low folate intake is associated with increased risk of colorectal adenoma and cancer in the majority of the epidemiologic studies ( 3 , 4 ). Serum and red blood cell folate have generally, although not always, been inversely associated with risk ( 3 ). Limited data suggest that intake of methionine, an essential source of one-carbon groups, may also be protective ( 3 ). High alcohol consumption, which interferes with folate utilization and other aspects of onecarbon metabolism (2), was associated with in creased risk, especially when folate intake was low ( 3 ). In rodent models, usually folate depletion enhanced and folate supplementation protected against the early stages of intestinal carcinogenesis ( 5 ). Although folate and methionine have received more attention as one-carbon donors in studies of chronic disease, choline and its metabolite betaine merit comparable consideration. Like 5-methyl tetrahydrofolate, choline, once oxidized to betaine, can transfer a one-carbon moiety to homocysteine to produce methionine and