Folate and carcinogenesis: an integrated scheme.
Collectively, the evidence from epidemiologic, animal and human studies strongly suggests that folate status modulates the risk of developing cancers in selected tissues, the most notable of which is the colorectum. Folate depletion appears to enhance carcinogenesis whereas folate supplementation above what is presently considered to be the basal requirement appears to convey a protective effect. The means by which this modulation of cancer risk is mediated is not known with certainty, but there are several plausible mechanisms which have been described. Folate plays a major role in the formation of S-adenosylmethionine, the universal methyl donor, as well as in the formation of purine and thymidine synthesis for DNA and RNA. Therefore, most mechanistic studies performed to date have focused on alterations in DNA methylation, disruption of DNA integrity and disruption of DNA repair, all of which have been observed with folate depletion. These aberrations in DNA are believed to enhance carcinogenesis by altering the expression of critical tumor suppressor genes and proto-oncogenes. Recently, the role of a common polymorphism of the methylenetetrahydrofolate reductase gene has been highlighted as well. This review presents those mechanisms which are the most likely candidates to explain folate's effects and it proposes an integrated scheme to explain how these mechanisms might interact.
Choi
S W
SW
Vitamin and Carcinogenesis Program, Jean Mayer U.S. Department of Agriculture Human Nutrition Research Center on Aging at Tufts University, Boston, Massachusetts, USA.
Mason
J B
JB
D000818:Animals; D003110:Colonic Neoplasms / Q000209:etiology* / Q000517:prevention & control; D019175:DNA Methylation / Q000187:drug effects*; D004260:DNA Repair / Q000187:drug effects; D005492:Folic Acid / Q000502:physiology* / Q000627:therapeutic use; D005494:Folic Acid Deficiency / Q000150:complications* / Q000378:metabolism; D006801:Humans; D008754:Methylenetetrahydrofolate Dehydrogenase (NADP) / Q000235:genetics / Q000502:physiology; D009696:Nucleic Acids / Q000378:metabolism*
D009696:Nucleic Acids; D005492:Folic Acid; D008754:Methylenetetrahydrofolate Dehydrogenase (NADP)