Effects of alcohol on folate metabolism: implications for carcinogenesis

Epidemiologic observations implicate excess ethanol ingestion as well as low dietary folate intake as risk factors for several cancers. Moreover, the epidemiologic observations support the concept of a synergistic effect between these two factors. Such a relation is biologically plausible because ethanol impedes the bioavailability of dietary folate and is known to inhibit select folate-dependent biochemical reactions. For example, alcohol ingestion in animals is known to inhibit folate-mediated methionine synthesis and thereby may interrupt critical methylation processes that are mediated by the activated form of methionine that provides substrate for biologic methylation, S-adenosylmethionine. Consistent with this observed inhibition of methionine synthesis is the observation that chronic alcohol ingestion in laboratory animals is known to produce hypomethylation of DNA in the colonic mucosa, a constant feature of early colorectal neoplasia. Inhibition of methionine synthase also creates a "methylfolate trap," analogous to what occurs in vitamin B-12 deficiency. In addition, some evidence indicates that alcohol may redirect the utilization of folate toward serine synthesis and thereby may interfere with a critical function of methylenetetrahydrofolate, thymidine synthesis. Although a mechanistic link between alcohol and impaired folate metabolism in the genesis of cancer is still not definitively established, such a link should be pursued in future studies because of the intimate metabolic relation between alcohol and folate metabolism. (c) 2005 Elsevier Inc. All rights reserved.