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4
*
Vitamin Bioavailability Laboratory, Jean Mayer U.S. Department of Agriculture Human Nutrition Research Center on Aging at Tufts University, Boston 02111;
Department of Gastroenterology, Stiftsklinik Augustinum, München, D-81375, Germany;
**
Division of Gastroenterology, Department of Medicine, St. Michael's Hospital and University of Toronto, Toronto, ON, M5S 1A8, Canada;
Department of Medicine, Salem Hospital, University of Heidelberg, Heidelberg, 69121, Germany; and
Divisions of Gastroenterology and Clinical Nutrition, Department of Medicine, New England Medical Center, Tufts University School of Medicine, Boston 02111
4To whom correspondence and reprint requests should be addressed.
Alcohol consumption has been implicated as an etiologic agent in colorectal carcinogenesis, but the mechanism by which alcohol enhances the development of colorectal cancer is not yet known. Recent reports indicate that alcohol consumption can diminish cellular S-adenosylmethionine levels, thus possibly altering normal patterns of DNA methylation, a phenomenon that is mediated by S-adenosylmethionine and whose abnormalities are observed in colonic neoplasia. This study investigated the effect of chronic alcohol consumption on genomic DNA methylation of rat colonic epithelium and methylation of the p53 tumor suppressor gene, abnormalities of which have been implicated in colonic carcinogenesis. Two groups of rats (n = 10/group) were pair-fed either an alcohol-containing or an isocaloric control Lieber-DeCarli diet for 4 wk. The extent of genomic DNA methylation was assessed by incubating the extracted DNA with [3H]S-adenosylmethionine and Sss1 methyltransferase. Gene-specific methylation was assessed by using semiquantitative polymerase chain reaction (PCR). Tritiated methyl uptake by colonic DNA (which is inversely correlated with genomic methylation) from alcohol-fed rats was 57% less than that in control DNA (P < 0.05). However, gene-specific DNA methylation, both in the p53 gene (exons 5–8) and in the ß-actin gene, a control gene, did not differ between the two groups. In conclusion, this study indicates that chronic alcohol consumption produces genomic DNA hypomethylation in the colonic mucosa. This may constitute a means by which carcinogenesis is enhanced, although further studies are required to establish causality.
KEY WORDS: • alcohol • DNA methylation • colorectal cancer • folate • rats
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