Chronic alcohol consumption induces genomic but not p53-specific DNA hypomethylation in rat colon.
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 [(3)H]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 beta-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.
Choi
S W
SW
Vitamin Bioavailability Laboratory, Jean Mayer U.S. Department of Agriculture Human Nutrition Research Center on Aging at Tufts University, Boston 02111, USA.
Stickel
F
F
Baik
H W
HW
Kim
Y I
YI
Seitz
H K
HK
Mason
J B
JB
D000818:Animals; D001835:Body Weight / Q000187:drug effects; D003106:Colon / Q000187:drug effects* / Q000378:metabolism; D015179:Colorectal Neoplasms / Q000139:chemically induced / Q000235:genetics*; D019175:DNA Methylation / Q000187:drug effects*; D004032:Diet; D000431:Ethanol / Q000008:administration & dosage / Q000633:toxicity*; D005492:Folic Acid / Q000097:blood / Q000378:metabolism; D016147:Genes, Tumor Suppressor / Q000187:drug effects; D016678:Genome; D008297:Male; D009929:Organ Size / Q000187:drug effects; D016133:Polymerase Chain Reaction; D051381:Rats; D017207:Rats, Sprague-Dawley; D016159:Tumor Suppressor Protein p53 / Q000187:drug effects / Q000235:genetics* / Q000378:metabolism
D016159:Tumor Suppressor Protein p53; D000431:Ethanol; D005492:Folic Acid