Methionine Sulfoxide Stimulates Hepatocarcinogenesis in Non-alcoholic Steatohepatitis (NASH) Mouse: Possible Role of Free Radical-mediated DNA Methylation

Abstract

We have reported the formation of 5-methylcytosine from cytosine in vitro, with methyl radicals generated from methionine sulfoxide (MetO). To confirm this reaction in vivo, MetO was added to the drinking water and administered to non-alcoholic steatohepatitis (NASH) mice, which develop hepatitis caused by endogenous oxidative stress. Histopathological examinations revealed incidences of hepatocellular carcinoma of 16.7% and 90% in the 0% and 3% MetO groups, respectively. Higher DNA methylation was detected in the promoter region of the p16 gene isolated from the livers of MetO-treated mice. The higher incidence of liver tumors may be due to the methyl radical-mediated formation of 5-methylcytosine in DNA, which triggers epigenetic changes.