INHIBITION OF DNA METHYLATION BY S-ADENOSYLETHIONINE WITH PRODUCTION OF METHYL-DEFICIENT DNA IN REGENERATING RAT-LIVER

Abstract

Ethionine, a liver carcinogen, was administered orally (300 mg/kg) to rats 17 h after partial hepatectomy. At 6 h after administration of ethionine, hepatic S-adenosylethionine levels were 30- to 40-fold greater than the hepatic level of S-adenosylmethionine. A 10-fold ratio of S-adenosylethionine to S-adenosylmethionine persisted 24 h after ethionine adminstration. When given 17 h after partial hepatectomy, ethionine produced a 30% inhibition of DNA synthesis, measured by the incorporation of [methyl-3H]thymidine at 23-24 h after partial hepatectomy (6-7 h after ethionine administration). DNA synthesized during this interval was methyl deficient as judged by the reduced incorporation of radioactivity from L-[methyl-3H]methionine into 5-methylcytosine residues of DNA. In an assay for DNA methylation in vitro using whole nuclei, methyl-deficient DNA was methylated by S-adenosylmethionine 8 times more than control DNA. DNA methylation was competitively inhibited by S-adenosylethionine. S-adenosylethionine, formed in vivo from ethionine, competitively inhibits methylation of DNA in vivo by S-adenosylmethionine, resulting in the production of methyl deficient DNA.