Hypomethylation of DNA in ethionine-fed rats

Abstract

Ethionine, the hepatocarcinogenic antimetabolite of methionine, was fed to rats in carcinogenic doses for 1-10 wk. Levels of 5-methyldeoxycytidine (5-MC) in nuclear DNA and total cellular levels of S-adenosylmethionine (AdoMet) and S-adenosylethionine (AdoEt) were determined at 1, 5 and 10 wk in livers of control and ethionine-treated animals. The percentage of deoxycytidine residues modified to 5-MC in hepatic DNA of ethionine-fed animals was the same as that in the control animals at 1 wk but was 3.6% and 7.6% lower than that observed in control animals at 5 and 10 wk, respectively. Significant levels of AdoEt, a DNA methylase inhibitor, as well as decreases in the levels of AdoMet were also observed in the livers of ethionine-fed animals. The levels of 5-MC, AdoMet and AdoEt were determined in the pancreas, kidneys, testes and thymus of control rats and rats fed ethionine for 10 wk. Only the testes, an organ known to be susceptible to the toxic effects of ethionine, showed a significant (P < 0.02) decrease in 5-MC in response to ethionine feeding. AdoEt was present in all tissues studied, except thymus, but at lower levels than those observed in the liver. Ethionine administration alone under conditions which cause tumors is sufficient for the production of hypomethylated DNA in the target organ and 1 extrahepatic tissue studied. Hypomethylation of hepatic DNA would appear to result from the accumulation of AdoEt coupled with the decreased levels of AdoMet.