Ethionine, a methionine analog, is a hepatocarcinogen in the rat. One of the major metabolites of ethionine is S-adenosylethionine (AdoEth), which is an analog of S-adenosylmethionine (AdoMet). AdoEth accumulates in the hepatic tissue of rats when given acutely or chronically and has been suspected to play a major role in ethionine carcinogenesis. We plan to study the synthesis and cellular distribution of AdoMet and AdoEth in various carcinogenic models. The tissue specificity will be examined in the rat. Species differences will be studied using the rat, hamster, mouse, and guinea pig. The synthesis of AdoEth will also be examined in animals fed a choline-devoid-0.05% ethionine diet. It has also been demonstrated from our laboratory that ethionine via AdoEth inhibits DNA and protein methylases producing a hypomethylated state. DNA and protein methylation will be studied in vivo by giving [3H-methyl]-methionine, in vitro with an enzymatic assay for the methylase enzymes, and by the use of restriction endonucleases. Ethionine is not carcinogenic to the hamster, therefore a comparative study of the rat and hamster should give a better understanding of the need for hypomethylated DNA and/or protein in carcinogenesis. The overall long term objective of this work is to decipher in a stepwise manner the biochemical mechanism of chemical carcinogenesis. The immediate work involves ethionine carcinogenesis as the working model.