CHEMOPREVENTIVE EFFECTS OF 2-(ALLYLTHIO)PYRAZINE ON HEPATIC LESION, MUTAGENESIS AND TUMORIGENESIS INDUCED BY VINYL CARBAMATE OR VINYL CARBAMATE EPOXIDE

2-(Allylthio)pyrazine (2-AP), synthesized for its possible use as a he patoprotective agent, has been found to selectively inhibit rat hepati c cytochrome P450 2E1 (Kim et al,, Biochem, Pharmacol., 53, 261-269, 1 997), while it enhances the activities of phase II detoxification enzy mes such as glutathione S-transferase and epoxide hydrolase, As part o f a program in evaluating the chemopreventive potential of 2-AP, we ha ve determined its effects on hepatotoxicity, mutagenicity and tumorige nicity of vinyl carbamate (VC), a prototypic hepatocarcinogen preferen tially activated by P450 2E1 to the ultimate carcinogenic metabolite v inyl carbamate epoxide (VCO), which undergoes detoxification by glutat hione conjugation and oxirane hydrolysis. Administration of 2-AP (100 mg/kg body wt) to male Sprague-Dawley rats by gavage, 2 days, 1 day an d 4 h prior to VC or VCO, markedly ameliorated the hepatotoxicity of t hese compounds as determined by decreased serum aspartate aminotransfe rase and alanine aminotransferase activities. Furthermore, 2-AP pre-tr eatment significantly suppressed the VC-induced hepatocarcinogenesis i n infant male B6C3F(1) mice, In a separate experiment, the multiplicit ies of skin tumors formed in female ICR mice treated with 5.8 mu mol o f VC or VCO were inhibited 58 and 70%, respectively, by pre-treatment with 2-AP by oral administration. The mutational spectrum of ras-oncog ene in papillomas was not altered by 2-AP pre-treatment. 2-AP also inh ibited the mutagenicity of VC in the Salmonella-microsome assay. Taken together, these findings suggest that 2-AP is a potential chemopreven tive agent.