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 ahepatoprotective agent, has been found to selectively inhibit rat hepaticcytochrome P450 2E1 (Kim et al., Biochem. Pharmacol., 53, 261- 269, 1997),while it enhances the activities of phase II detoxification enzymes such asglutathione S-transferase and epoxide hydrolase. As part of a program inevaluating the chemopreventive potential of 2-AP, we have determined itseffects on hepatotoxicity, mutagenicity and tumorigenicity of vinylcarbamate (VC), a prototypic hepatocarcinogen preferentially activated byP450 2E1 to the ultimate carcinogenic metabolite vinyl carbamate epoxide(VCO), which undergoes detoxification by glutathione conjugation andoxirane hydrolysis. Administration of 2-AP (100 mg/kg body wt) to maleSprague-Dawley rats by gavage, 2 days, 1 day and 4 h prior to VC or VCO,markedly ameliorated the hepatotoxicity of these compounds as determined bydecreased serum aspartate aminotransferase and alanine aminotransferaseactivities. Furthermore, 2-AP pre-treatment significantly suppressed theVC-induced hepatocarcinogenesis in infant male B6C3F1 mice. In a separateexperiment, the multiplicities of skin tumors formed in female ICR micetreated with 5.8 micromol of VC or VCO were inhibited 58 and 70%,respectively, by pre-treatment with 2-AP by oral administration. Themutational spectrum of ras-oncogene in papillomas was not altered by 2-APpre-treatment. 2-AP also inhibited the mutagenicity of VC in theSalmonella-microsome assay. Taken together, these findings suggest that2-AP is a potential chemopreventive agent.