2-(allylthio)pyrazine inhibition of aflatoxin B1-induced hepatotoxicity in rats: inhibition of cytochrome P450 2B- and 3A2-mediated bioactivation.

2-(Allylthio)pyrazine (2-AP), a synthetic organosulfur compound, exhibits hepatoprotective and chemopreventive effects. The effects of 2-AP on aflatoxin B1 (AFB1)-induced hepatotoxicity was studied in rats. 2-AP treatment substantially reduced AFB1-induced toxicity, as evidenced by reduction in the mortality rate of animals as well as decreases in serum alanine aminotransferase and sorbitol dehydrogenase activities. AFB -induced lipid peroxidation was also significantly reduced in rats by 2-AP treatment. Studies were extended to determine whether 2-AP was active in inhibiting cytochrome P450-mediated metabolic activation of AFB1. Covalent binding of AFB1 to calf thymus DNA in the presence of S-9 fraction was inhibited by 2-AP in vitro. Hepatic microsomal pentoxyresorufin-O-depentylase and ethoxyresorufin-O-deethylase activities were also potently inhibited by 2-AP. These results demonstrated that 2-AP was effective in protecting the liver against AFB1-induced toxicity and the mechanism of chemoprotection by 2-AP might involve inhibition of the P450 2B- and 3A2-mediated metabolism of AFB1.