Chemopreventive effects of 2-(allylthio)pyrazine

A series of organosulfur compounds were synthesized with the aim of developing chemopreventive compounds active against hepatotoxicity and chemical carcinogenesis. 2-(Allylthio) pyrazine (2-AP) was effective in inhibiting cytochrome P450 2E1-mediated catalytic activities and protein expression, and in inducing microsomal epoxide hydrolase and major glutathione S-transferases. 2-AP reduced the hepatotoxicity caused by toxicants and elevated cellular GSH content. Development of skin tumors, pulmonary adenoma and aberrant crypt foci in colon by various chemical carcinogens was inhibited by 2-AP pretreatment. Anticarcinogenic effects of 2-AP at the stage of initiation of tumors were also observed in the aflatoxin B-1 (AFB(1))-induced three-step medium-term hepatocarcinogenesis model. Reduction of AFB(1)-DNA adduct by 2-AP appeared to result from the decreased formation of AFB(1)-8,9-epoxide via suppression of cytochrome P450, while induction of GST by 2-AP increases the excretion of glutathione-conjugated AFB(1). 2-AP was a radioprotective agent effective against the lethal dose of total body irradiation and reduced radiation-induced injury in association with the elevation of detoxifying gene expression. 2-AP produces reactive oxygen species in vivo, which is not mediated with the thiol-dependent production of oxidants and that NF-kappa B activation is not involved in the induction of the detoxifying enzymes. The mechanism of chemoprotection by 2-AP may involve inhibition of the P450-mediated metabolic activation of chemical carcinogens and enhancement of electrophilic detoxification through induction of phase II detoxification enzymes which would facilitate the clearance of activated metabolites through conjugation reaction.