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Chemopreventive effects of 2-(Allylthio)pyrazine

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Abstract

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 expoxide 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 B1 (AFB1)-induced three-step medium-term hepatocarcinogenesis model. Reduction of AFB1-DNA adduct by 2-AP appeared to result from the decreased formation of AFB1-8,9-epoxide via suppression of cytochrome P450, while induction of GST by 2-AP increases the excretion of glutathione-conjugated AFB1. 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 speciesin vivo, which is not mediated with the thiol-dependent production of oxidants and that NF-κB 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.

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  1. College of Pharmacy, Seoul National University, 151-742, Seoul, Korea

    Nak Doo Kim & Sang Geon Kim

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Kim, N.D., Kim, S.G. Chemopreventive effects of 2-(Allylthio)pyrazine. Arch Pharm Res 22, 99–107 (1999). https://doi.org/10.1007/BF02976531

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