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KMID : 0043319990220020099
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Archives of Pharmacal Research
1999 Volume.22 No. 2 p.99 ~ p.107
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chemopreventive Effects of 2-(Allylthio) pyrazine
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Kim Nak-Doo
Kim Sang-Geon
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Abstract
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A series of organosulfur compounds were synthesized with the aim of developing chemopreventive compounds active against hepatotoxicity and chemical carcinogesis. 2-(Allylthio) prazine (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 toxicant sand 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 ()-induced three-step medium-term hepatocarcinogenesis model. Reduction of -DNA adduct by 2-AP appeared to result from the decreased formation of -8,9-epoxide via suppression of cytochrome P450, while induction of GST 2-AP increases the excretion of glutathione-conjugated . 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-KB 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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KEYWORD
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2-(Allylthio)pyrazine, Chemoprevention, Radioprotection, Hepatoprotective Agent, Cytochrome P450, Epoxide hydrolase, Glutathione S-transferase
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