• YAKHAK HOEJI
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• v.40 no.6
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• pp.727-733
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• 1996

2-(Allylthio)pyrazine is effective in selectively suppressing constitutive and inducible expression of cytochrome P450 2E1. The effect of 2-(allylthio)pyrazine against potentiat ed chemical injury was studied in rats. Vitamin-A pretreatment of rats substantially increased carbon tetrachloride hepatotoxicity, as supported by an ~4-fold increase in serum alanine aminotransferase (ALT) activity. Concomitant pretreatment of rats with 2-(allylthio)pyrazine at the daily dose of 200mg/kg resulted in a 76% decrease in vitamin-A-potentiated hepatotoxicity, which supported the possibility that 2-(allylthio)pyrazine protects the liver against chemical-induced hepatic injury by the mechanism associated with Kupffer cell inactivation. Pyridine pretreatment caused substantial enhancement in carbon tetrachloride hepatotoxicity. 2-(Allylthio)pyrazine treatment of rats reduced the pyridine-potentiated toxicity in a dose-dependent manner. Animals treated with both pyridine and 2-(allylthio)pyrazine prior to intoxicating dose of CCl$_4$ resulted in 85% and 47% decreases in pyridine-increased triglycerides and cholesterol levels in the liver. The protective effect of 2-(allylthio)pyrazine on the DNA strand breakage induced by benzenetriol was assessed by measuring the conversion of supercoiled ${\Phi}x$-174 DNA to the open relaxed form. 2-(Allylthio)pyrazine blocked the benzenetriol-induced conversion of supercoiled DNA to open circular form in a dose-dependent manner. The presence of 2-(allylthio)pyrazine at the doses from I to 10mM in the incubation mixture containing 5 ${\mu}$M benzenetriol completely protected benzenetriol-induced DNA strand breakage with the EC50 for the 2-(allylthio)pyrazine blocking being noted as ~220 ${\mu}$M, whereas allyl disulfide exerted protecting effect at relatively high concentrations (i.e. ~850 ${\mu}$M), suggesting that 2-(allylthio)pyrazine effectively scavenges the reactive oxygen species. These results provide evidence that 2-(allylthio)pyrazine blocks vitamin A- or pyridine-potentiated CCl$_4$ hepatotoxicity and that the agent is active in protecting DNA by scavenging the reactive oxygen species.

• Archives of Pharmacal Research
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• v.24 no.1
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• pp.16-20
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• 2001

2-(Allylthio)pyrazine derivatives were designed as a novel cancer chemopreventive agent that functions through selective inhibtion of cytochrome P-450 and induction of phase 11 enzymes involved in the detoxification of carcinogens. A practical preparation method of 2-(allylthio) pyrazine derivatives was established by the reaction of 2-mercaptopyrazine and allylbromides in the presence of a catalytic antioxidant, DABCO (1,4-diazabicyclo[2,2,2] octane), in dimethyl-formamide at below $50^{\circ}C$.

• Proceedings of the PSK Conference
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• 2000.04a
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• pp.158.2-158.2
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• 2000

• Archives of Pharmacal Research
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• v.22 no.2
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• pp.99-107
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• 1999

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 ($AFB_1$)-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 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-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.

• Proceedings of the Korean Society of Toxicology Conference
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• 1998.10a
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• pp.62-62
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• 1998