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Chemopreventive effects of 2-(allylthio)pyrazine on hepatic lesion, mutagenesis and tumorigenesis induced by vinyl carbamate or vinyl carbamate epoxide

 Young-Joon Surh  ;  Seong Gon Kim  ;  Kwang-Kyun Park  ;  Yeowon Sohn  ;  Jong-Min Lee  ;  Nak Doo Kim  ;  James A.Miller 
 CARCINOGENESIS, Vol.19(7) : 1263-1267, 1998 
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Animals ; Anticarcinogenic Agents/therapeutic use* ; Carcinogens/toxicity* ; Enzyme Inhibitors/therapeutic use* ; Female ; Liver Neoplasms, Experimental/chemically induced ; Liver Neoplasms, Experimental/prevention & control* ; Male ; Mice ; Mice, Inbred C3H ; Mice, Inbred C57BL ; Mice, Inbred ICR ; Mutagens/toxicity* ; Pyrazines/therapeutic use* ; Rats ; Rats, Sprague-Dawley ; Urethane/analogs & derivatives* ; Urethane/toxicity
2-(Allylthio)pyrazine (2-AP), synthesized for its possible use as a hepatoprotective agent, has been found to selectively inhibit rat hepatic cytochrome P450 2E1 (Kim et al., Biochem. Pharmacol., 53, 261-269, 1997), while it enhances the activities of phase II detoxification enzymes such as glutathione S-transferase and epoxide hydrolase. As part of a program in evaluating the chemopreventive potential of 2-AP, we have determined its effects on hepatotoxicity, mutagenicity and tumorigenicity of vinyl carbamate (VC), a prototypic hepatocarcinogen preferentially activated by P450 2E1 to the ultimate carcinogenic metabolite vinyl carbamate epoxide (VCO), which undergoes detoxification by glutathione conjugation and oxirane hydrolysis. Administration of 2-AP (100 mg/kg body wt) to male Sprague-Dawley rats by gavage, 2 days, 1 day and 4 h prior to VC or VCO, markedly ameliorated the hepatotoxicity of these compounds as determined by decreased serum aspartate aminotransferase and alanine aminotransferase activities. Furthermore, 2-AP pre-treatment significantly suppressed the VC-induced hepatocarcinogenesis in infant male B6C3F1 mice. In a separate experiment, the multiplicities of skin tumors formed in female ICR mice treated with 5.8 micromol of VC or VCO were inhibited 58 and 70%, respectively, by pre-treatment with 2-AP by oral administration. The mutational spectrum of ras-oncogene in papillomas was not altered by 2-AP pre-treatment. 2-AP also inhibited the mutagenicity of VC in the Salmonella-microsome assay. Taken together, these findings suggest that 2-AP is a potential chemopreventive agent.
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2. College of Dentistry (치과대학) > Dept. of Oral Biology (구강생물학교실) > 1. Journal Papers
Yonsei Authors
Park, Kwang Kyun(박광균)
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