IngentaConnect Chemopreventive effects of 2-(allylthio)pyrazine on hepatic lesio...

Authors: Surh Y.^{1, 5}; Kim S.²; Park K.³; Sohn Y.⁴; Lee J.¹; Kim N.¹; Miller J.²

Source: Carcinogenesis, Volume 19, Number 7, July 1998 , pp. 1263-1267(5)

Abstract:

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 effect 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 mgr mol 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.

Document Type: Original article

Affiliations: e-mail: surh@plaza.snu.ac.kr : 1: Seoul National University College of Pharmacy, Seoul 151-742, South Korea 2: McArdle Laboratory for Cancer Research, University of Wisconsin, Madison, WI 53706, USA 3: Yonsei University College of Dentistry, Seoul 120-752, South Korea 4: Korea Food and Drug Administration, Seoul 122-020, South Korea 5: Correspondence to: College of Pharmacy, Seoul National University, Shinlim-dong, Kwanak-gu, Seoul 151-742, South Korea

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