Inhibition of covalent DNA binding and mutagenicity of benzo(a)pyrene by isopropyl-2-(1,3-dithietane-2-ylidene)-2-(N-(4-methylthiazol-2-yl) carbamoyl)acetate (YH439), a novel hepatoprotective agent.

摘要

Isopropyl-2-(1,3-dithietane-2-ylidene)-2[N-(4-methyl-2-thiazol+ ++-2-yl) carbamoyl]acetate (YH439) was synthesized as a hepatoprotective drug for the treatment of chronic hepatitis and liver cirrhosis. In the present investigation, we have tested YH439 for its chemoprotective activity against the carcinogen benzo[a]pyrene. The drug exhibited dose-dependent protection against bacterial mutagenesis induced by benzo[a]pyrene its covalent binding to DNA in vitro mediated by rat hepatic postmitochondrial supernatant enriched with NADPH. The direct mutagenicity of benzo[a]pyrene-7,8-dihydrodiol-9,10-epoxide, the ultimate electrophilic and carcinogenic metabolite of benzo[a]pyrene, was also ameliorated by YH439 in a dose-dependent manner. The results of this study suggest that YH439 has a potential as a chemopreventive agent.