title: 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.
abstract: 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.
authors.affiliation: Department of Epidemiology and Public Health, Yale University School of Medicine, New Haven, CT 06520-8034, USA.
authors.forename: Y J
authors.initials: YJ
authors.lastname: Surh
authors.forename: M
authors.initials: M
authors.lastname: Shlyankevich
authors.forename: J W
authors.initials: JW
authors.lastname: Lee
authors.forename: J K
authors.initials: JK
authors.lastname: Yoo
mesh_terms: D015123:7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide / Q000633:toxicity; D000818:Animals; D016588:Anticarcinogenic Agents / Q000494:pharmacology; D016587:Antimutagenic Agents / Q000494:pharmacology*; D001564:Benzo(a)pyrene / Q000037:antagonists & inhibitors* / Q000378:metabolism* / Q000633:toxicity; D001711:Biotransformation; D004247:DNA / Q000378:metabolism*; D018736:DNA Adducts / Q000187:drug effects*; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008862:Microsomes, Liver / Q000378:metabolism; D015394:Molecular Structure; D009152:Mutagenicity Tests; D009153:Mutagens / Q000633:toxicity; D051381:Rats; D017207:Rats, Sprague-Dawley; D012486:Salmonella typhimurium / Q000187:drug effects; D013844:Thiazoles / Q000494:pharmacology*
chemical_list: D016588:Anticarcinogenic Agents; D016587:Antimutagenic Agents; D018736:DNA Adducts; D009153:Mutagens; D013844:Thiazoles; C098009:YH 439; D001564:Benzo(a)pyrene; D015123:7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide; D004247:DNA