title: Formation of a 3,4-diol-1,2-epoxide metabolite of benz[a]anthracene with cytotoxicity and genotoxicity in a human in vitro hepatocyte culture system.
abstract: Polycyclic aromatic hydrocarbons (PAHs) are environmental pollutants that require metabolic activation to exert their carcinogenic effects. This study investigated the 3,4-diol-1,2-epoxide formation of benz[a]anthracene (BA) and its toxic effects in a human in vitro hepatocyte culture system. Both mRNA and protein expression of metabolic enzymes which can activate PAHs to carcinogenic forms increased after BA exposure in HepG2 cells and our quantitative analysis showed that the formation of BA-3,4-diol-1,2-epoxide in medium extracts increased in a time-dependent manner. We also performed several comparative studies which show that much lower concentrations of BA-3,4-diol-1,2-epoxide had stronger cytotoxicity and genotoxicity than higher doses of BA. These results suggest that BA is activated as the major carcinogenic metabolite 3,4-diol-1,2-epoxide, in human in vitro culture systems by metabolic enzymes and that this metabolite has stronger cytotoxic and genotoxic effects than its parent compound.
authors.affiliation: Cellular and Molecular Toxicology Laboratory, Korea Institute of Science & Technology, PO Box 131, Cheongryang, Seoul, 130-650, Republic of Korea.
authors.forename: Mi-Kyung
authors.initials: MK
authors.lastname: Song
authors.forename: Youn-Jung
authors.initials: YJ
authors.lastname: Kim
authors.forename: Mee
authors.initials: M
authors.lastname: Song
authors.forename: Han-Seam
authors.initials: HS
authors.lastname: Choi
authors.forename: Yong-Keun
authors.initials: YK
authors.lastname: Park
authors.forename: Jae-Chun
authors.initials: JC
authors.lastname: Ryu
mesh_terms: D000429:Alcohol Oxidoreductases / Q000096:biosynthesis / Q000235:genetics; D017209:Apoptosis / Q000187:drug effects; D001551:Benz(a)Anthracenes / Q000378:metabolism / Q000633:toxicity*; D001711:Biotransformation; D002274:Carcinogens, Environmental / Q000378:metabolism / Q000633:toxicity*; D002453:Cell Cycle / Q000187:drug effects; D002478:Cells, Cultured; D020552:Comet Assay; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis / Q000235:genetics; D004249:DNA Damage; D004305:Dose-Response Relationship, Drug; D004790:Enzyme Induction; D056945:Hep G2 Cells; D022781:Hepatocytes / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D009153:Mutagens / Q000378:metabolism / Q000633:toxicity*; D012333:RNA, Messenger / Q000096:biosynthesis; D013997:Time Factors
chemical_list: D001551:Benz(a)Anthracenes; D002274:Carcinogens, Environmental; D009153:Mutagens; D012333:RNA, Messenger; C026832:3,4-dihydroxy-1,2-epoxy-1,2,3,4-tetrahydrobenz(a)anthracene; D003577:Cytochrome P-450 Enzyme System; D000429:Alcohol Oxidoreductases