title: Formation of a novel quinone epoxide metabolite of troglitazone with cytotoxicity to HepG2 cells.
abstract: Troglitazone, an oral antidiabetic drug, was reported to cause adverse hepatic effects in certain individuals, leading to its withdrawal from the market. After incubation of troglitazone (100 microM) with the human hepatoma cell line, HepG2 cells, and human primary hepatocytes for 48 to 72 h, an unknown peak was detected in the cell culture. The formation of this peak from troglitazone (100 microM) was also catalyzed by expressed CYP3A4, and further HPLC analysis revealed that there were three metabolites (metabolite A, B, and C) in the peak. The major metabolite, metabolite C (M-C) was identified as an epoxide of a quinone metabolite of troglitazone by comparison with a synthetic authentic standard using tandem mass spectrometry, (1)H NMR, and (13)C NMR analyses. The other two metabolites (M-A and M-B) were stereoisomers with the same molecular weight as M-C, probably produced from M-C by intramolecular rearrangement at the epoxide moiety. M-C showed a weak cytotoxicity in HepG2 cells at low concentrations, as assessed by the crystal violet-staining assay. Since epoxides are generally regarded as the chemically reactive species, M-C may play a role in idiosyncrasy of troglitazone hepatotoxicity via individual differences either in the formation or degradation of this metabolite.
authors.affiliation: Faculty of Pharmaceutical Sciences, Kanazawa University, Kanazawa, Japan.
authors.forename: Yui
authors.initials: Y
authors.lastname: Yamamoto
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Yamazaki
authors.forename: Tomoko
authors.initials: T
authors.lastname: Ikeda
authors.forename: Terumi
authors.initials: T
authors.lastname: Watanabe
authors.forename: Haruo
authors.initials: H
authors.lastname: Iwabuchi
authors.forename: Miki
authors.initials: M
authors.lastname: Nakajima
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Yokoi
mesh_terms: D000970:Antineoplastic Agents / Q000378:metabolism / Q000633:toxicity*; D016227:Benzoquinones / Q000378:metabolism*; D002470:Cell Survival / Q000187:drug effects; D002839:Chromans / Q000378:metabolism* / Q000494:pharmacology / Q000633:toxicity*; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004852:Epoxy Compounds / Q000378:metabolism*; D006131:Growth Inhibitors / Q000378:metabolism / Q000633:toxicity; D022781:Hepatocytes / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D006801:Humans; D007202:Indicators and Reagents / Q000378:metabolism; D006899:Mixed Function Oxygenases / Q000378:metabolism; D013844:Thiazoles / Q000378:metabolism* / Q000494:pharmacology / Q000633:toxicity*; D045162:Thiazolidinediones; D000077288:Troglitazone; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D016227:Benzoquinones; D002839:Chromans; D004852:Epoxy Compounds; D006131:Growth Inhibitors; D007202:Indicators and Reagents; D013844:Thiazoles; D045162:Thiazolidinediones; C004532:quinone; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; C104464:CYP3A protein, human; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D000077288:Troglitazone