RRC ID 80084
Author Yamamoto Y, Yamazaki H, Ikeda T, Watanabe T, Iwabuchi H, Nakajima M, Yokoi T.
Title Formation of a novel quinone epoxide metabolite of troglitazone with cytotoxicity to HepG2 cells.
Journal Drug Metab Dispos
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.
Volume 30(2)
Pages 155-60
Published 2002-2-1
DOI 10.1124/dmd.30.2.155
PMID 11792684
MeSH Antineoplastic Agents / metabolism Antineoplastic Agents / toxicity* Benzoquinones / metabolism* Cell Survival / drug effects Chromans / metabolism* Chromans / pharmacology Chromans / toxicity* Cytochrome P-450 CYP3A Cytochrome P-450 Enzyme System / metabolism Dose-Response Relationship, Drug Epoxy Compounds / metabolism* Growth Inhibitors / metabolism Growth Inhibitors / toxicity Hepatocytes / drug effects Hepatocytes / enzymology Hepatocytes / metabolism* Humans Indicators and Reagents / metabolism Mixed Function Oxygenases / metabolism Thiazoles / metabolism* Thiazoles / pharmacology Thiazoles / toxicity* Thiazolidinediones* Troglitazone Tumor Cells, Cultured / drug effects Tumor Cells, Cultured / enzymology Tumor Cells, Cultured / metabolism*
IF 3.231
Human and Animal Cells Hep G2