PT  - JOURNAL ARTICLE
AU  - Yui Yamamoto
AU  - Hiroshi Yamazaki
AU  - Tomoko Ikeda
AU  - Terumi Watanabe
AU  - Haruo Iwabuchi
AU  - Miki Nakajima
AU  - Tsuyoshi Yokoi
TI  - Formation of a Novel Quinone Epoxide Metabolite of Troglitazone with Cytotoxic to HepG2 Cells
AID  - 10.1124/dmd.30.2.155
DP  - 2002 Feb 01
TA  - Drug Metabolism and Disposition
PG  - 155--160
VI  - 30
IP  - 2
4099  - http://dmd.aspetjournals.org/content/30/2/155.short
4100  - http://dmd.aspetjournals.org/content/30/2/155.full
SO  - Drug Metab Dispos2002 Feb 01; 30
AB  - 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 μM) 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 μM) 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,1H NMR, and 13C 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. The American Society for Pharmacology and Experimental Therapeutics