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Vol. 30, Issue 2, 155-160, February 2002

Formation of a Novel Quinone Epoxide Metabolite of Troglitazone with Cytotoxic to HepG2 Cells

Yui Yamamoto, Hiroshi Yamazaki, Tomoko Ikeda, Terumi Watanabe, Haruo Iwabuchi, Miki Nakajima, and Tsuyoshi Yokoi

Faculty of Pharmaceutical Sciences, Kanazawa University, Kanazawa, Japan (Y.Y., H.Y., M.N., T.Y.); and Drug Metabolism and Pharmacokinetics Research Laboratories, Sankyo Company Limited, Tokyo, Japan (T.I., T.W., H.I.)

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.

Copyright © 2002 by The American Society for Pharmacology and Experimental Therapeutics


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Copyright © 2002 by the American Society for Pharmacology and Experimental Therapeutics.