RT Journal Article
SR Electronic
T1 Formation of a Novel Quinone Epoxide Metabolite of Troglitazone with Cytotoxic to HepG2 Cells
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 155
OP 160
DO 10.1124/dmd.30.2.155
VO 30
IS 2
A1 Yui Yamamoto
A1 Hiroshi Yamazaki
A1 Tomoko Ikeda
A1 Terumi Watanabe
A1 Haruo Iwabuchi
A1 Miki Nakajima
A1 Tsuyoshi Yokoi
YR 2002
UL http://dmd.aspetjournals.org/content/30/2/155.abstract
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