Abstract
Troglitazone, a new oral antidiabetic drug, has been reported to cause idiosyncratic hapatitis in certain individuals. The mechanism for hepatic failure was investigated with comparison between troglitazone and its metabolites and other thiazolidinedions. Oxidation pathway of troglitazone to a qunone-type metabolite was catalyzed mainly by CYP2C8 and CYP3A4 in human liver microsomes. Inhibitory effects of troglitazone and its metabolites on drug oxidation activities of human CYPs were not potent. Autoimmune antigen was identified in patients with idiosyncratic hepatitis. Hepatic toxicity did not appear in troglitazone treated rats after modifications of sulfotransferase, gluclonosyl-trasferase, or glutathione S-transferase activities. Treatment of HepG2 cell lines with troglitazone and a quinone type-metabolite showed time- and concentration-dependent cytotoxicity. Troglitazone induced apoptotic cell death in HepG2 cells. Taking these results into consideration, the causal factor(s) for idiosyncratic hepatitis in human remained unclear.
