Study of Metabolism and Cytotoxicity of Troglitazone

摘要

Troglitazone, a new oral antidiabetic drug, has been reported to cause idiosyncratic hepatitis in certain individuals. The mechanism for the hepatic failure was investigated with comparison between troglitazone and its metabolites and other thiazolidinediones, pioglitazone and rosiglitazone. Hepatic toxicity did not appear in rats in troglitazone-administered study after modifications of sulfotransferase and glucuronosyltrasferase activities and glutathione concentration. Oxidation pathway of troglitazone to a quinine-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 P450s would not be potent, based on its low blood concentrations and high protein binding ratio. An autoimmune antibody against aldo-lase B was identified in two patients with troglitazone-induced idiosyncratic hepatitis. However, this antibody was also detected in some other hepatic diseases, in spite of no cases in health control subjects. Trantment 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 characterized by internucleosomal DNA fragmentation and nuclear condensation. Taking these results into copnsideration, the causal factor (s) for idiosyncratic hepatitis i human remained unclear.