Cytotoxicity and apoptosis produced by troglitazone in human hepatoma cells.
Troglitazone is an antidiabetic agent that increases the insulin sensitivity of target tissues in non-insulin-dependent diabetes mellitus. It has been reported that troglitazone causes severe hepatic injury in certain individuals. In the present study, the mechanism for the hepatic injury by troglitazone was investigated with human hepatoma cell lines. HepG2 cells were incubated with troglitazone, its metabolites M-1 (sulfate), M-2 (gulucronide), M-3 (quinone), and other thiazolidinediones (pioglitazone and rosiglitazone). Troglitazone exhibited time- and concentration-dependent cytotoxicity and M-3 also exhibited weak cytotoxicity. Troglitazone induced apoptotic cell death characterized by internucleosomal DNA fragmentation and nuclear condensation. As other thiazolidinediones, pioglitazone and rosiglitazone, did not induce cell death and apoptosis in the present study, the affinity to PPARgamma may not affect the induction of apoptosis by troglitazone. These results suggest that troglitazone induces apoptotic hepatocyte death which it may be one of the factors of liver injury in humans.
Yamamoto
Y
Y
Division of Drug Metabolism, Faculty of Pharmaceutical Sciences, Kanazawa University, Japan.
Nakajima
M
M
Yamazaki
H
H
Yokoi
T
T
D017209:Apoptosis / Q000187:drug effects*; D006528:Carcinoma, Hepatocellular; D002470:Cell Survival / Q000187:drug effects; D002839:Chromans / Q000378:metabolism / Q000633:toxicity*; D053938:DNA Fragmentation; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007004:Hypoglycemic Agents / Q000378:metabolism / Q000633:toxicity*; D000077205:Pioglitazone; D000077154:Rosiglitazone; D013778:Tetrazolium Salts / Q000378:metabolism; D013844:Thiazoles / Q000378:metabolism / Q000633:toxicity*; D045162:Thiazolidinediones; D000077288:Troglitazone; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000378:metabolism / Q000473:pathology
D002839:Chromans; D007004:Hypoglycemic Agents; D013778:Tetrazolium Salts; D013844:Thiazoles; D045162:Thiazolidinediones; D000077154:Rosiglitazone; D000077288:Troglitazone; D000077205:Pioglitazone