Troglitazone induces a rapid drop of mitochondrial membrane potential in liver HepG2 cells

Troglitazone, a thiazolidinedione containing compound, was widely used to treat non-insulin dependent-diabetes. Unfortunately, troglitazone was associated with a sporadic liver toxicity that led to accessation of its use clinically. Here we show that troglitazone induces a rapid and dose-dependent drop of mitochondrial membrane potential in liver HepG2 cells. The decrease in mitochondrial membrane potential induced by 100 muM troglitazone was completed after 5 min and similar in magnitude to that caused by carbonyl cyanide m-chloro phenylhydrazone. The troglitazone- induced loss of mitochondrial membrane potential preceded changes in cell permeability and cell count. In addition, troglitazone- induced a rise of intracellular calcium,subsequent to the drop in mitochondrial membrane potential,which was blocked by EGTA and the Na+/Ca2+ exchange inhibitor bepridil. Finally, application of 100 muM troglitazone for 24 h to HepG2 cells resulted in activation of caspase 3. The results of this study shed light on the molecular mechanisms by which troglitazone can cause cytotoxicity. (C) 2004 Elsevier Ireland Ltd. All rights reserved.