Cytotoxic effect of peroxisome proliferator fenofibrate on human HepG2 hepatoma cell line and relevant mechanisms.

The aim of this work was to investigate the effects of hypolipidemic agent fenofibrate (FF), a peroxisome proliferator (PP), on human HepG2 cells and to characterize the intracellular events involved. The results showed that, in contrast to the tumor-promoting effects in rodents, high FF concentrations induced human HepG2 cell death through a mechanism involving an increase in the levels of reactive oxygen species (ROS) and intracellular GSH depletion, which led, through mitochondrial dysfunction and perturbation of intracellular Ca(2+) homeostasis, to cell death. The nuclear receptor peroxisome proliferator-activated receptor-alpha (PPAR(alpha)) was expressed following FF treatment. The results suggest that, although long-term administration of PPs causes liver cancer in susceptible species (e.g., rodents), FF inhibits the growth of human HepG2 cells in a dose-related manner and oxidative stress was involved in this effect.