Effect of pioglitazone on endotoxin-induced decreases in hepatic drug-metabolizing enzyme activity and expression of CYP3A2 and CYP2C11.

It has been reported that peroxisome proliferator-activated receptor-gamma (PPAR-gamma) ligands ameliorate the expression of inducible nitric oxide synthase (iNOS) by endotoxin. In the present study, we investigated the effect of pioglitazone, a potent PPAR-gamma ligand, on the endotoxin-induced reduction of hepatic drug-metabolizing enzyme activity and on the down-regulation of the expression of hepatic cytochrome P450 (CYP) 3A2 and CYP2C11 proteins in rats. Endotoxin (1 mg/kg) significantly decreased hepatic drug-metabolizing enzyme activity in vivo, as represented by the systemic clearance of antipyrine and protein levels of CYP3A2 and CYP2C11 24 h after intraperitoneal injection. Pretreatment with pioglitazone (10 mg/kg, 4 times at 10-min intervals) significantly protected the endotoxin-induced decreases in the systemic clearance of antipyrine and protein levels of CYP3A2, but not CYP2C11, with no biochemical and histopathological changes in the liver. Pioglitazone alone had no effect on the systemic clearance of antipyrine and protein levels of CYP3A2 or CYP2C11. Pioglitazone significantly protected endotoxin-induced overexpression of iNOS in the liver, but not the overproduction of nitric oxide (NO) in plasma. It is unlikely that the protective effect of pioglitazone against endotoxin-induced decreases in the hepatic drug-metabolizing enzyme activity and protein levels of CYP3A2 in the liver is due to the inhibition of the overproduction of NO.