Defective expression of cytochrome P450 proteins in the liver of the genetically obese Zucker rat

Abstract

The hepatic expression of xenobiotic-metabolising cytochrome P450 isoforms in the genetically obese Zucker rat, a model of obesity, was compared to that of its lean littermate. Cytochrome P450 (CYP) levels were determined using diagnostic substrates and/or immunologically in Western blot analyses. When compared with the lean Zucker rat, the obese animal exhibited hyperglycaemia, hypercholesterolaemia, marked hyperinsulinaemia and hypertriglyceridaemia but was normoketonaemic. CYP3A and CYP1A2 levels were higher in the obese Zucker rat when compared with the lean littermate but, in contrast, a protein recognised by human CYP2D6 and, to a lesser extent, CYP2C11 levels were lower. Pretreatment with acetone, dexamethasone and clofibrate resulted in enhanced p-nitrophenol hydroxylase (CYP2E), erythromycin N-demethylase (CYP3A) and lauric acid hydroxylase (CYP4A) activities respectively in the liver of the lean Zucker rat but, in contrast, the obese Zucker rat was refractive to such treatment; similarly, hepatic apoprotein levels of the CYP2E and CYP4A subfamilies were increased markedly only in the lean Zucker rat. It is concluded that CYP2E, CYP3A and CYP4A subfamilies are poorly expressed in the obese Zucker rat, and this rat strain may serve as a good model for elucidating the molecular mechanisms of induction of these cytochrome P450 proteins.