Differential Regulation of Hepatic Cytochrome P450 Monooxygenases

Abstract

Cytochrome P450 (CYP) is a superfamily of hemoproteins that are able to metabolize a large number of xenobiotics through oxidative, reductive, and peroxidative mechanisms. Many intermediary metabolites of carbohydrates and lipids are produced in diabetes that are known to modulate the cytochrome P450 monooxygenases. During the oxidation of its substrates, the cytochrome P450 monooxygenases generate reactive oxygen species. The present study investigated the expression of major cytochrome P450 isozymes in streptozotocin-induced diabetes with concomitant insulin therapy. Male rats were randomly assigned to untreated control, streptozotocin-induced diabetic, insulin-treated groups and monitored for 4 wk. Uncontrolled hyperglycemia in the early phase of diabetes was associated with differential regulation of cytochrome P450 isozymes, including upregulation of CYP1A2-dependent 7-ethoxyresorufin O-deethylase (EROD) activity and expression of CYP1A2, CYP1B1 and heme oxygenase (HO)-2 proteins. Insulin therapy ameliorated the EROD activity and the expression of CYP1A2, CYP1B1 and HO-2 proteins. In addition, CYP2B1 and 2E1 proteins were markedly induced in the diabetic group. Insulin therapy resulted in complete amelioration of CYP2E1 protein and partial amelioration of CYP2B1 protein. By contrast, CYP2C11 and CYP3A1 protein expression were decreased over 99% and 95%, respectively, in the diabetic group. CYP2C11 protein was partially ameliorated by insulin therapy, whereas CYP3A1 was not affected.