Downregulation of male-specific cytochrome P450s 2C11 and 3A2 in bile duct-ligated male rats: Importance to reduced hepatic content of cytochrome P450 in cholestasis

Abstract

The effects of bile duct ligation (BDL) on the activity and content of individual hepatic mixed-function oxidases (MFOs) was examined. Five days after BDL, hepatic microsomal total cytochrome P450 (CYP) content and NADPH-cytochrome P450-reductase (P450-reductase) activity were reduced to 56% and 57% of control, respectively. MFO activities attributable to the sexually undifferentiated CYPs 1A, 2A1, 2C6, and 2E1 were decreased to 32% to 52% of control, but the activities of two male sex-specific CYPs, 2C11 and 3A2, were reduced to a significantly greater extent ( P < .05). The microsomal contents of CYP proteins 2C6 and 2E1 were decreased after BDL to 61% and 63% of control, whereas 2C11 and 3A2 proteins were 21% and 45% of control. Corresponding reductions of the messenger RNA (mRNA) species for CYP 2C11 (9% of control) and 3A2 (37%) were detected, whereas there was no reduction of 2C6 mRNA. These findings are consistent with downregulation of the CYP 2C11 and 3A2 genes. Nuclear run-on studies performed 3 days after BDL showed that there was a generalized impairment of gene transcription after BDL, but a disproportionate reduction in transcription of CYPs 2C11 and 3A2. A possible explanation for downregulation of CYP 2C11 and 3A2 was provided by the observation that serum estradiol concentrations were threefold greater in BDL male rats, while serum testosterone was reduced; estradiol is known to downregulate CYPs 2C11 and 3A2. It is concluded that male sex-specific CYP enzymes are decreased to a greater extent than other microsomal proteins in BDL male rats. It is proposed that the reduced activity of steroid metabolizing enzymes, which occurs after BDL, results in altered serum sex steroid concentrations, which, in turn, lead to decreased transcription of CYP 2C11 and 3A2 genes.