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
✍ Scribed by Jiezhong Chen; Michael Murray; Christopher Liddle; Xing-Mai Jiang; Geoffrey C. Farrell
- Publisher
- John Wiley and Sons
- Year
- 1995
- Tongue
- English
- Weight
- 951 KB
- Volume
- 22
- Category
- Article
- ISSN
- 0270-9139
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✦ Synopsis
The effects of bile duct ligation (BDL) on the activity and content of individual hepatic mixed-function oxi- dases (IMFOs) 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 lA, 2A1, 2C6, and 2E1 were decreased to 32% to 52% of control, but the activities of two male sex-specific CYPs, 2 C l l 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 2 C l l and 3A2 proteins were 21% and 45% of control. Corresponding reductions of the messenger RNA (mRNA) species for CYP 2Cll (% of control) and 3A2 (37%) were detected, whereas there was no reduction of 2C6 mFtNA. These findings are consistent with downregulation of the CYP 2Cll 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 2 C l l and 3A2. A possible explanation for downregulation of CYP 2Cll 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 2 C l l and 3A2. It is concluded that male sex-specific CYP enzymes are decreased to a greater extent than other microsomal