PRETRANSLATIONAL DOWN-REGULATION OF CYTOCHROMES P450 2C11 AND 3A2 IN MALE-RAT LIVER BY TUMOR-NECROSIS-FACTOR-ALPHA

被引：49

作者：

NADIN, L ^{[1
]}

BUTLER, AM ^{[1
]}

FARRELL, GC ^{[1
]}

MURRAY, M ^{[1
]}

机构：

[1] UNIV SYDNEY, WESTMEAD HOSP, DEPT MED, STORR LIVER UNIT, WESTMEAD, NSW 2145, AUSTRALIA

来源：

GASTROENTEROLOGY | 1995年 / 109卷 / 01期

基金：

英国医学研究理事会;

关键词：

D O I：

10.1016/0016-5085(95)90285-6

中图分类号：

R57 [消化系及腹部疾病];

学科分类号：

摘要：

Background & Aims: The cytokine tumor necrosis factor alpha (TNF-alpha) is a primary inflammatory mediator after liver injury. Several cytokines impair the regulation of cytochrome P450 (CYP) genes in liver, but the specificity of these effects remains unclear. This study investigated the effects of recombinant murine TNF-alpha on the expression of specific constitutive CYPs in male rat liver. Methods: Microsomal steroid hydroxylation was used to indicate the activities of specific CYPs after TNF-alpha treatment and immunoblotting to correlate CYP activities with protein contents. CYP messenger RNA levels were measured by solution hybridization. Results: Testosterone 2 alpha-/16 alpha- and 6 beta-hydroxylations, mediated respectively by CYPs 2C11 and 3A2, were decreased after TNF-alpha treatment, whereas 7 alpha-hydroxylation (CYP 2A1) was unchanged. Similarly, progesterone 2 alpha/16 alpha- (CYP 2C11) and 6 beta-hydroxylations (CYP 3A2), but not 21-hydroxylation (CYP 2C6), were decreased after TNF-alpha treatment. 2C11 and 3A2 apoproteins and messenger RNAs, but not 2A1 apoprotein, were decreased after TNF-alpha treatment; changes in messenger RNAs were evident 4 hours after treatment. Conclusions: TNF-alpha down-regulates CYPs 2C11 and 3A2 in male rat liver at a pretranslational level, whereas two other constitutive CYPs, 2A1 and 2C6, seem refractory to TNF-alpha. Thus, impaired CYP regulation by TNF-alpha resembles the combined effects of autologous interferons (on 3A2) and interleukins (on 2C11).

引用

页码：198 / 205

页数：8

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