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

Background & Aims: The cytokine tumor necrosis factor alpha (TNF-alpha ) is a primary inflammatory mediator after liver injury. Several cytok ines impair the regulation of cytochrome P450 (CYP) genes in liver, bu t the specificity of these effects remains unclear. This study investi gated the effects of recombinant murine TNF-alpha on the expression of specific constitutive CYPs in male rat liver. Methods: Microsomal ste roid hydroxylation was used to indicate the activities of specific CYP s after TNF-alpha treatment and immunoblotting to correlate CYP activi ties 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 (C YP 2A1) was unchanged. Similarly, progesterone 2 alpha/16 alpha- (CYP 2C11) and 6 beta-hydroxylations (CYP 3A2), but not 21-hydroxylation (C YP 2C6), were decreased after TNF-alpha treatment. 2C11 and 3A2 apopro teins and messenger RNAs, but not 2A1 apoprotein, were decreased after TNF-alpha treatment; changes in messenger RNAs were evident 4 hours a fter treatment. Conclusions: TNF-alpha down-regulates CYPs 2C11 and 3A 2 in male rat liver at a pretranslational level, whereas two other con stitutive CYPs, 2A1 and 2C6, seem refractory to TNF-alpha. Thus, impai red CYP regulation by TNF-alpha resembles the combined effects of auto logous interferons (on 3A2) and interleukins (on 2C11).