SELECTIVE SUPPRESSION OF CYTOCHROME-P-450 GENE-EXPRESSION BY INTERLEUKIN-1 AND INTERLEUKIN-6 IN RAT-LIVER

Inflammatory stimuli suppress constitutive hepatic expression of the CYP2C11 and CYP2C12 genes in male and female rat livers, respectively. We have shown previously that injection of interleukin-1 (IL1), but not interleukin-6 (IL6), to female rats also suppresses CYP2C12. In the present study, we examined the effects of these cytokines on CYP2C12 expression in rat hepatocyte cultures, and their in vivo effects on expression of multiple cytochrome P-450 (P450) gene products in male rat livers. IL1 suppressed the expression of CYP2C12 mRNA and protein in hepatocytes cultured on Matrigel in the presence of growth hormone. No consistent effect of IL6 was observed. Maximal suppression of CYP2C12 mRNA after 24 h of IL1 treatment reached 12 and 32% of control levels in two separate experiments. The approximate ED(50) for IL1 was 5 ng/ml. CYP2C12 protein was suppressed to 28% of control levels as early as 12 h after IL1 treatment. Injection of IL1, low doses of dexamethasone, or both, in male rats produced decreases in total P450, and in CYP3A2 and CYP2C11 mRNA and protein expression similar to effects previously seen for CYP2C12 expression in females. CYP2E1 mRNA and protein was significantly suppressed only by the combination of IL1 and dexamethasone. IL6 treatment of male rats down-regulated the CYP2C11 and CYP2E1 mRNAs at a dose of 4.5 mu g/kg, which was lower than that required to induce haptoglobin mRNA, a prototype acute phase gene product. CYP2C11 protein content of the microsomes was also decreased by IL6 treatment, with a slower time-course than for suppression of its mRNA. No significant effects of IL6 treatment were seen on CYP3A2 mRNA or CYP3A2/1 proteins. These results demonstrate that IL1 and IL6 treatments in vivo differentially affect subsets of P450 gene products in rat liver.