Abstract

Inflammatory stimuli such as bacterial lipopolysaccharide (LPS) have been shown to down-regulate the mRNA and protein expression of hepatic cytochrome P-450 (P-450) isozymes 2C11, 2C12, 2E1 and 3A2 and to induce the mRNA expression of the P-450 4A subfamily. In this study, we examined the effects of irritants on the hepatic and renal expression of P-450 2C11, 2E1 and 3A2 and the 4A subfamily in the rat. Fischer 344 rats were administered doses of SiO₂ (Celite), BaSO₄, kaolin and LPS intraperitoneally and killed after different times for hepatic and renal RNA and microsome isolation. The administration of each irritant was found to suppress hepatic P-450 2C11 mRNA and protein and to induce P-450 4A1, 4A2 and 4A3 mRNA expression while having no significant effect on P-450 2E1 or 3A2. P-450 4A2, 4A3 and 2E1 mRNAs were all induced in the kidney cortices of the irritant- and LPS-treated rats. The effects of BaSO₄and SiO₂ were found to be dose dependent. Chlorzoxazone-6-hydroxylase activity increased in the kidneys of irritant-treated rats, which is consistent with an increased expression of P-450 2E1. All irritants were found to induce the mRNA for the acute-phase protein fibrinogen; however, in contrast to LPS treatment, none of the irritants that were tested induced hepatic inducible nitric oxide synthase mRNA expression. These findings demonstrate the induction of renal P-450 isozymes after irritant and LPS administration. The findings of this study also suggest that different inflammatory stimuli affect the individual P-450 isozymes differentially.