Downregulation of hepatic cytochrome P450 in chronic renal failure

Chronic renal failure (CRF) is associated with a decrease in drug metabolis m. The mechanism remains poorly understood. The present study investigated the repercussions of CRF on liver cytochrome P450 (CYP450). Three groups of rats were defined: control, control paired-fed, and CRF. Total CYP450 acti vity, protein expression of several CYP450 isoforms as well as their mRNA, and the in vitro N-demethylation of erythromycin were assessed in liver mic rosomes. The regulation of liver CYP450 by dexamethasone and phenobarbital was assessed in CRF rats. Compared with control and control paired-fed rats , creatinine clearance was reduced by 60% (P < 0.01) in CRF rats. Weight wa s reduced by 30% (P < 0.01) in control paired-fed and CRF rats, compared wi th control animals. There was no difference in the CYP450 parameters betwee n control and control paired-fed. Compared with control paired-fed rats, to tal CYP450 was reduced by 47% (P < 0.001) in CRF rats. Protein expression o f CYP2C11, CYP3A1, and CYP3A2 were considerably reduced (>40%, P < 0.001) i n rats with CRF. The levels of CYP1A2, CYP2C6, CYP2D, and CYP2E1 were the s ame in the three groups. Northern blot analysis revealed a marked downregul ation in gene expression of CYP2C11, 3A1, and 3A2 in CRF rats. Although liv er CYP450 was reduced in CRF, its induction by dexamethasone and phenobarbi tal was present. N-demethylation of erythromycin was decreased by 50% in CR F rats compared with control (P < 0.001). In conclusion, CRF in rats is ass ociated with a decrease in liver cytochrome P450 activity (mainly in CYP2C1 1, CYP3A1, and 3A2), secondary to reduced gene expression.