title: Downregulation of intestinal cytochrome p450 in chronic renal failure.
abstract: Chronic renal failure (CRF) is associated with a decrease in intestinal drug metabolism. The mechanisms remain poorly understood, but one hypothesis involves a reduction in cytochrome P450 levels. This study aimed to investigate the effects of CRF on intestinal cytochrome P450. Two groups of rats were defined, i.e., rats with CRF (induced by 5/6 nephrectomy) and control pair-fed rats. Total cytochrome P450 levels and protein and mRNA expression of cytochrome P450 isoforms, as well as in vitro N-demethylation of erythromycin (a probe for CYP3A activity) and 7-ethoxyresorufin o-deethylase activity (a probe for CYP1A), were assessed in intestinal microsomes. Body weights were similar in the two groups. Creatinine clearance was reduced by 77% (P < 0.001) in CRF rats, compared with control pair-fed animals. Total intestinal cytochrome P450 activity was reduced by 32% (P < 0.001) in CRF rats. CYP1A1 and CYP3A2 protein expression was considerably reduced (>40%, P < 0.001) in rats with CRF. CYP2B1, CYP2C6, and CYP2C11 levels were the same in the two groups. RT-PCR assays revealed marked downregulation of CYP1A1 and CYP3A2 gene expression in CRF rats (P < 0.001). Although intestinal cytochrome P450 levels were reduced in CRF, induction by dexamethasone was present. N-Demethylation of erythromycin and 7-ethoxyresorufin o-deethylase activity were decreased by 25% (P < 0.05) in CRF rats, compared with control rats. In conclusion, CRF in rats is associated with decreases in intestinal cytochrome P450 activity (mainly CYP1A1 and CYP3A2) secondary to reduced gene expression.
authors.affiliation: Nephrology Service and Centre de Recherche Guy-Bernier, Hôpital Maisonneuve-Rosemont, Faculty of Medicine, Université de Montréal, Québec, Canada.
authors.forename: Francois A
authors.initials: FA
authors.lastname: Leblond
authors.forename: Martin
authors.initials: M
authors.lastname: Petrucci
authors.forename: Pierre
authors.initials: P
authors.lastname: Dubé
authors.forename: Gilbert
authors.initials: G
authors.lastname: Bernier
authors.forename: Alain
authors.initials: A
authors.lastname: Bonnardeaux
authors.forename: Vincent
authors.initials: V
authors.lastname: Pichette
mesh_terms: D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases / Q000032:analysis / Q000235:genetics*; D019363:Cytochrome P-450 CYP1A1 / Q000032:analysis / Q000235:genetics*; D051544:Cytochrome P-450 CYP3A; D015536:Down-Regulation; D004790:Enzyme Induction; D004917:Erythromycin / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic; D007422:Intestines / Q000201:enzymology*; D007676:Kidney Failure, Chronic / Q000201:enzymology*; D008297:Male; D008565:Membrane Proteins; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D008565:Membrane Proteins; D012333:RNA, Messenger; D004917:Erythromycin; D001189:Aryl Hydrocarbon Hydroxylases; C465260:Cyp3a2 protein, rat; D019363:Cytochrome P-450 CYP1A1; D051544:Cytochrome P-450 CYP3A