Downregulation of intestinal cytochrome p450 in chronic renal failure.
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.
Leblond
Francois A
FA
Nephrology Service and Centre de Recherche Guy-Bernier, Hôpital Maisonneuve-Rosemont, Faculty of Medicine, Université de Montréal, Québec, Canada.
Petrucci
Martin
M
Dubé
Pierre
P
Bernier
Gilbert
G
Bonnardeaux
Alain
A
Pichette
Vincent
V
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
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