Downregulation of hepatic cytochrome P450 in chronic renal failure.
Chronic renal failure (CRF) is associated with a decrease in drug metabolism. 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 activity, protein expression of several CYP450 isoforms as well as their mRNA, and the in vitro N-demethylation of erythromycin were assessed in liver microsomes. 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 was reduced by 30% (P: < 0.01) in control paired-fed and CRF rats, compared with control animals. There was no difference in the CYP450 parameters between control and control paired-fed. Compared with control paired-fed rats, total CYP450 was reduced by 47% (P: < 0.001) in CRF rats. Protein expression of CYP2C11, CYP3A1, and CYP3A2 were considerably reduced (>40%, P: < 0.001) in rats with CRF. The levels of CYP1A2, CYP2C6, CYP2D, and CYP2E1 were the same in the three groups. Northern blot analysis revealed a marked downregulation in gene expression of CYP2C11, 3A1, and 3A2 in CRF rats. Although liver CYP450 was reduced in CRF, its induction by dexamethasone and phenobarbital was present. N-demethylation of erythromycin was decreased by 50% in CRF rats compared with control (P: < 0.001). In conclusion, CRF in rats is associated with a decrease in liver cytochrome P450 activity (mainly in CYP2C11, CYP3A1, and 3A2), secondary to reduced gene expression.
Leblond
Francois
F
Service de Néphrologie et Centre de Recherche Guy-Bernier, Hôpital Maisonneuve-Rosemont, Université de Montréal, Québec, Canada.
Guévin
Carl
C
Service de Néphrologie et Centre de Recherche Guy-Bernier, Hôpital Maisonneuve-Rosemont, Université de Montréal, Québec, Canada.
Demers
Christian
C
Centre Hospitalier Universitaire de Montréal, Faculté de Médecine, Université de Montréal, Québec, Canada.
Pellerin
Isabelle
I
Service de Néphrologie et Centre de Recherche Guy-Bernier, Hôpital Maisonneuve-Rosemont, Université de Montréal, Québec, Canada.
Gascon-Barré
Marielle
M
Centre Hospitalier Universitaire de Montréal, Faculté de Médecine, Université de Montréal, Québec, Canada.
Pichette
Vincent
V
Service de Néphrologie et Centre de Recherche Guy-Bernier, Hôpital Maisonneuve-Rosemont, Université de Montréal, Québec, Canada.
D000818:Animals; D001835:Body Weight; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D003907:Dexamethasone / Q000494:pharmacology; D015536:Down-Regulation; D004917:Erythromycin / Q000378:metabolism; D007527:Isoenzymes / Q000378:metabolism; D007676:Kidney Failure, Chronic / Q000201:enzymology*; D008099:Liver / Q000201:enzymology*; D008297:Male; D010634:Phenobarbital / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley
D007527:Isoenzymes; D004917:Erythromycin; D003907:Dexamethasone; D003577:Cytochrome P-450 Enzyme System; D010634:Phenobarbital