Effects of serum from patients with chronic renal failure on rat hepatic cytochrome P450.
1. In humans, chronic renal failure (CRF) is associated with decreased hepatic drug metabolism, particularly that mediated by the cytochrome P450 (P450). The mechanisms remain poorly understood. The present study aimed to investigate the effects of the serum of patients with CRF on liver P450, and to evaluate whether renal replacement therapies (dialysis or transplantation) impede the inhibition of CRF serum on P450. 2. Rat hepatocytes were incubated for 24 h with serum from patients with severe CRF and from controls to measure (1) P450 level, (2) protein expression and mRNA levels of P450 isoforms and (3) metabolic activities of CYP3A and CYP1A. Similar experiments were performed with serum of patients once on chronic hemodialysis and after kidney transplantation. 3. In rat hepatocytes incubated for 24 h with serum from patients with CRF, P450 level and protein expression, as well as mRNA levels of P450 isoforms (CYP1A2, 2C6, 2C11, 2D1/2D2, 3A2 and 4A1/4A3), were decreased by more than 45% (P<0.001) compared to control serum, while the levels of CYP2E1 were not modified. CYP3A and CYP1A activities were decreased by 51 and 59% (P<0.001), respectively. The inhibitory effect of serum obtained from patients before first dialysis was similar after 1 or 6 months on chronic hemodialysis but was lost after successful kidney transplantation. In CRF serum, the fraction containing proteins between 10 and 15 kDa decreases P450. 4. Human uremic serum contains mediator(s) that decreases rat hepatic P450 activity and expression secondary to reduced gene expression. The inhibitory effect of serum persists even after initiation of dialysis, but disappears after normalization of renal function following kidney transplantation.
Michaud
Josée
J
Service de néphrologie et Centre de recherche Guy-Bernier, Hôpital Maisonneuve-Rosemont, Faculté de Médecine, Université de Montréal, 5415 boul.de l'Assomption, Montreal, Québec, Canada H1T 2H4.
Dubé
Pierre
P
Naud
Judith
J
Leblond
Francois A
FA
Desbiens
Karine
K
Bonnardeaux
Alain
A
Pichette
Vincent
V
D000328:Adult; D000368:Aged; D000818:Animals; D002478:Cells, Cultured; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis / Q000097:blood* / Q000235:genetics; D004305:Dose-Response Relationship, Drug; D005260:Female; D022781:Hepatocytes / Q000201:enzymology*; D006801:Humans; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000097:blood / Q000235:genetics; D007676:Kidney Failure, Chronic / Q000097:blood* / Q000201:enzymology*; D008099:Liver / Q000201:enzymology*; D008297:Male; D008875:Middle Aged; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D044967:Serum / Q000502:physiology*
D065607:Cytochrome P-450 Enzyme Inhibitors; D007527:Isoenzymes; D012333:RNA, Messenger; D003577:Cytochrome P-450 Enzyme System