Effect of hemodialysis on hepatic cytochrome P450 functional expression.
Cytochrome P450 (CYP) functional expression is reduced in uremia and normalized after restoration of kidney function via transplantation. The aim of this study was to evaluate the effect of conventional hemodialysis on the functional expression of CYP1A, 2C, and 3A. We also investigated the role of nuclear factor-kappaB (NF-kappaB) in CYP regulation during uremia. Primary cultures of normal rat hepatocytes were incubated with serum obtained from end-stage renal disease patients pre- and post-hemodialysis and healthy control subjects, in the presence and absence of the NF-kappaB inhibitor andrographolide. Uremic pre-hemodialysis serum caused significant reductions (P<0.01) in CYP1A (44%), 2C (27%), and 3A (35%) protein expression compared to control serum, while dialyzed serum (i.e., obtained immediately post-hemodialysis) had no effect. CYP1A2, 2C11, and 3A2 mRNA expression, as well as CYP3A activity, were similarly impacted by uremic serum and were improved to >80% of control values after hemodialysis. NF-kappaB inhibition nearly eliminated the effect of uremic serum on CYP functional expression. This is the first study to demonstrate that conventional hemodialysis acutely improves altered CYP functional expression observed in rat hepatocytes incubated with uremic human serum.
Service de Néphrologie et Centre de Recherche Guy-Bernier, Hôpital Maisonneuve-Rosemont, Canada.
Josée
J
Michaud
Thomas D
TD
Nolin
Judith
J
Naud
Mélina
M
Dani
Jean-Philippe
JP
Lafrance
Francois A
FA
Leblond
Jonathan
J
Himmelfarb
Vincent
V
Pichette
D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases / Q000378:metabolism; D002478:Cells, Cultured; D019388:Cytochrome P-450 CYP1A2 / Q000378:metabolism; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism*; D000072467:Cytochrome P450 Family 2; D003580:Cytochromes; D004224:Diterpenes / Q000494:pharmacology; D015536:Down-Regulation; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D022781:Hepatocytes / Q000187:drug effects / Q000201:enzymology*; D006801:Humans; D007676:Kidney Failure, Chronic / Q000097:blood / Q000628:therapy*; D008099:Liver / Q000187:drug effects / Q000201:enzymology*; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D008875:Middle Aged; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D006435:Renal Dialysis; D039181:Steroid 16-alpha-Hydroxylase / Q000378:metabolism; D014511:Uremia / Q000097:blood / Q000628:therapy*
D003580:Cytochromes; D004224:Diterpenes; D008565:Membrane Proteins; D016328:NF-kappa B; D012333:RNA, Messenger; C030419:andrographolide; D003577:Cytochrome P-450 Enzyme System; D001189:Aryl Hydrocarbon Hydroxylases; C450279:CYP2C11 protein, rat; C017170:Cyp1a2 protein, rat; C465260:Cyp3a2 protein, rat; D019388:Cytochrome P-450 CYP1A2; D051544:Cytochrome P-450 CYP3A; D000072467:Cytochrome P450 Family 2; D039181:Steroid 16-alpha-Hydroxylase