Effects of Chronic Renal Failure on Brain Cytochrome P450 in Rats.
Chronic renal failure (CRF) impedes renal excretion of drugs and their metabolism by reducing the expression of liver cytochrome P450 (P450). Uremic serum contains factors, such as parathyroid hormone (PTH), that decrease liver P450s. The P450s are also involved in the metabolism of xenobiotics in the brain. This study investigates: 1) the effects of CRF on rat brain P450, 2) the role of PTH in the downregulation of brain P450s in CRF rats, and 3) the effects of PTH on P450s in astrocytes. Protein and mRNA expression of P450s were assessed in the brain of CRF and control (CTL) rats, as well as from CTL or CRF rats that underwent parathyroidectomy (PTX) 1 week before nephrectomy. CYP3A activity was measured using 3-[(3, 4-difluorobenzyl) oxy]-5, 5-dimethyl-4-[4-methylsulfonyl) phenyl] furan-2(5H)-1 metabolism in brain microsomal preparation. CYP3A protein expression was assessed in primary cultured astrocytes incubated with serum obtained from CRF or CTL rats or with PTH. Significant downregulations (≥40%) of CYP1A, CYP2C11, and CYP3A proteins were observed in microsomes from CRF rat brains. CYP3A activity reduction was also observed. CYP3A expression and activity were unaffected in PTX-pretreated CRF rats. Serum of PTX-treated CRF rats had no impact on CYP3A levels in astrocytes compared with that of untreated CRF rats. Finally, PTH addition to normal calf serum induced a reduction in CYP3A protein similar to CRF serum, suggesting that CRF-induced hyperparathyroidism is associated with a significant decrease in P450 drug-metabolizing enzymes in the brain, which may have implications in drug response.
Service de néphrologie et Centre de recherche de l'Hôpital Maisonneuve-Rosemont (J.N., J.H., C.L., S.B., F.A.L., V.P.), and Département de pharmacologie (J.N., J.H., V.P.), Faculté de Médecine, Université de Montréal, Québec, Canada.
Judith
J
Naud
Service de néphrologie et Centre de recherche de l'Hôpital Maisonneuve-Rosemont (J.N., J.H., C.L., S.B., F.A.L., V.P.), and Département de pharmacologie (J.N., J.H., V.P.), Faculté de Médecine, Université de Montréal, Québec, Canada.
Jessica
J
Harding
Service de néphrologie et Centre de recherche de l'Hôpital Maisonneuve-Rosemont (J.N., J.H., C.L., S.B., F.A.L., V.P.), and Département de pharmacologie (J.N., J.H., V.P.), Faculté de Médecine, Université de Montréal, Québec, Canada.
Caroline
C
Lamarche
Service de néphrologie et Centre de recherche de l'Hôpital Maisonneuve-Rosemont (J.N., J.H., C.L., S.B., F.A.L., V.P.), and Département de pharmacologie (J.N., J.H., V.P.), Faculté de Médecine, Université de Montréal, Québec, Canada.
Stephanie
S
Beauchemin
Service de néphrologie et Centre de recherche de l'Hôpital Maisonneuve-Rosemont (J.N., J.H., C.L., S.B., F.A.L., V.P.), and Département de pharmacologie (J.N., J.H., V.P.), Faculté de Médecine, Université de Montréal, Québec, Canada.
Francois A
FA
Leblond
Service de néphrologie et Centre de recherche de l'Hôpital Maisonneuve-Rosemont (J.N., J.H., C.L., S.B., F.A.L., V.P.), and Département de pharmacologie (J.N., J.H., V.P.), Faculté de Médecine, Université de Montréal, Québec, Canada vpichette.hmr@ssss.gouv.qc.ca.
Vincent
V
Pichette
D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics / Q000378:metabolism; D001253:Astrocytes / Q000201:enzymology; D001921:Brain / Q000201:enzymology*; D002478:Cells, Cultured; D019363:Cytochrome P-450 CYP1A1 / Q000235:genetics / Q000378:metabolism; D019392:Cytochrome P-450 CYP2E1 / Q000235:genetics / Q000378:metabolism; D051544:Cytochrome P-450 CYP3A / Q000235:genetics / Q000378:metabolism; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism*; D000072467:Cytochrome P450 Family 2 / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D015971:Gene Expression Regulation, Enzymologic; D007676:Kidney Failure, Chronic / Q000201:enzymology* / Q000235:genetics; D008297:Male; D009392:Nephrectomy; D010281:Parathyroid Hormone / Q000378:metabolism; D016105:Parathyroidectomy; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D017207:Rats, Sprague-Dawley; D039181:Steroid 16-alpha-Hydroxylase / Q000235:genetics / Q000378:metabolism
D010281:Parathyroid Hormone; D012333:RNA, Messenger; D003577:Cytochrome P-450 Enzyme System; D019392:Cytochrome P-450 CYP2E1; D001189:Aryl Hydrocarbon Hydroxylases; C450279:CYP2C11 protein, rat; C504568:Cyp2d1 protein, rat; D019363:Cytochrome P-450 CYP1A1; D051544:Cytochrome P-450 CYP3A; D000072467:Cytochrome P450 Family 2; D039181:Steroid 16-alpha-Hydroxylase