title: Decreased nuclear receptor activity and epigenetic modulation associates with down-regulation of hepatic drug-metabolizing enzymes in chronic kidney disease.
abstract: Patients with chronic kidney disease (CKD) require many medications. CYP2C and CYP3A drug-metabolizing enzymes play a critical role in determining the pharmacokinetics of the majority of prescribed medications. These enzymes are transcriptionally regulated by the nuclear receptors pregnane X receptor (PXR) and hepatic nuclear factor 4α (HNF-4α). Expression of CYP2C and CYP3A is decreased in CKD; however, the mechanisms by which this occurs is unknown. We induced CKD in rats by 5/6 nephrectomy and used chromatin immunoprecipitation (ChIP) to determine nuclear receptor- and epigenetic alteration-mediated differences in the promoter region of the CYP2C and CYP3A genes. RNA polymerase II and HNF-4α binding was decreased 76 and 57% in the CYP2C11 promotor and 71 and 77% in the CYP3A2 promoter, respectively (P<0.05). ChIP also revealed a 57% decrease in PXR binding to the CYP3A2 promoter in CKD rats (P<0.05). The decrease in PXR and HNF-4α binding was accompanied by diminished histone 4 acetylation in the CYP3A2 promoter (48%) and histone 3 acetylation in the CYP2C11 (77%) and CYP3A2 (77%) promoter loci for nuclear receptor activation (P<0.05). This study suggests that decreased nuclear receptor binding and histone acetylation may contribute to the mechanism of drug-metabolizing enzyme down-regulation and altered pharmacokinetics in CKD.
authors.affiliation: Department of Physiology and Pharmacology.
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Velenosi
authors.affiliation: Department of Physiology and Pharmacology.
authors.forename: David A
authors.initials: DA
authors.lastname: Feere
authors.affiliation: Department of Physiology and Pharmacology.
authors.forename: Gurjeev
authors.initials: G
authors.lastname: Sohi
authors.affiliation: Department of Physiology and Pharmacology, Lawson Health Research Institute, London, Ontario, Canada Department of Obstetrics and Gynecology, and.
authors.forename: Daniel B
authors.initials: DB
authors.lastname: Hardy
authors.affiliation: Department of Physiology and Pharmacology, Lawson Health Research Institute, London, Ontario, Canada Department of Medicine, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada; and brad.urquhart@schulich.uwo.ca.
authors.forename: Bradley L
authors.initials: BL
authors.lastname: Urquhart
mesh_terms: D000107:Acetylation; D000818:Animals; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism*; D015536:Down-Regulation; D044127:Epigenesis, Genetic; D006657:Histones / Q000378:metabolism; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism*; D007676:Kidney Failure, Chronic / Q000201:enzymology*; D008862:Microsomes, Liver / Q000201:enzymology*; D011401:Promoter Regions, Genetic; D051381:Rats; D017207:Rats, Sprague-Dawley; D060888:Real-Time Polymerase Chain Reaction; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*
chemical_list: D006657:Histones; D007527:Isoenzymes; D018160:Receptors, Cytoplasmic and Nuclear; D003577:Cytochrome P-450 Enzyme System
keywords: chromatin immunoprecipitation; cytochrome P450; histone modification; pharmacokinetics; uremia