Decreased nuclear receptor activity and epigenetic modulation associates with down‐regulation of hepatic drug‐metabolizing enzymes in chronic kidney disease. Issue 12 (10th September 2014)

• Record Type: Journal Article
• Authors: Velenosi, Thomas J.; Feere, David A.; Sohi, Gurjeev; Hardy, Daniel B.; Urquhart, Bradley L.
• Is Part Of: FASEB journal. Volume 28:Issue 12(2014)
• Page Start: 5388
• Page End: 5397
• Publication Date: 2014-09-10
• Subjects: cytochrome P450 -- chromatin immunoprecipitation -- pharmacokinetics -- uremia -- histone modification; Biology -- Periodicals; Biology, Experimental -- Periodicals; 570
• DOI: 10.1096/fj.14-258780
• Languages: English
• ISSNs: 0892-6638

Abstract

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 (HNF4α). 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.–Velenosi, T. J., Feere, D. A., Sohi, G., Hardy, D. B., Urquhart, B. L. Decreased nuclear receptor activity and epigenetic modulation associates with down‐regulation of hepatic drug‐metabolizing enzymes in chronic kidney disease. FASEB J. 28, 5388–5397 (2014). www.fasebj.org