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 4␣ (HNF-4␣). 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 alterationmediated differences in the promoter region of the CYP2C and CYP3A genes. RNA polymerase II and HNF-4␣ 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-4␣ 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. Patients with chronic kidney disease (CKD) take many medications to manage their CKD and comorbidities (1). Subtherapeutic dosing and overdosing result in adverse drug events commonly associated with CKD, which translate into therapeutic ineffectiveness or druginduced toxicity. It is estimated that one medicationrelated problem occurs with every 2.7 medication exposures in patients undergoing dialysis (2). Several reports have suggested that altered pharmacokinetics in CKD at least partially mediates this increase in adverse drug events (3-5). Although it is well known that the renal clearance of drugs is altered in CKD, the effect on nonrenal drug clearance is not well understood.Hepatic drug metabolism is the major route of drug elimination and is mediated predominantly by the cytochrome P450 (CYP) superfamily of oxidizing enzymes. The CYP isoforms, CYP2C and CYP3A, metabolize the majority (43%) of clinically used drugs (6). Several studies have reported down-regulation of CYP2C and CYP3A enzymes in CKD (3,(7)(8)(9). In addition, in vitro studies in which rat primary hepatocytes were incubated with uremic serum demonstrate a decrease in expression of CYP2C11 and CYP3A2, which are rat orthologs for human CYP2C9 and CYP3A4, respectively (10). Consistent with these studies, surgical induction of CKD in rats results in a pronounced decrease of hepatic CYP2C and CYP3A function and expression (3,7,11). Although decreased CYP2C and CYP3A function and protein expression appear to be secondary to decreased mRNA expression, the molecular mechanism(s) by which this occurs in CKD is unclear.

CYP3A5 Polymorphism affects the increase in CYP3A activity after living Kidney transplantation in patients with end stage renal disease

“…Evaluation of plasma concentrations of indoxyl sulfate and parathyroid hormone may help to reveal the mechanism in patients with ESRD. Furthermore, a recent study suggests that CYP3A downregulation in renal failure may be mediated by decreased binding with the pregnane X receptor (PXR), a nuclear receptor that transcriptionally regulates CYP3A [33]. Recovery of PXR binding after kidney transplantation may also be involved in the increase in CYP3A activity after kidney transplantation.…”

Mechanism for Increased Expression of UGT2B in the Liver of Mice with Neuropathic Pain

“…51) It has also been reported that a decrease in the acetylation of histones near PXRE, which is located on the promoter of CYP3A2, leads to a decrease in the transcriptional activity of CYP3A2 in rats with chronic kidney disease. 52) In addition, it has been reported that there is an enhancement in histone acetyltransferase (HAT) activity at the time of neuropathic pain. 53) A possible mechanism underlying the increased expression of UGT2B can be proposed based on these reports.…”

Nuclear Receptors in Drug Metabolism, Drug Response and Drug Interactions

“…PXR-mediated CYP3A4 induction was regulated by PRMT1, which methylated histone H4 at arginine-3 that is located within a PXR-responsive chromatin region in the CYP3A4 gene [94]. In a rat model of chronic kidney disease, reduced Cyp2C and Cyp3A expression, and associated reduction in PXR and HNF4- α binding to cognate sites in the Cyp2C11 and Cyp3A2 promoters, was accompanied by reduced histone H4 acetylation at the Cyp3A2 promoter regulatory region and reduced histone H3 acetylation at the PXR- and HNF4- α -bound regulatory loci of Cyp2C11 and Cyp3A2 promoters [95]. …”