Drug discovery technologies to identify and characterize modulators of the pregnane X receptor and the constitutive androstane receptor

Abstract

The pregnane X receptor (PXR) and the constitutive androstane receptor (CAR) are ligandactivated nuclear receptors (NRs) that are notorious for their role in drug metabolism, causing unintended drug-drug interactions and decreasing drug efficacy. They control the xenobiotic detoxification system by regulating the expression of an array of drug-metabolizing enzymes and transporters that excrete exogenous chemicals and maintain homeostasis of endogenous metabolites. Much effort has been invested in recognizing potential drugs for clinical use that can activate PXR and CAR to enhance the expression of their target genes, and in identifying PXR and CAR inhibitors that can be used as co-therapeutics to prevent adverse effects. Here, we present current technologies and assays used in the quest to characterize PXR and CAR modulators, which range from biochemical to cell-based and animal models.

Drug Mimicry: Promiscuous Receptors PXR and AhR, and Microbial Metabolite Interactions in the Intestine

“…The PXR is activated by xenobiotics that induce drug-metabolizing enzymes, causing pharmacokinetic drug interactions, which is undesired [18]. Xenobiotic ligands of the PXR are structurally unrelated compounds, including drugs (e.g., rifampicin), natural compounds (e.g., hyperforin and solomonsterols) and environmental pollutants (e.g., phthalates and bisphenols) [19,20]. Currently, the PXR is 'deorphanized' and endogenous ligands such as bile acids, estrogens, or vitamin K2, were identified.…”

“…Besides the central role in the regulation of xenobiotic-metabolizing enzymes, the PXR controls the intermediary metabolism of lipids, glucose, and bile acids, and it is involved in the etiology of various diseases such as diabetes, metabolic syndrome, cardiovascular pathologies, inflammatory bowel disease, acute kidney injury, neurological pathologies, and cancer [20]. Hence, the therapeutic targeting of the PXR with both agonists and antagonists is of particular interest [19,20].…”

Metabolism-Disrupting Chemicals and the Constitutive Androstane Receptor CAR

“…The constitutive androstane receptor (CAR, NR1I3) is a member of nuclear receptor subfamily 1I, together with its sisters vitamin D receptor (VDR, NR1I1) and pregnane X receptor (PXR, NR1I2), and a subject of intense research for the past 20 years. The many earlier review articles on CAR properties, target genes, evolution, and other aspects have been listed previously [ 72 ] and later progress in the field is also well-documented (e.g., [ 73 , 74 , 75 , 76 , 77 , 78 ]). Therefore, we provide below only an overview on key characteristics of CAR.…”

Hsa-miR-4277 Decelerates the Metabolism or Clearance of Sorafenib in HCC Cells and Enhances the Sensitivity of HCC Cells to Sorafenib by Targeting cyp3a4

“…Ultimately, this accelerates elimination of the therapeutic and results in drug resistance through negative feedback regulation ( 18 , 19 ). Although related studies have expanded our understanding of PXR in HCC, much remains unclear; PXR is not the only metabolism-related nuclear receptor in HCC cells, and the CAR/NR1I3 (constitutive androstane receptor/nuclear receptor subfamily 1 group I member 3) may have similar functions to PXR ( 20 , 21 ). By inhibiting the activity of PXR alone, CAR may have a compensatory effect on the function of PXR.…”