title: Small-molecule modulators of PXR and CAR.
abstract: Two nuclear receptors, the pregnane X receptor (PXR) and the constitutive androstane receptor (CAR), participate in the xenobiotic detoxification system by regulating the expression of drug-metabolizing enzymes and transporters in order to degrade and excrete foreign chemicals or endogenous metabolites. This review aims to expand the perceived relevance of PXR and CAR beyond their established role as master xenosensors to disease-oriented areas, emphasizing their modulation by small molecules. Structural studies of these receptors have provided much-needed insight into the nature of their binding promiscuity and the important elements that lead to ligand binding. Reports of species- and isoform-selective activation highlight the need for further scrutiny when extrapolating from animal data to humans, as animal models are at the forefront of early drug discovery. This article is part of a Special Issue entitled: Xenobiotic nuclear receptors: New Tricks for An Old Dog, edited by Dr. Wen Xie.
authors.affiliation: Department of Chemical Biology and Therapeutics, 262 Danny Thomas Place, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
authors.forename: Sergio C
authors.initials: SC
authors.lastname: Chai
authors.affiliation: Department of Chemical Biology and Therapeutics, 262 Danny Thomas Place, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
authors.forename: Milu T
authors.initials: MT
authors.lastname: Cherian
authors.affiliation: Department of Chemical Biology and Therapeutics, 262 Danny Thomas Place, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
authors.forename: Yue-Ming
authors.initials: YM
authors.lastname: Wang
authors.affiliation: Department of Chemical Biology and Therapeutics, 262 Danny Thomas Place, St. Jude Children's Research Hospital, Memphis, TN 38105, USA. Electronic address: Taosheng.Chen@stjude.org.
authors.forename: Taosheng
authors.initials: T
authors.lastname: Chen
mesh_terms: D000818:Animals; D002166:Camptothecin / Q000737:chemistry / Q000494:pharmacology*; D000090702:Constitutive Androstane Receptor; D003375:Coumestrol / Q000737:chemistry / Q000494:pharmacology*; D004734:Energy Metabolism / Q000187:drug effects / Q000235:genetics; D005786:Gene Expression Regulation; D006801:Humans; D008658:Inactivation, Metabolic / Q000187:drug effects / Q000235:genetics; D007654:Ketoconazole / Q000737:chemistry / Q000494:pharmacology*; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008687:Metformin / Q000737:chemistry / Q000494:pharmacology*; D000077297:Pregnane X Receptor; D011485:Protein Binding; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D011987:Receptors, Steroid / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D054852:Small Molecule Libraries / Q000737:chemistry / Q000494:pharmacology; D013045:Species Specificity; D013379:Substrate Specificity
chemical_list: D000090702:Constitutive Androstane Receptor; D000077297:Pregnane X Receptor; D018160:Receptors, Cytoplasmic and Nuclear; D011987:Receptors, Steroid; D054852:Small Molecule Libraries; D008687:Metformin; D007654:Ketoconazole; D003375:Coumestrol; D002166:Camptothecin
keywords: Binding promiscuity; CAR; Detoxification; PXR; Small molecule; Xenobiotic