title: Mechanisms of xenobiotic receptor activation: Direct vs. indirect.
abstract: The so-called xenobiotic receptors (XRs) have functionally evolved into cellular sensors for both endogenous and exogenous stimuli by regulating the transcription of genes encoding drug-metabolizing enzymes and transporters, as well as those involving energy homeostasis, cell proliferation, and/or immune responses. Unlike prototypical steroid hormone receptors, XRs are activated through both direct ligand-binding and ligand-independent (indirect) mechanisms by a plethora of structurally unrelated chemicals. This review covers research literature that discusses direct vs. indirect activation of XRs. A particular focus is centered on the signaling control of the constitutive androstane receptor (CAR), the pregnane X receptor (PXR), and the aryl hydrocarbon receptor (AhR). We expect that this review will shed light on both the common and distinct mechanisms associated with activation of these three XRs. 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 Pharmaceutical Sciences, University of Maryland School of Pharmacy, 20 Penn Street, Baltimore, MD 21201, United States.
authors.forename: Bryan
authors.initials: B
authors.lastname: Mackowiak
authors.affiliation: Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, 20 Penn Street, Baltimore, MD 21201, United States. Electronic address: hwang@rx.umaryland.edu.
authors.forename: Hongbing
authors.initials: H
authors.lastname: Wang
mesh_terms: D000818:Animals; D000090702:Constitutive Androstane Receptor; D004734:Energy Metabolism / Q000187:drug effects* / Q000235:genetics; D005786:Gene Expression Regulation; D006360:Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008658:Inactivation, Metabolic / Q000187:drug effects / Q000235:genetics; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D008099:Liver / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D020928:Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D000077297:Pregnane X Receptor; D018336:Receptors, Aryl Hydrocarbon / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D011987:Receptors, Steroid / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D015262:Xenobiotics / Q000494:pharmacology*
chemical_list: D000090702:Constitutive Androstane Receptor; D006360:Heat-Shock Proteins; D036341:Intercellular Signaling Peptides and Proteins; D000077297:Pregnane X Receptor; C486574:RETNLB protein, human; D018336:Receptors, Aryl Hydrocarbon; D018160:Receptors, Cytoplasmic and Nuclear; D011987:Receptors, Steroid; D015262:Xenobiotics; D020928:Mitogen-Activated Protein Kinases
keywords: Activation mechanism; AhR; CAR; PXR; Xenobiotic receptor