title: Orphan nuclear receptors constitutive androstane receptor and pregnane X receptor share xenobiotic and steroid ligands.
abstract: Xenobiotics induce the transcription of cytochromes P450 (CYPs) 2B and 3A through the constitutive androstane receptor (CAR; NR1I3) and pregnane X receptor (PXR; NR1I2), respectively. In this report, we have systematically compared a series of xenobiotics and natural steroids for their effects on mouse and human CAR and PXR. Our results demonstrate dual regulation of PXR and CAR by a subset of compounds that affect CYP expression. Moreover, there are marked pharmacological differences between the mouse (m) and human (h) orthologs of both CAR and PXR. For example, the planar hydrocarbon 1, 4-bis[2-(3,5-dichloropyridyl-oxy)]benzene activates mCAR and hPXR but has little or no activity on hCAR and mPXR. In contrast, the CAR deactivator androstanol activates both mouse and human PXR. Similarly, the PXR activator clotrimazole is a potent deactivator of hCAR. Using radioligand binding and fluorescence resonance energy transfer assays, we demonstrate that several of the compounds that regulate mouse and human CAR, including natural steroids, bind directly to the receptors. Our results suggest that CAR, like PXR, is a steroid receptor that is capable of recognizing structurally diverse compounds. Moreover, our findings underscore the complexity in the physiologic response to xenobiotics.
authors.affiliation: Department of Molecular Endocrinology, Glaxo Wellcome Research and Development, Research Triangle Park, North Carolina 27709, USA.
authors.forename: L B
authors.initials: LB
authors.lastname: Moore
authors.forename: D J
authors.initials: DJ
authors.lastname: Parks
authors.forename: S A
authors.initials: SA
authors.lastname: Jones
authors.forename: R K
authors.initials: RK
authors.lastname: Bledsoe
authors.forename: T G
authors.initials: TG
authors.lastname: Consler
authors.forename: J B
authors.initials: JB
authors.lastname: Stimmel
authors.forename: B
authors.initials: B
authors.lastname: Goodwin
authors.forename: C
authors.initials: C
authors.lastname: Liddle
authors.forename: S G
authors.initials: SG
authors.lastname: Blanchard
authors.forename: T M
authors.initials: TM
authors.lastname: Willson
authors.forename: J L
authors.initials: JL
authors.lastname: Collins
authors.forename: S A
authors.initials: SA
authors.lastname: Kliewer
mesh_terms: D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases; D002460:Cell Line; D003022:Clotrimazole / Q000494:pharmacology; D000090702:Constitutive Androstane Receptor; D065702:Cytochrome P-450 CYP2B6; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics; D006801:Humans; D007700:Kinetics; D008024:Ligands; D051379:Mice; D015735:Mifepristone / Q000494:pharmacology; D010089:Oxidoreductases, N-Demethylating / Q000235:genetics; D000077297:Pregnane X Receptor; D011487:Protein Conformation / Q000187:drug effects; D018160:Receptors, Cytoplasmic and Nuclear / Q000737:chemistry / Q000378:metabolism*; D011987:Receptors, Steroid / Q000737:chemistry / Q000378:metabolism*; D011994:Recombinant Proteins / Q000737:chemistry / Q000378:metabolism; D013256:Steroids / Q000378:metabolism / Q000494:pharmacology*; D014157:Transcription Factors / Q000737:chemistry / Q000378:metabolism*; D014158:Transcription, Genetic / Q000187:drug effects; D014162:Transfection; D015262:Xenobiotics / Q000493:pharmacokinetics / Q000494:pharmacology*
chemical_list: D000090702:Constitutive Androstane Receptor; D008024:Ligands; C000625852:NR1I2 protein, human; C000716327:NR1I3 protein, human; C000625853:Nr1i2 protein, mouse; C000716328:Nr1i3 protein, mouse; D000077297:Pregnane X Receptor; D018160:Receptors, Cytoplasmic and Nuclear; D011987:Receptors, Steroid; D011994:Recombinant Proteins; D013256:Steroids; D014157:Transcription Factors; D015262:Xenobiotics; D015735:Mifepristone; D003577:Cytochrome P-450 Enzyme System; D001189:Aryl Hydrocarbon Hydroxylases; C585599:CYP2B6 protein, human; D065702:Cytochrome P-450 CYP2B6; D051544:Cytochrome P-450 CYP3A; D010089:Oxidoreductases, N-Demethylating; D003022:Clotrimazole