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Orphan Nuclear Receptors Constitutive Androstane Receptor And Pregnane X Receptor Share Xenobiotic And Steroid Ligands*

L. Moore, D. Parks, S. Jones, R. Bledsoe, T. Consler, J. Stimmel, B. Goodwin, C. Liddle, S. Blanchard, T. Willson, J. Collins, S. Kliewer
Published 2000 · Chemistry, Medicine

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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.
This paper references
10.1128/MCB.14.3.1544
A new orphan member of the nuclear hormone receptor superfamily that interacts with a subset of retinoic acid response elements.
M. Baes (1994)
10.1016/0006-2952(94)90468-5
Biphasic regulation of cytochrome P450 2B1/2 mRNA expression by dexamethasone in primary cultures of adult rat hepatocytes maintained on matrigel.
T. Kocarek (1994)
Comparative analysis of cytochrome P4503A induction in primary cultures of rat, rabbit, and human hepatocytes.
T. Kocarek (1995)
10.1016/S0076-6879(96)72044-X
Use of human hepatocytes to study P450 gene induction.
S. Strom (1996)
10.1074/JBC.272.38.23565
Differential Transactivation by Two Isoforms of the Orphan Nuclear Hormone Receptor CAR*
H. S. Choi (1997)
10.1006/ABIO.1997.2557
Development of a scintillation proximity assay for peroxisome proliferator-activated receptor gamma ligand binding domain.
J. Nichols (1998)
10.1073/PNAS.95.21.12208
Identification of a human nuclear receptor defines a new signaling pathway for CYP3A induction.
G. Bertilsson (1998)
10.1016/S0092-8674(00)80900-9
An Orphan Nuclear Receptor Activated by Pregnanes Defines a Novel Steroid Signaling Pathway
S. Kliewer (1998)
10.1101/GAD.12.20.3195
SXR, a novel steroid and xenobiotic-sensing nuclear receptor.
B. Blumberg (1998)
10.1172/JCI3703
The human orphan nuclear receptor PXR is activated by compounds that regulate CYP3A4 gene expression and cause drug interactions.
J. Lehmann (1998)
10.1128/MCB.18.10.5652
The Nuclear Orphan Receptor CAR-Retinoid X Receptor Heterodimer Activates the Phenobarbital-Responsive Enhancer Module of the CYP2B Gene
(1998)
10.1038/26996
Androstane metabolites bind to and deactivate the nuclear receptor CAR-β
B. M. Forman (1998)
10.1126/SCIENCE.284.5415.757
Orphan nuclear receptors: shifting endocrinology into reverse.
S. Kliewer (1999)
10.1074/jbc.274.10.6043
The Repressed Nuclear Receptor CAR Responds to Phenobarbital in Activating the Human CYP2B6 Gene*
T. Sueyoshi (1999)
10.1006/ABBI.1999.1351
P450 gene induction by structurally diverse xenochemicals: central role of nuclear receptors CAR, PXR, and PPAR.
D. Waxman (1999)
10.1124/MOL.56.5.851
Molecular mechanisms of cytochrome P-450 induction by xenobiotics: An expanded role for nuclear hormone receptors.
U. Savas (1999)
10.1126/SCIENCE.284.5418.1365
Bile acids: natural ligands for an orphan nuclear receptor.
D. Parks (1999)
10.1128/MCB.19.9.6318
Phenobarbital-Responsive Nuclear Translocation of the Receptor CAR in Induction of the CYP2B Gene
T. Kawamoto (1999)
10.1124/MOL.56.6.1329
The orphan human pregnane X receptor mediates the transcriptional activation of CYP3A4 by rifampicin through a distal enhancer module.
B. Goodwin (1999)
10.1210/ME.14.1.27
The Pregnane X Receptor: A Promiscuous Xenobiotic Receptor That Has Diverged during Evolution
Stacey A. Jones (2000)



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10.1002/9781119171003.CH4
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10.1177/01926233211019288
Proceedings of the 2020 Classic Examples in Toxicologic Pathology XXVII
T. Nolte (2021)
10.1007/s11356-020-11990-8
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Ruijing Liu (2021)
10.1007/978-3-030-78315-0_7
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S. Chai (2021)
10.1016/j.scitotenv.2021.150631
Assessment of binding potencies of polychlorinated biphenyls and polybrominated diphenyl ethers with Baikal seal and mouse constitutive androstane receptors: Comparisons across species and congeners.
P. Dau (2021)
10.3389/fendo.2021.665521
A Comparative Study of Human and Zebrafish Pregnane X Receptor Activities of Pesticides and Steroids Using In Vitro Reporter Gene Assays
N. Creusot (2021)
10.1016/j.bbadis.2021.166101
The xenobiotic receptors PXR and CAR in liver physiology, an update.
Xinran Cai (2021)
10.1124/dmd.121.000415
PXR and the gut-liver axis: a recent update.
M. Dutta (2021)
10.1093/toxsci/kfab023
Targeting xenobiotic nuclear receptors PXR and CAR to prevent cobicistat hepatotoxicity.
Amina I. Shehu (2021)
10.1016/j.tox.2020.152394
Comparative studies on the effects of sodium phenobarbital and two other constitutive androstane receptor (CAR) activators on induction of cytochrome P450 enzymes and replicative DNA synthesis in cultured hepatocytes from wild type and CAR knockout rats.
Manuela Goettel (2020)
10.1080/19390211.2020.1846658
Possible Herb-Drug Interaction Risk of Some Nutritional and Beauty Supplements on Antiretroviral Therapy in HIV Patients
M. Haron (2020)
10.3390/cells9112426
Constitutive Androstane Receptor: A Peripheral and a Neurovascular Stress or Environmental Sensor
Fabiana Oliviero (2020)
10.1371/journal.pone.0231813
The membrane receptors that appeared before their ligand: The different proposed scenarios
Anne-Catherine Grandchamp (2020)
10.1016/b978-0-12-820018-6.00009-0
In vitro characterization and in vitro to in vivo predictions of drug-drug interactions
N. Isoherranen (2020)
10.1002/9781119436812.ch30
Pathophysiologic Basis for Alternative Therapies for Cholestasis
C. Fuchs (2020)
10.3390/cells9112520
CITCO as an Adjuvant Facilitates CHOP-Based Lymphoma Treatment in hCAR-Transgenic Mice
Ritika Kurian (2020)
10.1093/toxsci/kfaa076
Combining in vivo and organotypic in vitro approaches to assess the human relevance of Basimglurant (RG7090), a potential CAR activator.
R. Nudischer (2020)
10.1002/ardp.202000082
PXR–ABC drug transporters/CYP‐mediated ursolic acid transport and metabolism in vitro and vivo
Wen Jinhua (2020)
10.1124/dmd.120.000010
Nrf2 Antioxidative System is Involved in Cytochrome P450 Gene Expression and Activity: A Delay in Pentobarbital Metabolism in Nrf2-Deficient Mice
T. Ashino (2020)
10.1016/j.ejmech.2020.113106
Design, synthesis, and biological studies of novel 3-benzamidobenzoic acid derivatives as farnesoid X receptor partial agonist.
Lijun Hu (2020)
10.1016/j.scitotenv.2020.140599
Autophagy-related neurotoxicity is mediated via AHR and CAR in mouse neurons exposed to DDE.
A. Wnuk (2020)
10.1016/j.dmpk.2020.11.002
Adenosine deaminases acting on RNA modulate the expression of the human pregnane X receptor.
Seiya Takemoto (2020)
10.3390/cells9102306
Metabolism-Disrupting Chemicals and the Constitutive Androstane Receptor CAR
Jenni Küblbeck (2020)
10.1080/17425255.2020.1746268
Nuclear receptor CAR-mediated liver cancer and its species differences
Ryota Shizu (2020)
10.1080/03602532.2020.1858856
Cytochrome P450 expression and regulation in the brain
W. Kuban (2020)
10.1093/toxsci/kfaa026
Quantitative Transcriptional Biomarkers of Xenobiotic Receptor Activation in Rat Liver for The Early Assessment of Drug Safety Liabilities.
A. Podtelezhnikov (2020)
10.3390/genes11020186
Identification of Functional Transcriptional Binding Sites within Chicken Abcg2 Gene Promoter and Screening Its Regulators
Yujuan Zhang (2020)
10.2174/1389200220666190325141422
Herb-Drug Interactions and Hepatotoxicity.
M. Parvez (2019)
10.2174/1389200219666180918152241
The Role of Xenobiotic Receptors on Hepatic Glycolipid Metabolism.
Ke Chen (2019)
10.1016/j.toxlet.2019.05.024
Stilbene compound trans-3,4,5,4´-tetramethoxystilbene, a potential anticancer drug, regulates constitutive androstane receptor (Car) target genes, but does not possess proliferative activity in mouse liver.
J. Dušek (2019)
10.1016/j.jsbmb.2018.10.014
A reduced protein diet modulates enzymes of vitamin D and cholesterol metabolism in young ruminants
M. Wilkens (2019)
10.1093/toxsci/kfy269
Sequence Variations in pxr (nr1i2) From Zebrafish (Danio rerio) Strains Affect Nuclear Receptor Function
Roger Lille-Langøy (2018)
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