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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
A new orphan member of the nuclear hormone receptor superfamily that interacts with a subset of retinoic acid response elements.
M. Baes (1994)
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)
Use of human hepatocytes to study P450 gene induction.
S. Strom (1996)
Differential Transactivation by Two Isoforms of the Orphan Nuclear Hormone Receptor CAR*
H. S. Choi (1997)
Development of a scintillation proximity assay for peroxisome proliferator-activated receptor gamma ligand binding domain.
J. Nichols (1998)
Identification of a human nuclear receptor defines a new signaling pathway for CYP3A induction.
G. Bertilsson (1998)
An Orphan Nuclear Receptor Activated by Pregnanes Defines a Novel Steroid Signaling Pathway
S. Kliewer (1998)
SXR, a novel steroid and xenobiotic-sensing nuclear receptor.
B. Blumberg (1998)
The human orphan nuclear receptor PXR is activated by compounds that regulate CYP3A4 gene expression and cause drug interactions.
J. Lehmann (1998)
The Nuclear Orphan Receptor CAR-Retinoid X Receptor Heterodimer Activates the Phenobarbital-Responsive Enhancer Module of the CYP2B Gene
Androstane metabolites bind to and deactivate the nuclear receptor CAR-β
B. M. Forman (1998)
Orphan nuclear receptors: shifting endocrinology into reverse.
S. Kliewer (1999)
The Repressed Nuclear Receptor CAR Responds to Phenobarbital in Activating the Human CYP2B6 Gene*
T. Sueyoshi (1999)
P450 gene induction by structurally diverse xenochemicals: central role of nuclear receptors CAR, PXR, and PPAR.
D. Waxman (1999)
Molecular mechanisms of cytochrome P-450 induction by xenobiotics: An expanded role for nuclear hormone receptors.
U. Savas (1999)
Bile acids: natural ligands for an orphan nuclear receptor.
D. Parks (1999)
Phenobarbital-Responsive Nuclear Translocation of the Receptor CAR in Induction of the CYP2B Gene
T. Kawamoto (1999)
The orphan human pregnane X receptor mediates the transcriptional activation of CYP3A4 by rifampicin through a distal enhancer module.
B. Goodwin (1999)
The Pregnane X Receptor: A Promiscuous Xenobiotic Receptor That Has Diverged during Evolution
Stacey A. Jones (2000)

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