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Molecular Endocrinology 14 (1):27
Copyright © 2000 by The Endocrine Society

The Pregnane X Receptor: A Promiscuous Xenobiotic Receptor That Has Diverged during Evolution

Stacey A. Jones1, Linda B. Moore1, Jennifer L. Shenk1, G. Bruce Wisely, Geraldine A. Hamilton, David D. McKee, Nicholas C. O. Tomkinson, Edward L. LeCluyse, Millard H. Lambert, Timothy M. Willson, Steven A. Kliewer and John T. Moore

Departments of Molecular Endocrinology (S.A.J., L.B.M., J.L.S., G.B.W., D.D.M., S.A.K., J.T.M.), Medicinal Chemistry (N.C.O.T, T.M.W.), and Structural Chemistry (M.H.L) Glaxo Wellcome Inc. Research and Development Research Triangle Park, North Carolina 27709
Department of Drug Delivery and Disposition (G.A.H., E.L.L.) School of Pharmacy University of North Carolina at Chapel Hill Chapel Hill, North Carolina 27599

Transcription of genes encoding cytochrome P450 3A (CYP3A) monooxygenases is induced by a variety of xenobiotics and natural steroids. There are marked differences in the compounds that induce CYP3A gene expression between species. Recently, the mouse and human pregnane X receptor (PXR) were shown to be activated by compounds that induce CYP3A expression. However, most studies of CYP3A regulation have been performed using rabbit and rat hepatocytes. Here, we report the cloning and characterization of PXR from these two species. PXR is remarkably divergent between species, with the rabbit, rat, and human receptors sharing only approximately 80% amino acid identity in their ligand-binding domains. This sequence divergence is reflected by marked pharmacological differences in PXR activation profiles. For example, the macrolide antibiotic rifampicin, the antidiabetic drug troglitazone, and the hypocholesterolemic drug SR12813 are efficacious activators of the human and rabbit PXR but have little activity on the rat and mouse PXR. Conversely, pregnane 16{alpha}-carbonitrile is a more potent activator of the rat and mouse PXR than the human and rabbit receptor. The activities of xenobiotics in PXR activation assays correlate well with their ability to induce CYP3A expression in primary hepatocytes. Through the use of a novel scintillation proximity binding assay, we demonstrate that many of the compounds that induce CYP3A expression bind directly to human PXR. These data establish PXR as a promiscuous xenobiotic receptor that has diverged during evolution.




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T. K. Tippin, G. Hamilton, L. Moore, E. J. Beaudet, S. Jolley, T. A. Brodie, R. C. Andrews, J. D. Becherer, D. L. McDougald, M. D. Gaul, et al.
CYP3A INDUCTION BY N-HYDROXYFORMAMIDE TUMOR NECROSIS FACTOR-{alpha} CONVERTING ENZYME/MATRIX METALLOPROTEINASE INHIBITORS: USE OF A PREGNANE X RECEPTOR ACTIVATION ASSAY AND PRIMARY HEPATOCYTE CULTURE FOR ASSESSING INDUCTION POTENTIAL IN HUMANS
Drug Metab. Dispos., July 1, 2003; 31(7): 870 - 877.
[Abstract] [Full Text] [PDF]

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S. A. Kliewer
The Nuclear Pregnane X Receptor Regulates Xenobiotic Detoxification
J. Nutr., July 1, 2003; 133(7): 2444S - 2447.
[Abstract] [Full Text] [PDF]

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 EndocrinologyHome page
G. K. Whitfield, H. T. L. Dang, S. F. Schluter, R. M. Bernstein, T. Bunag, L. A. Manzon, G. Hsieh, C. Encinas Dominguez, J. H. Youson, M. R. Haussler, et al.
Cloning of a Functional Vitamin D Receptor from the Lamprey (Petromyzon marinus), an Ancient Vertebrate Lacking a Calcified Skeleton and Teeth
Endocrinology, June 1, 2003; 144(6): 2704 - 2716.
[Abstract] [Full Text] [PDF]

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J. M. Maglich, D. J. Parks, L. B. Moore, J. L. Collins, B. Goodwin, A. N. Billin, C. A. Stoltz, S. A. Kliewer, M. H. Lambert, T. M. Willson, et al.
Identification of a Novel Human Constitutive Androstane Receptor (CAR) Agonist and Its Use in the Identification of CAR Target Genes
J. Biol. Chem., May 2, 2003; 278(19): 17277 - 17283.
[Abstract] [Full Text] [PDF]

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 Drug Metab. Dispos.Home page
J. L. Raucy
Regulation of CYP3A4 Expression in Human Hepatocytes by Pharmaceuticals and Natural Products
Drug Metab. Dispos., May 1, 2003; 31(5): 533 - 539.
[Abstract] [Full Text] [PDF]

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 Drug Metab. Dispos.Home page
S. C. Nallani, B. Goodwin, J. M. Maglich, D. J. Buckley, A. R. Buckley, and P. B. Desai
Induction of Cytochrome P450 3A by Paclitaxel in Mice: Pivotal Role of the Nuclear Xenobiotic Receptor, Pregnane X Receptor
Drug Metab. Dispos., May 1, 2003; 31(5): 681 - 684.
[Abstract] [Full Text] [PDF]

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 International Journal of ToxicologyHome page
M. R. Lee, Y. J. Kim, D. Y. Hwang, T. S. Kang, J. H. Hwang, C. H. Lim, H. K. Kang, J. S. Goo, H. J. Lim, K. S. Ahn, et al.
An In Vitro Bioassay for Xenobiotics Using the SXR-Driven Human CYP3A4/lac Z Reporter Gene
International Journal of Toxicology, May 1, 2003; 22(3): 207 - 213.
[Abstract] [PDF]

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M.-F. Yueh, Y.-H. Huang, A. Hiller, S. Chen, N. Nguyen, and R. H. Tukey
Involvement of the Xenobiotic Response Element (XRE) in Ah Receptor-mediated Induction of Human UDP-glucuronosyltransferase 1A1
J. Biol. Chem., April 18, 2003; 278(17): 15001 - 15006.
[Abstract] [Full Text] [PDF]

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J. Sahi, C. B. Black, G. A. Hamilton, X. Zheng, S. Jolley, K. A. Rose, D. Gilbert, E. L. LeCluyse, and M. W. Sinz
Comparative Effects of Thiazolidinediones on in Vitro P450 Enzyme Induction and Inhibition
Drug Metab. Dispos., April 1, 2003; 31(4): 439 - 446.
[Abstract] [Full Text] [PDF]

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Y. Kawamata, R. Fujii, M. Hosoya, M. Harada, H. Yoshida, M. Miwa, S. Fukusumi, Y. Habata, T. Itoh, Y. Shintani, et al.
A G Protein-coupled Receptor Responsive to Bile Acids
J. Biol. Chem., March 7, 2003; 278(11): 9435 - 9440.
[Abstract] [Full Text] [PDF]

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 Proc. Natl. Acad. Sci. USAHome page
I. Dussault, H.-D. Yoo, M. Lin, E. Wang, M. Fan, A. K. Batta, G. Salen, S. K. Erickson, and B. M. Forman
Identification of an endogenous ligand that activates pregnane X receptor-mediated sterol clearance
PNAS, February 4, 2003; 100(3): 833 - 838.
[Abstract] [Full Text] [PDF]

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 Proc. Natl. Acad. Sci. USAHome page
B. Goodwin, K. C. Gauthier, M. Umetani, M. A. Watson, M. I. Lochansky, J. L. Collins, E. Leitersdorf, D. J. Mangelsdorf, S. A. Kliewer, and J. J. Repa
Identification of bile acid precursors as endogenous ligands for the nuclear xenobiotic pregnane X receptor
PNAS, January 7, 2003; 100(1): 223 - 228.
[Abstract] [Full Text] [PDF]

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 Drug Metab. Dispos.Home page
T. A. Kocarek, M. S. Dahn, H. Cai, S. C. Strom, and N. A. Mercer-Haines
Regulation of CYP2B6 and CYP3A Expression by Hydroxymethylglutaryl Coenzyme A Inhibitors in Primary Cultured Human Hepatocytes
Drug Metab. Dispos., December 1, 2002; 30(12): 1400 - 1405.
[Abstract] [Full Text] [PDF]

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S. A. Kliewer, B. Goodwin, and T. M. Willson
The Nuclear Pregnane X Receptor: A Key Regulator of Xenobiotic Metabolism
Endocr. Rev., October 1, 2002; 23(5): 687 - 702.
[Abstract] [Full Text] [PDF]

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J. Raucy, L. Warfe, M.-F. Yueh, and S. W. Allen
A Cell-Based Reporter Gene Assay for Determining Induction of CYP3A4 in a High-Volume System
J. Pharmacol. Exp. Ther., October 1, 2002; 303(1): 412 - 423.
[Abstract] [Full Text] [PDF]

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A. Takeshita, M. Taguchi, N. Koibuchi, and Y. Ozawa
Putative Role of the Orphan Nuclear Receptor SXR (Steroid and Xenobiotic Receptor) in the Mechanism of CYP3A4 Inhibition by Xenobiotics
J. Biol. Chem., August 30, 2002; 277(36): 32453 - 32458.
[Abstract] [Full Text] [PDF]

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C. Handschin, M. Podvinec, R. Amherd, R. Looser, J.-C. Ourlin, and U. A. Meyer
Cholesterol and Bile Acids Regulate Xenosensor Signaling in Drug-mediated Induction of Cytochromes P450
J. Biol. Chem., August 9, 2002; 277(33): 29561 - 29567.
[Abstract] [Full Text] [PDF]

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H. Xiong, K. Yoshinari, K. L. R. Brouwer, and M. Negishi
Role of Constitutive Androstane Receptor in the In Vivo Induction of Mrp3 and CYP2B1/2 by Phenobarbital
Drug Metab. Dispos., August 1, 2002; 30(8): 918 - 923.
[Abstract] [Full Text] [PDF]

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J. L. Raucy, L. Mueller, K. Duan, S. W. Allen, S. Strom, and J. M. Lasker
Expression and Induction of CYP2C P450 Enzymes in Primary Cultures of Human Hepatocytes
J. Pharmacol. Exp. Ther., August 1, 2002; 302(2): 475 - 482.
[Abstract] [Full Text] [PDF]

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 Hum Exp ToxicolHome page
J D Tugwood and C T Montague
Biology and toxicology of PPARg ligands
Human and Experimental Toxicology, August 1, 2002; 21(8): 429 - 437.
[Abstract] [PDF]

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G. Luo, M. Cunningham, S. Kim, T. Burn, J. Lin, M. Sinz, G. Hamilton, C. Rizzo, S. Jolley, D. Gilbert, et al.
CYP3A4 Induction by Drugs: Correlation between a Pregnane X Receptor Reporter Gene Assay and CYP3A4 Expression in Human Hepatocytes
Drug Metab. Dispos., July 1, 2002; 30(7): 795 - 804.
[Abstract] [Full Text] [PDF]

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 Mol. Endocrinol.Home page
J. Wu, C. Xia, J. Meier, S. Li, X. Hu, and D. S. Lala
The Hypolipidemic Natural Product Guggulsterone Acts as an Antagonist of the Bile Acid Receptor
Mol. Endocrinol., July 1, 2002; 16(7): 1590 - 1597.
[Abstract] [Full Text] [PDF]

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 Mol. Endocrinol.Home page
T. M. Willson and J. T. Moore
Minireview: Genomics Versus Orphan Nuclear Receptors--A Half-Time Report
Mol. Endocrinol., June 1, 2002; 16(6): 1135 - 1144.
[Abstract] [Full Text] [PDF]

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 Toxicol SciHome page
D. R. Johnson and C. D. Klaassen
Regulation of Rat Multidrug Resistance Protein 2 by Classes of Prototypical Microsomal Enzyme Inducers That Activate Distinct Transcription Pathways
Toxicol. Sci., June 1, 2002; 67(2): 182 - 189.
[Abstract] [Full Text] [PDF]

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 Drug Metab. Dispos.Home page
S. L. Ripp, J. L. Fitzpatrick, J. M. Peters, and R. A. Prough
Induction of CYP3A Expression by Dehydroepiandrosterone: Involvement of the Pregnane X Receptor
Drug Metab. Dispos., May 1, 2002; 30(5): 570 - 575.
[Abstract] [Full Text] [PDF]

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 Drug Metab. Dispos.Home page
P. B. Desai, S. C. Nallani, R. S. Sane, L. B. Moore, B. J. Goodwin, D. J. Buckley, and A. R. Buckley
Induction of Cytochrome P450 3A4 in Primary Human Hepatocytes and Activation of the Human Pregnane X Receptor by Tamoxifen and 4-Hydroxytamoxifen
Drug Metab. Dispos., May 1, 2002; 30(5): 608 - 612.
[Abstract] [Full Text] [PDF]

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 Mol. Endocrinol.Home page
L. B. Moore, J. M. Maglich, D. D. McKee, B. Wisely, T. M. Willson, S. A. Kliewer, M. H. Lambert, and J. T. Moore
Pregnane X Receptor (PXR), Constitutive Androstane Receptor (CAR), and Benzoate X Receptor (BXR) Define Three Pharmacologically Distinct Classes of Nuclear Receptors
Mol. Endocrinol., May 1, 2002; 16(5): 977 - 986.
[Abstract] [Full Text] [PDF]

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 Mol. Pharmacol.Home page
G. L. Guo, J. Staudinger, K. Ogura, and C. D. Klaassen
Induction of Rat Organic Anion Transporting Polypeptide 2 by Pregnenolone-16alpha -carbonitrile Is via Interaction with Pregnane X Receptor
Mol. Pharmacol., April 1, 2002; 61(4): 832 - 839.
[Abstract] [Full Text] [PDF]

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 Drug Metab. Dispos.Home page
G. L. Guo, D. R. Johnson, and C. D. Klaassen
Postnatal Expression and Induction by Pregnenolone-16alpha -Carbonitrile of the Organic Anion-Transporting Polypeptide 2 in Rat Liver
Drug Metab. Dispos., March 1, 2002; 30(3): 283 - 288.
[Abstract] [Full Text] [PDF]

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S. A. Kliewer and T. M. Willson
Regulation of xenobiotic and bile acid metabolism by the nuclear pregnane X receptor
J. Lipid Res., March 1, 2002; 43(3): 359 - 364.
[Abstract] [Full Text] [PDF]

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 Drug Metab. Dispos.Home page
S. Ekins and J. A. Erickson
A Pharmacophore for Human Pregnane X Receptor Ligands
Drug Metab. Dispos., January 1, 2002; 30(1): 96 - 99.
[Abstract] [Full Text] [PDF]

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 J. Pharmacol. Exp. Ther.Home page
G. L. Guo, S. Choudhuri, and C. D. Klaassen
Induction Profile of Rat Organic Anion Transporting Polypeptide 2 (oatp2) by Prototypical Drug-Metabolizing Enzyme Inducers That Activate Gene Expression through Ligand-Activated Transcription Factor Pathways
J. Pharmacol. Exp. Ther., January 1, 2002; 300(1): 206 - 212.
[Abstract] [Full Text] [PDF]

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 Drug Metab. Dispos.Home page
E. Hustert, A. Zibat, E. Presecan-Siedel, R. Eiselt, R. Mueller, C. Fu{beta}, I. Brehm, U. Brinkmann, M. Eichelbaum, L. Wojnowski, et al.
Natural Protein Variants of Pregnane X Receptor with Altered Transactivation Activity Toward CYP3A4
Drug Metab. Dispos., November 1, 2001; 29(11): 1454 - 1459.
[Abstract] [Full Text] [PDF]

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 Drug Metab. Dispos.Home page
J. Staudinger, Y. Liu, A. Madan, S. Habeebu, and C. D. Klaassen
Coordinate Regulation of Xenobiotic and Bile Acid Homeostasis by Pregnane X Receptor
Drug Metab. Dispos., November 1, 2001; 29(11): 1467 - 1472.
[Abstract] [Full Text] [PDF]

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 J. Biol. Chem.Home page
E. G. Schuetz, S. Strom, K. Yasuda, V. Lecureur, M. Assem, C. Brimer, J. Lamba, R. B. Kim, V. Ramachandran, B. J. Komoroski, et al.
Disrupted Bile Acid Homeostasis Reveals an Unexpected Interaction among Nuclear Hormone Receptors, Transporters, and Cytochrome P450
J. Biol. Chem., October 12, 2001; 276(42): 39411 - 39418.
[Abstract] [Full Text] [PDF]

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 Mol. Endocrinol.Home page
C. Nugent, J. B. Prins, J. P. Whitehead, D. Savage, J. M. Wentworth, V. K. Chatterjee, and S. O'Rahilly
Potentiation of Glucose Uptake in 3T3-L1 Adipocytes by PPAR{gamma} Agonists Is Maintained in Cells Expressing a PPAR{gamma} Dominant-Negative Mutant: Evidence for Selectivity in the Downstream Responses to PPAR{gamma} Activation
Mol. Endocrinol., October 1, 2001; 15(10): 1729 - 1738.
[Abstract] [Full Text] [PDF]

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 Mol. Pharmacol.Home page
C. Handschin, M. Podvinec, R. Looser, R. Amherd, and U. A. Meyer
Multiple Enhancer Units Mediate Drug Induction of CYP2H1 by Xenobiotic-Sensing Orphan Nuclear Receptor Chicken Xenobiotic Receptor
Mol. Pharmacol., October 1, 2001; 60(4): 681 - 689.
[Abstract] [Full Text] [PDF]

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 Mol. Endocrinol.Home page
C. Handschin, M. Podvinec, J. Stockli, K. Hoffmann, and U. A. Meyer
Conservation of Signaling Pathways of Xenobiotic-Sensing Orphan Nuclear Receptors, Chicken Xenobiotic Receptor, Constitutive Androstane Receptor, and Pregnane X Receptor, from Birds to Humans
Mol. Endocrinol., September 1, 2001; 15(9): 1571 - 1585.
[Abstract] [Full Text] [PDF]

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 Mol. Pharmacol.Home page
B. Goodwin, L. B. Moore, C. M. Stoltz, D. D. McKee, and S. A. Kliewer
Regulation of the Human CYP2B6 Gene by the Nuclear Pregnane X Receptor
Mol. Pharmacol., September 1, 2001; 60(3): 427 - 431.
[Abstract] [Full Text] [PDF]

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 Mol. Pharmacol.Home page
K. C. Falkner, J. A. Pinaire, G.-H. Xiao, T. E. Geoghegan, and R. A. Prough
Regulation of the Rat Glutathione S-Transferase A2 Gene by Glucocorticoids: Involvement of Both the Glucocorticoid and Pregnane X Receptors
Mol. Pharmacol., September 1, 2001; 60(3): 611 - 619.
[Abstract] [Full Text] [PDF]

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 Drug Metab. Dispos.Home page
L. C. Quattrochi and P. S. Guzelian
CYP3A Regulation: From Pharmacology to Nuclear Receptors
Drug Metab. Dispos., April 13, 2001; 29(5): 615 - 622.
[Abstract] [Full Text]


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