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Pregnane X receptor

Systematic Nomenclature: NR1I2

Family: 1I. Vitamin D receptor-like receptors

Contents:
Gene and Protein Information
Previous and Unofficial Names
Database Links
Selected 3D Structures
Agonists
Antagonists
DNA Binding
Co-binding Partners
Main Co-regulators
Main Target Genes
Tissue Distribution
Physiological Consequences of Altering Gene Expression
Phenotypes, Alleles and Disease Models
Clinically-Relevant Mutations and Pathophysiology
Biologically Significant Variants
References
Gene and Protein Information
Species AA Chromosomal Location Gene Symbol Gene Name Reference
Human 434 3q12-q13.3 NR1I2 nuclear receptor subfamily 1, group I, member 2 1,3,17
Mouse 431 16 B3 Nr1i2 nuclear receptor subfamily 1, group I, member 2 17
Rat 431 11q21 Nr1i2 nuclear receptor subfamily 1, group I, member 2 38
Previous and Unofficial Names
PXR
ONR1
BXR
SXR
PAR2
Orphan nuclear receptor PAR1
pregnane-activated receptor
steroid and xenobiotic receptor
MGC108643
pregnane X receptor (nuclear receptor sub family 1, group I, member 2)
nuclear receptor subfamily 1 group I member 2
nuclear receptor subfamily 1, group 1, member 2
orphan nuclear receptor PXR
PXR.1
PXR.2
mPXR
Database Links
DrugBank Target 1284 (Hs)
Ensembl ENSG00000144852 (Hs), ENSMUSG00000022809 (Mm), ENSRNOG00000002906 (Rn)
Entrez Gene 8856 (Hs), 18171 (Mm), 84385 (Rn)
GeneCards NR1I2 (Hs)
GenitoUrinary Development Molecular Anatomy Project Nr1i2 (Mm)
HomoloGene 40757 (Hs)
Human Protein Reference Database 04346 (Hs)
InterPro Q9UJ26 (Hs), O54915 (Mm), Q9R1A7 (Rn)
KEGG Gene hsa:8856 (Hs), mmu:18171 (Mm), rno:84385 (Rn)
NURSA Receptor 1I2
OMIM 603065 (Hs)
PharmGKB Gene PA378 (Hs)
PhosphoSitePlus O75469 (Hs), O54915 (Mm), Q9R1A7 (Rn)
RefSeq Nucleotide NM_033013 (Hs), NM_010936 (Mm), NM_001098404 (Mm), NM_052980 (Rn)
RefSeq Protein NP_071285 (Hs), NP_148934 (Hs), NP_003880 (Hs), NP_035066 (Mm), NP_443212 (Rn)
TreeFam ENSG00000144852 (Hs), ENSMUSG00000022809 (Mm), ENSRNOG00000002906 (Rn)
UniProt Q9UJ26 (Hs), O54915 (Mm), Q9R1A7 (Rn)
1I. Vitamin D receptor-like receptors
Selected 3D Structures
Image of receptor 3D structure from RCSB PDB
Description:  Tethered PXR-LBD/SRC-1p - apoprotein
PDB Id:  3CTB
Resolution:  2.0Å
Species:  Human
References:  32
Image of receptor 3D structure from RCSB PDB
Description:  Tethered PXR-LBD/SRC-1p complexed with SR-12813
PDB Id:  3HVL
Ligand:  SR12813
Resolution:  2.1Å
Species:  Human
References:  32
Search for other structures on the PDB
Search by keyword: Pregnane X receptor Search by accession number: Q9UJ26, Q9R1A7, O54915
Natural/Endogenous Ligand(s)
Comments: Xenobiotics, steroids and benzoates have been proposed as the natural ligands
Agonists
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Affinity Units Reference
17β-estradiol Hs Agonist - - 15
clotrimazole Hs Agonist - - 1
nifedipine Hs Agonist - - 1
phenobarbital Hs Agonist - - 19
vitamin K2 Mm Agonist - - 30
hyperforin Hs Agonist 7.6 pEC50 21,33
SR12813 Hs Agonist 6.7 pEC50 15
pregnenolone-16α-carbonitrile Mm Agonist 6.5 pEC50 17
(+)-S20 Hs Agonist 6.4 pEC50 22
dexamethasone Mm Agonist 6.1 pEC50 17
schisandrin A Mm Agonist 5.9 pEC50 23
rifampicin Hs Agonist 5.5 – 6.0 pEC50 3,19
S20 (racemic mixture) Hs Agonist 5.7 pEC50 22
schisandrin A Hs Agonist 5.7 pEC50 23
lovastatin Hs Full agonist 5.3 – 6.0 pEC50 19
5β-cholestane-3α,7α,12α-triol Mm Agonist 5.5 pEC50 7
5β-cholestane-3α,7α,12α-triol Hs Agonist 5.3 pEC50 12
taxol Hs Agonist 5.3 pEC50 29
lithocholic acid Hs Agonist 5.05 pEC50 27
mifepristone Hs Agonist 5.0 pEC50 19
3-keto-lithocholic acid Hs Agonist 4.8 pEC50 27
pregnanedione Hs Agonist 6.4 pIC50 15
View species-specific agonist tables
Agonist Comments
Some environmental xenobiotics (e.g., polychlorinated biphenyls or PCBs, 1,1-dichloro-2,2-bis (p-chlorophenyl)ethylene))[25,34], and pesticides (e.g., transnonachlor and chlordane)[25] have also been shown to activate PXR.
Antagonists
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Affinity Units Reference
ecteinascidin 743 Mm Antagonist 8.52 pIC50 29
Antagonist Comments
The notion that Ecteinascidin 743 (ET-743) as a PXR antagonist is controversial. It was thought the inhibitory effect may result from the cytotoxicity of this potent antineoplastic agent.
DNA Binding
Structure:  Heterodimer, RXR partner
HRE core sequence:  AGGTCA
Response element:  DR3, Other - see comments
DNA Binding Comments
The PXR forms a heterodimer with RXR, a requirement for binding and activation. The heterodimers formed between PXR and RXR can interact with DR-3 (TGAACTn3TGAACT) (3); ER6 (TGAACTn6AGGTCA) ER6 (5) (This ER6 was also termed IR6 in ref #2); DR4 (6, 33); ER8 (7); IR0 (8) or PBRE (9, 31).
Co-binding Partners
Name Interaction Effect Reference
PIT1 Physical Cellular localization 11
Main Co-regulators
Name Activity Specific Ligand dependent AF-2 dependent Comments References
NCOA1 Co-activator No No No 17
NRIP1 Co-activator No No No 4
PPARGC1A Co-activator No No No 2
FOXO1 Co-activator No No No 18
NR0B2 Co-repressor No No No 24
GRIP1 Co-activator No No No 28
NCOR2 Co-repressor No No No 29,31
Main Target Genes
Name Species Effect Technique Comments References
cytochrome P450 Human Activated Transient transfection, EMSA, Other mCYP3A11, rCYP3A23, hCYP3A4, hCYP2C8, hCYP2C9, mCYP2B10, hCYP2B6 (h-human,m-mouse,r-rat) 1,3,5,8,13,17,29,35
Slco1a4 Mouse Activated Transient transfection, EMSA, Other Oatp2, Slc21a5 14
Abcc2 Mouse Activated Transient transfection, EMSA 16
Ugt1a1 Mouse Activated Transient transfection, EMSA 37
Sult2a1 Mouse Activated Transient transfection, EMSA 26
Abcb1b Mouse Activated Transient transfection, EMSA 10
Alas1 Mouse Activated Transient transfection, EMSA 9
Tissue Distribution
Liver, intestine
Expression level:  High
Species:  Human
Technique:  Immunohistochemistry, Northern blot, Q-PCR
References:  1,3,15,17,19,38
Tissue Distribution Comments
low levels in kidney and lungs. A similar pattern is seen in mice
Physiological Consequences of Altering Gene Expression
Impaired drug metabolism induced by specific xenobiotics, such as loss of CYP3A11 inducibility in response to PCN and dexamethasone. Sensitivity to bile acid induced toxicity.
Species:  Mouse
Tissue: 
Technique:  Knock-out
References:  27,35-36
Acquired responsiveness to hPXR-specific ligands, such as refampicin; loss of responsiveness to rodent-specific ligands, such as PCN
Species:  Mouse
Tissue: 
Technique:  hPXR transgenic mice and hPXR transgenic with PXR KO background (“humanized” mice)
References:  35
Increased bilirubin and cortisone clearance; Increased detoxification of bile acids; Increased protection against xenobiotic toxicants, such as zoxazolamine and tribromonoethanol
Species:  Mouse
Tissue: 
Technique:  transgene of a constitutively activated hPXR into the liver of the transgenic mice
References:  35-37
Phenotypes, Alleles and Disease Models Mouse data from MGI

Click here to show/hide data

Allele Composition & genetic background Accession Phenotype Id Phenotype Reference
Nr1i2tm1Sakl Nr1i2tm1Sakl/Nr1i2tm1Sakl
involves: 129S1/Sv * 129X1/SvJ * C57BL/6		 MGI:1337040  MP:0005319 abnormal enzyme/ coenzyme level PMID: 11248085 
Nr1i2tm1Sakl Nr1i2tm1Sakl/Nr1i2tm1Sakl
involves: 129S1/Sv * 129X1/SvJ * C57BL/6		 MGI:1337040  MP:0008872 abnormal physiological response to xenobiotic PMID: 11248085 
Nr1i2tm1Sakl Nr1i2tm1Sakl/Nr1i2tm1Sakl
involves: 129S1/Sv * 129X1/SvJ		 MGI:1337040  MP:0004001 decreased hepatocyte proliferation PMID: 19815629 
Nr1i2tm1Rev Nr1i2tm1Rev/Nr1i2tm1Rev
involves: 129S4/SvJae * C57BL/6J		 MGI:1337040  MP:0008874 decreased physiological sensitivity to xenobiotic PMID: 10935643 
Nr1i2tm1Sakl Nr1i2tm1Sakl/Nr1i2tm1Sakl
involves: 129S1/Sv * 129X1/SvJ * C57BL/6		 MGI:1337040  MP:0008874 decreased physiological sensitivity to xenobiotic PMID: 11602523 
Nr1i2tm1(NR1I2)Arte Nr1i2tm1(NR1I2)Arte/Nr1i2tm1(NR1I2)Arte
involves: C57BL/6		 MGI:1337040  MP:0008874 decreased physiological sensitivity to xenobiotic PMID: 18677425 
Nr1i2tm3Arte Nr1i2tm3Arte/Nr1i2tm3Arte
involves: C57BL/6		 MGI:1337040  MP:0008874 decreased physiological sensitivity to xenobiotic PMID: 18677425 
Nr1i2tm3Arte|Nr1i3tm1.1Arte Nr1i2tm3Arte/Nr1i2tm3Arte,Nr1i3tm1.1Arte/Nr1i3tm1.1Arte
involves: C57BL/6		 MGI:1337040  MGI:1346307  MP:0008874 decreased physiological sensitivity to xenobiotic PMID: 18677425 
Nr1i2tm1(NR1I2)Arte|Nr1i3tm1.1Arte Nr1i2tm1(NR1I2)Arte/Nr1i2tm1(NR1I2)Arte,Nr1i3tm1.1Arte/Nr1i3tm1.1Arte
involves: C57BL/6		 MGI:1337040  MGI:1346307  MP:0008874 decreased physiological sensitivity to xenobiotic PMID: 18677425 
Nr1i2tm1Sakl Nr1i2tm1Sakl/Nr1i2tm1Sakl
involves: 129S1/Sv * 129X1/SvJ * C57BL/6		 MGI:1337040  MP:0009747 impaired behavioral response to xenobiotic PMID: 11248085 
Nr1i2tm1(NR1I2)Arte Nr1i2tm1(NR1I2)Arte/Nr1i2tm1(NR1I2)Arte
involves: C57BL/6		 MGI:1337040  MP:0008873 increased physiological sensitivity to xenobiotic PMID: 18677425 
Clinically-Relevant Mutations and Pathophysiology
Disease:  breast cancer
Role:  Low PXR receptor level
Comments:  The levels of PXR mRNA in ER positive tumors were significantly lower that those observed in the ER negative tumors
References:  6
Mutations not determined
Disease:  breast cancer
Role:  A significant positive correlation was detected between the SXR/hPXR labeling index and both the histologic grade and the lymph node status of the carcinoma cases
References:  20
Mutations not determined
Biologically Significant Variants
PXR2: Encoded by transcript variant 2 . This variant (2) has a different 5' UTR than other variants. It encodes a single full-length product (isoform 2) with an amino-terminal extension not found in other isoforms.
Protein accession:  NP_071285 
Amino acids:  473
Type:  Splice variant
Species:  Human
References: 
PXR1: main isoform
Protein accession:  NP_003880 
Amino acids:  434
Type:  Splice variant
Species:  Human
References:  1,3,19
PXR3: has a different 5' UTR than variant 2. It encodes an isoform (3) that lacks 39 amino-terminal and 37 internal amino acids compared to isoform 2; the reading frame is maintained. Isoform 3 uses a non-AUG translation initiation codon.
Protein accession:  NP_148934 
Amino acids:  397
Type:  Splice variant
Species:  Human
References: 

REFERENCES

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2. Bhalla, S; Ozalp, C; Fang, S; Xiang, L; Kemper, JK. (2004) Ligand-activated pregnane X receptor interferes with HNF-4 signaling by targeting a common coactivator PGC-1alpha. Functional implications in hepatic cholesterol and glucose metabolism. J. Biol. Chem., 279 (43): 45139-47. [PMID:15322103]

3. Blumberg, B; Sabbagh, W; Juguilon, H; Bolado, J; van Meter, CM; Ong, ES; Evans, RM. (1998) SXR, a novel steroid and xenobiotic-sensing nuclear receptor. Genes Dev., 12 (20): 3195-205. [PMID:9784494]

4. Cavaillès, V; Dauvois, S; L'Horset, F; Lopez, G; Hoare, S; Kushner, PJ; Parker, MG. (1995) Nuclear factor RIP140 modulates transcriptional activation by the estrogen receptor. EMBO J., 14 (15): 3741-51. [PMID:7641693]

5. Chen, Y; Kissling, G; Negishi, M; Goldstein, JA. (2005) The nuclear receptors constitutive androstane receptor and pregnane X receptor cross-talk with hepatic nuclear factor 4alpha to synergistically activate the human CYP2C9 promoter. J. Pharmacol. Exp. Ther., 314 (3): 1125-33. [PMID:15919766]

6. Dotzlaw, H; Leygue, E; Watson, P; Murphy, LC. (1999) The human orphan receptor PXR messenger RNA is expressed in both normal and neoplastic breast tissue. Clin. Cancer Res., 5 (8): 2103-7. [PMID:10473093]

7. Dussault, I; Yoo, HD; Lin, M; Wang, E; Fan, M; Batta, AK; Salen, G; Erickson, SK; Forman, BM. (2003) Identification of an endogenous ligand that activates pregnane X receptor-mediated sterol clearance. Proc. Natl. Acad. Sci. U.S.A., 100 (3): 833-8. [PMID:12569201]

8. Ferguson, SS; Chen, Y; LeCluyse, EL; Negishi, M; Goldstein, JA. (2005) Human CYP2C8 is transcriptionally regulated by the nuclear receptors constitutive androstane receptor, pregnane X receptor, glucocorticoid receptor, and hepatic nuclear factor 4alpha. Mol. Pharmacol., 68 (3): 747-57. [PMID:15933212]

9. Fraser, DJ; Zumsteg, A; Meyer, UA. (2003) Nuclear receptors constitutive androstane receptor and pregnane X receptor activate a drug-responsive enhancer of the murine 5-aminolevulinic acid synthase gene. J. Biol. Chem., 278 (41): 39392-401. [PMID:12881517]

10. Geick, A; Eichelbaum, M; Burk, O. (2001) Nuclear receptor response elements mediate induction of intestinal MDR1 by rifampin. J. Biol. Chem., 276 (18): 14581-7. [PMID:11297522]

11. Gonzalez, MM; Carlberg, C. (2002) Cross-repression, a functional consequence of the physical interaction of non-liganded nuclear receptors and POU domain transcription factors. J. Biol. Chem., 277 (21): 18501-9. [PMID:11891224]

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13. Goodwin, B; Moore, LB; Stoltz, CM; McKee, DD; Kliewer, SA. (2001) Regulation of the human CYP2B6 gene by the nuclear pregnane X receptor. Mol. Pharmacol., 60 (3): 427-31. [PMID:11502872]

14. Guo, GL; Staudinger, J; Ogura, K; Klaassen, CD. (2002) Induction of rat organic anion transporting polypeptide 2 by pregnenolone-16alpha-carbonitrile is via interaction with pregnane X receptor. Mol. Pharmacol., 61 (4): 832-9. [PMID:11901222]

15. Jones, SA; Moore, LB; Shenk, JL; Wisely, GB; Hamilton, GA; McKee, DD; Tomkinson, NC; LeCluyse, EL; Lambert, MH; Willson, TM; Kliewer, SA; Moore, JT. (2000) The pregnane X receptor: a promiscuous xenobiotic receptor that has diverged during evolution. Mol. Endocrinol., 14 (1): 27-39. [PMID:10628745]

16. Kast, HR; Goodwin, B; Tarr, PT; Jones, SA; Anisfeld, AM; Stoltz, CM; Tontonoz, P; Kliewer, S; Willson, TM; Edwards, PA. (2002) Regulation of multidrug resistance-associated protein 2 (ABCC2) by the nuclear receptors pregnane X receptor, farnesoid X-activated receptor, and constitutive androstane receptor. J. Biol. Chem., 277 (4): 2908-15. [PMID:11706036]

17. Kliewer, SA; Moore, JT; Wade, L; Staudinger, JL; Watson, MA; Jones, SA; McKee, DD; Oliver, BB; Willson, TM; Zetterström, RH; Perlmann, T; Lehmann, JM. (1998) An orphan nuclear receptor activated by pregnanes defines a novel steroid signaling pathway. Cell, 92 (1): 73-82. [PMID:9489701]

18. Kodama, S; Koike, C; Negishi, M; Yamamoto, Y. (2004) Nuclear receptors CAR and PXR cross talk with FOXO1 to regulate genes that encode drug-metabolizing and gluconeogenic enzymes. Mol. Cell. Biol., 24 (18): 7931-40. [PMID:15340055]

19. Lehmann, JM; McKee, DD; Watson, MA; Willson, TM; Moore, JT; Kliewer, SA. (1998) The human orphan nuclear receptor PXR is activated by compounds that regulate CYP3A4 gene expression and cause drug interactions. J. Clin. Invest., 102 (5): 1016-23. [PMID:9727070]

20. Miki, Y; Suzuki, T; Kitada, K; Yabuki, N; Shibuya, R; Moriya, T; Ishida, T; Ohuchi, N; Blumberg, B; Sasano, H. (2006) Expression of the steroid and xenobiotic receptor and its possible target gene, organic anion transporting polypeptide-A, in human breast carcinoma. Cancer Res., 66 (1): 535-42. [PMID:16397270]

21. Moore, LB; Goodwin, B; Jones, SA; Wisely, GB; Serabjit-Singh, CJ; Willson, TM; Collins, JL; Kliewer, SA. (2000) St. John's wort induces hepatic drug metabolism through activation of the pregnane X receptor. Proc. Natl. Acad. Sci. U.S.A., 97 (13): 7500-2. [PMID:10852961]

22. Mu, Y; Stephenson, CR; Kendall, C; Saini, SP; Toma, D; Ren, S; Cai, H; Strom, SC; Day, BW; Wipf, P; Xie, W. (2005) A pregnane X receptor agonist with unique species-dependent stereoselectivity and its implications in drug development. Mol. Pharmacol., 68 (2): 403-13. [PMID:15872116]

23. Mu, Y; Zhang, J; Zhang, S; Zhou, HH; Toma, D; Ren, S; Huang, L; Yaramus, M; Baum, A; Venkataramanan, R; Xie, W. (2006) Traditional Chinese medicines Wu Wei Zi (Schisandra chinensis Baill) and Gan Cao (Glycyrrhiza uralensis Fisch) activate pregnane X receptor and increase warfarin clearance in rats. J. Pharmacol. Exp. Ther., 316 (3): 1369-77. [PMID:16267138]

24. Ourlin, JC; Lasserre, F; Pineau, T; Fabre, JM; Sa-Cunha, A; Maurel, P; Vilarem, MJ; Pascussi, JM. (2003) The small heterodimer partner interacts with the pregnane X receptor and represses its transcriptional activity. Mol. Endocrinol., 17 (9): 1693-703. [PMID:12805410]

25. Schuetz, EG; Brimer, C; Schuetz, JD. (1998) Environmental xenobiotics and the antihormones cyproterone acetate and spironolactone use the nuclear hormone pregnenolone X receptor to activate the CYP3A23 hormone response element. Mol. Pharmacol., 54 (6): 1113-7. [PMID:9855641]

26. Sonoda, J; Xie, W; Rosenfeld, JM; Barwick, JL; Guzelian, PS; Evans, RM. (2002) Regulation of a xenobiotic sulfonation cascade by nuclear pregnane X receptor (PXR). Proc. Natl. Acad. Sci. U.S.A., 99 (21): 13801-6. [PMID:12370413]

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28. Sugatani, J; Nishitani, S; Yamakawa, K; Yoshinari, K; Sueyoshi, T; Negishi, M; Miwa, M. (2005) Transcriptional regulation of human UGT1A1 gene expression: activated glucocorticoid receptor enhances constitutive androstane receptor/pregnane X receptor-mediated UDP-glucuronosyltransferase 1A1 regulation with glucocorticoid receptor-interacting protein 1. Mol. Pharmacol., 67 (3): 845-55. [PMID:15557560]

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33. Wentworth, JM; Agostini, M; Love, J; Schwabe, JW; Chatterjee, VK. (2000) St John's wort, a herbal antidepressant, activates the steroid X receptor. J. Endocrinol., 166 (3): R11-6. [PMID:10974665]

34. Wyde, ME; Bartolucci, E; Ueda, A; Zhang, H; Yan, B; Negishi, M; You, L. (2003) The environmental pollutant 1,1-dichloro-2,2-bis (p-chlorophenyl)ethylene induces rat hepatic cytochrome P450 2B and 3A expression through the constitutive androstane receptor and pregnane X receptor. Mol. Pharmacol., 64 (2): 474-81. [PMID:12869653]

35. Xie, W; Barwick, JL; Downes, M; Blumberg, B; Simon, CM; Nelson, MC; Neuschwander-Tetri, BA; Brunt, EM; Guzelian, PS; Evans, RM. (2000) Humanized xenobiotic response in mice expressing nuclear receptor SXR. Nature, 406 (6794): 435-9. [PMID:10935643]

36. Xie, W; Radominska-Pandya, A; Shi, Y; Simon, CM; Nelson, MC; Ong, ES; Waxman, DJ; Evans, RM. (2001) An essential role for nuclear receptors SXR/PXR in detoxification of cholestatic bile acids. Proc. Natl. Acad. Sci. U.S.A., 98 (6): 3375-80. [PMID:11248086]

37. Xie, W; Yeuh, MF; Radominska-Pandya, A; Saini, SP; Negishi, Y; Bottroff, BS; Cabrera, GY; Tukey, RH; Evans, RM. (2003) Control of steroid, heme, and carcinogen metabolism by nuclear pregnane X receptor and constitutive androstane receptor. Proc. Natl. Acad. Sci. U.S.A., 100 (7): 4150-5. [PMID:12644700]

38. Zhang, H; LeCulyse, E; Liu, L; Hu, M; Matoney, L; Zhu, W; Yan, B. (1999) Rat pregnane X receptor: molecular cloning, tissue distribution, and xenobiotic regulation. Arch. Biochem. Biophys., 368 (1): 14-22. [PMID:10415106]

To cite this database page, please use the following:

1I. Vitamin D receptor-like receptors: Pregnane X receptor. Last modified on 01/04/2013. Accessed on 22/05/2013. IUPHAR database (IUPHAR-DB), http://www.iuphar-db.org/DATABASE/ObjectDisplayForward?objectId=606.


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