関: Pregnane X receptor

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出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2016/09/21 03:23:22」(JST)

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In the field of molecular biology, the pregnane X receptor (PXR), also known as the steroid and xenobiotic sensing nuclear receptor (SXR) or nuclear receptor subfamily 1, group I, member 2 (NR1I2) is a protein that in humans is encoded by the NR1I2 (nuclear Receptor subfamily 1, group I, member 2) gene.^[3]^[4]^[5]

Function

PXR is a nuclear receptor whose primary function is to sense the presence of foreign toxic substances and in response up regulate the expression of proteins involved in the detoxification and clearance of these substances from the body.^[6] PXR belongs to the nuclear receptor superfamily, members of which are transcription factors characterized by a ligand-binding domain and a DNA-binding domain. The encoded protein is a transcriptional regulator of the cytochrome P450 gene CYP3A4, binding to the response element of the CYP3A4 promoter as a heterodimer with the 9-cis retinoic acid receptor RXR. It is activated by a range of compounds that induce CYP3A4, including dexamethasone and rifampicin.^[5]^[7]

Ligands

Agonists

PXR is activated by a large number of endogenous and exogenous chemicals including steroids (e.g., progesterone, 17α-hydroxyprogesterone, 17α-hydroxypregnenolone, 5α-dihydroprogesterone, 5β-dihydroprogesterone, allopregnanolone, corticosterone, cyproterone acetate, spironolactone, dexamethasone, mifepristone), antibiotics (e.g., rifampicin, rifaximin), antimycotics, bile acids, hyperforin (a constituent of the herbal antidepressant St. John's Wort), and many herbal and other compounds (e.g., meclizine, paclitaxel).^[6]

Antagonists

Ketoconazole is an example of one of the relatively few-known antagonists of the PXR.^[8]

Mechanism

Like other type II nuclear receptors, when activated, it forms a heterodimer with the retinoid X receptor, and binds to hormone response elements on DNA which elicits expression of gene products.^[6]

One of the primary targets of PXR activation is the induction of CYP3A4, an important phase I oxidative enzyme that is responsible for the metabolism of many drugs.^[4]^[5] In addition, PXR up regulates the expression of phase II conjugating enzymes such as glutathione S-transferase^[9] and phase III transport uptake and efflux proteins such as OATP2^[10] and MDR1.^[11]^[12]

References

^ "Human PubMed Reference:".
^ "Mouse PubMed Reference:".
^ Entrez result for NR1I2.
^ ^a ^b Lehmann JM, McKee DD, Watson MA, Willson TM, Moore JT, Kliewer SA (September 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. doi:10.1172/JCI3703. PMC 508967. PMID 9727070.
^ ^a ^b ^c Bertilsson G, Heidrich J, Svensson K, Asman M, Jendeberg L, Sydow-Bäckman M, Ohlsson R, Postlind H, Blomquist P, Berkenstam A (October 1998). "Identification of a human nuclear receptor defines a new signaling pathway for CYP3A induction". Proc. Natl. Acad. Sci. U.S.A. 95 (21): 12208–13. doi:10.1073/pnas.95.21.12208. PMC 22810. PMID 9770465.
^ ^a ^b ^c Kliewer S, Goodwin B, Willson T (2002). "The nuclear pregnane X receptor: a key regulator of xenobiotic metabolism". Endocr. Rev. 23 (5): 687–702. doi:10.1210/er.2001-0038. PMID 12372848.
^ "Entrez Gene: NR1I2 nuclear receptor subfamily 1, group I, member 2".
^ Li H, Dou W, Padikkala E, Mani S (2013). "Reverse yeast two-hybrid system to identify mammalian nuclear receptor residues that interact with ligands and/or antagonists". J Vis Exp (81): e51085. doi:10.3791/51085. PMC 3904218. PMID 24300333.
^ Falkner KC, Pinaire JA, Xiao GH, Geoghegan TE, Prough RA (September 2001). "Regulation of the rat glutathione S-transferase A2 gene by glucocorticoids: involvement of both the glucocorticoid and pregnane X receptors". Mol. Pharmacol. 60 (3): 611–9. PMID 11502894.
^ Staudinger JL, Goodwin B, Jones SA, Hawkins-Brown D, MacKenzie KI, LaTour A, Liu Y, Klaassen CD, Brown KK, Reinhard J, Willson TM, Koller BH, Kliewer SA (March 2001). "The nuclear receptor PXR is a lithocholic acid sensor that protects against liver toxicity". Proc. Natl. Acad. Sci. U.S.A. 98 (6): 3369–74. doi:10.1073/pnas.051551698. PMC 30660. PMID 11248085.
^ Synold TW, Dussault I, Forman BM (May 2001). "The orphan nuclear receptor SXR coordinately regulates drug metabolism and efflux". Nat. Med. 7 (5): 584–90. doi:10.1038/87912. PMID 11329060.
^ Geick A, Eichelbaum M, Burk O (May 2001). "Nuclear receptor response elements mediate induction of intestinal MDR1 by rifampin". J. Biol. Chem. 276 (18): 14581–7. doi:10.1074/jbc.M010173200. PMID 11297522.

External links

pregnane X receptor at the US National Library of Medicine Medical Subject Headings (MeSH)

This article incorporates text from the United States National Library of Medicine, which is in the public domain.

Nuclear Receptor Resource Page http://nrresource.org/nr_page_collection/nr1i2-pregnane-x-receptor.html

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「プレグナン受容体」

NR1I2
Available structures
PDB	Ortholog search: PDBe RCSB
List of PDB id codes
	1ILG, 1ILH, 1M13, 1NRL, 1SKX, 2O9I, 2QNV, 3CTB, 3HVL, 3R8D, 4J5W, 4J5X, 4NY9, 4S0S, 4S0T, 4XHD, 4X1F, 4X1G, 4XAO, 5A86
Identifiers
Aliases	NR1I2, BXR, ONR1, PAR, PAR1, PAR2, PARq, PRR, PXR, SAR, SXR, nuclear receptor subfamily 1 group I member 2
External IDs	OMIM: 603065 MGI: 1337040 HomoloGene: 40757 GeneCards: 8856
Gene ontology
Molecular function	• DNA binding; • sequence-specific DNA binding; • RNA polymerase II regulatory region sequence-specific DNA binding; • transcription factor activity, sequence-specific DNA binding; • transcriptional activator activity, RNA polymerase II transcription regulatory region sequence-specific binding; • transcription coactivator activity; • zinc ion binding; • metal ion binding; • steroid hormone receptor activity; • RNA polymerase II transcription factor activity, ligand-activated sequence-specific DNA binding; • protein binding; • drug binding;
Cellular component	• nucleoplasm; • nucleus;
Biological process	• steroid metabolic process; • regulation of transcription, DNA-templated; • exogenous drug catabolic process; • xenobiotic transport; • drug export; • transcription, DNA-templated; • positive regulation of transcription, DNA-templated; • positive regulation of gene expression; • xenobiotic metabolic process; • transcription initiation from RNA polymerase II promoter; • negative regulation of transcription, DNA-templated; • signal transduction; • steroid hormone mediated signaling pathway; • positive regulation of transcription from RNA polymerase II promoter; • intracellular receptor signaling pathway;
	Sources:Amigo / QuickGO
RNA expression pattern
	; ;
	More reference expression data
Orthologs
	8856
	18171
	ENSG00000144852
	ENSMUSG00000022809
	O75469
	O54915
	NM_033013; NM_003889; NM_022002
	NM_001098404; NM_010936
	NP_003880.3; NP_071285.1; NP_148934.1
	NP_001091874.1; NP_035066.1
	Wikidata
View/Edit Human	View/Edit Mouse

　　[★]

英: pregnane X receptor, PXR

「P」

　　[★]

[1] "Human PubMed Reference:".

[2] "Mouse PubMed Reference:".

[3] Entrez result for NR1I2.

[pmid9727070-4] Lehmann JM, McKee DD, Watson MA, Willson TM, Moore JT, Kliewer SA (September 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. doi:10.1172/JCI3703. PMC 508967. PMID 9727070.

[pmid9770465-5] Bertilsson G, Heidrich J, Svensson K, Asman M, Jendeberg L, Sydow-Bäckman M, Ohlsson R, Postlind H, Blomquist P, Berkenstam A (October 1998). "Identification of a human nuclear receptor defines a new signaling pathway for CYP3A induction". Proc. Natl. Acad. Sci. U.S.A. 95 (21): 12208–13. doi:10.1073/pnas.95.21.12208. PMC 22810. PMID 9770465.

[Kliewer-6] Kliewer S, Goodwin B, Willson T (2002). "The nuclear pregnane X receptor: a key regulator of xenobiotic metabolism". Endocr. Rev. 23 (5): 687–702. doi:10.1210/er.2001-0038. PMID 12372848.

[entrez-7] "Entrez Gene: NR1I2 nuclear receptor subfamily 1, group I, member 2".

[pmid24300333-8] Li H, Dou W, Padikkala E, Mani S (2013). "Reverse yeast two-hybrid system to identify mammalian nuclear receptor residues that interact with ligands and/or antagonists". J Vis Exp (81): e51085. doi:10.3791/51085. PMC 3904218. PMID 24300333.

[pmid11502894-9] Falkner KC, Pinaire JA, Xiao GH, Geoghegan TE, Prough RA (September 2001). "Regulation of the rat glutathione S-transferase A2 gene by glucocorticoids: involvement of both the glucocorticoid and pregnane X receptors". Mol. Pharmacol. 60 (3): 611–9. PMID 11502894.

[pmid11248085-10] Staudinger JL, Goodwin B, Jones SA, Hawkins-Brown D, MacKenzie KI, LaTour A, Liu Y, Klaassen CD, Brown KK, Reinhard J, Willson TM, Koller BH, Kliewer SA (March 2001). "The nuclear receptor PXR is a lithocholic acid sensor that protects against liver toxicity". Proc. Natl. Acad. Sci. U.S.A. 98 (6): 3369–74. doi:10.1073/pnas.051551698. PMC 30660. PMID 11248085.

[pmid11329060-11] Synold TW, Dussault I, Forman BM (May 2001). "The orphan nuclear receptor SXR coordinately regulates drug metabolism and efflux". Nat. Med. 7 (5): 584–90. doi:10.1038/87912. PMID 11329060.

[pmid11297522-12] Geick A, Eichelbaum M, Burk O (May 2001). "Nuclear receptor response elements mediate induction of intestinal MDR1 by rifampin". J. Biol. Chem. 276 (18): 14581–7. doi:10.1074/jbc.M010173200. PMID 11297522.

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PXR