Pregnane X receptor

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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.[1][2][3]

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.[4] PXR belongs to the nuclear receptor superfamily, members of which are transcription factors characterized by a ligand-binding domain and a DNA-binding domain. PXR 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.[3][5]

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).[4] Cafestol found in coffee is also an agonist.[6]

Antagonists

Ketoconazole is an example of one of the relatively few-known antagonists of the PXR.[7][8] SPA70 (also known as LC-1) was recently identified and characterized as a potent and selective PXR antagonist.[9][10]

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.[4]

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.[2][3] In addition, PXR up regulates the expression of phase II conjugating enzymes such as glutathione S-transferase[11] and phase III transport uptake and efflux proteins such as OATP2[12] and MDR1.[13][14]

See also

References

  1. Entrez result for NR1I2.
  2. 2.0 2.1 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. PMC 508967Freely accessible. PMID 9727070. doi:10.1172/JCI3703. 
  3. 3.0 3.1 3.2 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. PMC 22810Freely accessible. PMID 9770465. doi:10.1073/pnas.95.21.12208. 
  4. 4.0 4.1 4.2 Kliewer S, Goodwin B, Willson T (2002). "The nuclear pregnane X receptor: a key regulator of xenobiotic metabolism". Endocr. Rev. 23 (5): 687–702. PMID 12372848. doi:10.1210/er.2001-0038. 
  5. "Entrez Gene: NR1I2 nuclear receptor subfamily 1, group I, member 2". 
  6. Ricketts, Marie-Louise; Boekschoten, Mark V.; Kreeft, Arja J.; Hooiveld, Guido J. E. J.; Moen, Corina J. A.; Müller, Michael; Frants, Rune R.; Kasanmoentalib, Soemini; Post, Sabine M. (July 2007). "The cholesterol-raising factor from coffee beans, cafestol, as an agonist ligand for the farnesoid and pregnane X receptors". Molecular Endocrinology (Baltimore, Md.). 21 (7): 1603–1616. ISSN 0888-8809. PMID 17456796. doi:10.1210/me.2007-0133. 
  7. 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. PMC 3904218Freely accessible. PMID 24300333. doi:10.3791/51085. 
  8. Mani S, Dou W, Redinbo MR (2013). "PXR antagonists and implication in drug metabolism". Drug Metabolism Reviews. 45 (1): 60–72. PMC 3583015Freely accessible. PMID 23330542. doi:10.3109/03602532.2012.746363. 
  9. Lin W, Goktug AN, Wu J, Currier DG, Chen T (2017). "High-Throughput Screening Identifies 1,4,5-Substituted 1,2,3-Triazole Analogs as Potent and Specific Antagonists of Pregnane X Receptor". Assay and Drug Development Technologies. PMID 29112465. doi:10.1089/adt.2017.809. 
  10. Lin W, Wang YM, Chai SC, Lv L, Zheng J, Wu J, Zhang Q, Wang YD, Griffin PR, Chen T (2017). "SPA70 is a potent antagonist of human pregnane X receptor". Nature Communications. 8 (1): 741. PMC 5622171Freely accessible. PMID 28963450. doi:10.1038/s41467-017-00780-5. 
  11. 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. 
  12. 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. PMC 30660Freely accessible. PMID 11248085. doi:10.1073/pnas.051551698. 
  13. 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. PMID 11329060. doi:10.1038/87912. 
  14. 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. PMID 11297522. doi:10.1074/jbc.M010173200. 

Further reading

External links

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

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