Pregnane X receptor explained

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^[4] 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 St. John's Wort), and other compounds such as meclizine, paclitaxel, cafestol,^[6] and forskolin.^{[7] [8]}

Antagonists

Ketoconazole is an example of one of the relatively few-known antagonists of the PXR.^{[9] [10]} SPA70 (also known as LC-1) was recently identified and characterized as a potent and selective PXR antagonist.^{[11] [12]}

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^[13] and phase III transport uptake and efflux proteins such as OATP2^[14] and MDR1.^{[15] [16]}

See also

• Constitutive androstane receptor
• Farnesoid X receptor

Further reading

• Watkins RE, Noble SM, Redinbo MR . Structural insights into the promiscuity and function of the human pregnane X receptor . Current Opinion in Drug Discovery & Development . 5 . 1 . 150–8 . January 2002 . 11865669 .
• Maruyama K, Sugano S . Oligo-capping: a simple method to replace the cap structure of eukaryotic mRNAs with oligoribonucleotides . Gene . 138 . 1–2 . 171–4 . January 1994 . 8125298 . 10.1016/0378-1119(94)90802-8 .
• Suzuki Y, Yoshitomo-Nakagawa K, Maruyama K, Suyama A, Sugano S . Construction and characterization of a full length-enriched and a 5'-end-enriched cDNA library . Gene . 200 . 1–2 . 149–56 . October 1997 . 9373149 . 10.1016/S0378-1119(97)00411-3 .
• Kliewer SA, Moore JT, Wade L, Staudinger JL, Watson MA, Jones SA, McKee DD, Oliver BB, Willson TM, Zetterström RH, Perlmann T, Lehmann JM . An orphan nuclear receptor activated by pregnanes defines a novel steroid signaling pathway . Cell . 92 . 1 . 73–82 . January 1998 . 9489701 . 10.1016/S0092-8674(00)80900-9 . 16954668 . free .
• Lehmann JM, McKee DD, Watson MA, Willson TM, Moore JT, Kliewer SA . The human orphan nuclear receptor PXR is activated by compounds that regulate CYP3A4 gene expression and cause drug interactions . The Journal of Clinical Investigation . 102 . 5 . 1016–23 . September 1998 . 9727070 . 508967 . 10.1172/JCI3703 .
• Bertilsson G, Heidrich J, Svensson K, Asman M, Jendeberg L, Sydow-Bäckman M, Ohlsson R, Postlind H, Blomquist P, Berkenstam A . Identification of a human nuclear receptor defines a new signaling pathway for CYP3A induction . Proceedings of the National Academy of Sciences of the United States of America . 95 . 21 . 12208–13 . October 1998 . 9770465 . 22810 . 10.1073/pnas.95.21.12208 . 1998PNAS...9512208B . free .
• Blumberg B, Sabbagh W, Juguilon H, Bolado J, van Meter CM, Ong ES, Evans RM . SXR, a novel steroid and xenobiotic-sensing nuclear receptor . Genes & Development . 12 . 20 . 3195–205 . October 1998 . 9784494 . 317212 . 10.1101/gad.12.20.3195 .
• Dotzlaw H, Leygue E, Watson P, Murphy LC . The human orphan receptor PXR messenger RNA is expressed in both normal and neoplastic breast tissue . Clinical Cancer Research . 5 . 8 . 2103–7 . August 1999 . 10473093 .
• Geick A, Eichelbaum M, Burk O . Nuclear receptor response elements mediate induction of intestinal MDR1 by rifampin . The Journal of Biological Chemistry . 276 . 18 . 14581–7 . May 2001 . 11297522 . 10.1074/jbc.M010173200 . free .
• Watkins RE, Wisely GB, Moore LB, Collins JL, Lambert MH, Williams SP, Willson TM, Kliewer SA, Redinbo MR . The human nuclear xenobiotic receptor PXR: structural determinants of directed promiscuity . Science . 292 . 5525 . 2329–33 . June 2001 . 11408620 . 10.1126/science.1060762 . 20871563 .
• Zhang J, Kuehl P, Green ED, Touchman JW, Watkins PB, Daly A, Hall SD, Maurel P, Relling M, Brimer C, Yasuda K, Wrighton SA, Hancock M, Kim RB, Strom S, Thummel K, Russell CG, Hudson JR, Schuetz EG, Boguski MS . The human pregnane X receptor: genomic structure and identification and functional characterization of natural allelic variants . Pharmacogenetics . 11 . 7 . 555–72 . October 2001 . 11668216 . 10.1097/00008571-200110000-00003 .
• Gonzalez MM, Carlberg C . Cross-repression, a functional consequence of the physical interaction of non-liganded nuclear receptors and POU domain transcription factors . The Journal of Biological Chemistry . 277 . 21 . 18501–9 . May 2002 . 11891224 . 10.1074/jbc.M200205200 . free .
• Takeshita A, Taguchi M, Koibuchi N, Ozawa Y . Putative role of the orphan nuclear receptor SXR (steroid and xenobiotic receptor) in the mechanism of CYP3A4 inhibition by xenobiotics . The Journal of Biological Chemistry . 277 . 36 . 32453–8 . September 2002 . 12072427 . 10.1074/jbc.M111245200 . free .
• Frungieri MB, Weidinger S, Meineke V, Köhn FM, Mayerhofer A . Proliferative action of mast-cell tryptase is mediated by PAR2, COX2, prostaglandins, and PPARgamma : Possible relevance to human fibrotic disorders . Proceedings of the National Academy of Sciences of the United States of America . 99 . 23 . 15072–7 . November 2002 . 12397176 . 137545 . 10.1073/pnas.232422999 . 2002PNAS...9915072F . free .
• Fukuen S, Fukuda T, Matsuda H, Sumida A, Yamamoto I, Inaba T, Azuma J . Identification of the novel splicing variants for the hPXR in human livers . Biochemical and Biophysical Research Communications . 298 . 3 . 433–8 . November 2002 . 12413960 . 10.1016/S0006-291X(02)02469-5 .
• Chang TK, Bandiera SM, Chen J . Constitutive androstane receptor and pregnane X receptor gene expression in human liver: interindividual variability and correlation with CYP2B6 mRNA levels . Drug Metabolism and Disposition . 31 . 1 . 7–10 . January 2003 . 12485946 . 10.1124/dmd.31.1.7 . 42133087 .
• Dussault I, Yoo HD, Lin M, Wang E, Fan M, Batta AK, Salen G, Erickson SK, Forman BM . Identification of an endogenous ligand that activates pregnane X receptor-mediated sterol clearance . Proceedings of the National Academy of Sciences of the United States of America . 100 . 3 . 833–8 . February 2003 . 12569201 . 298687 . 10.1073/pnas.0336235100 . 2003PNAS..100..833D . free .
• Kawana K, Ikuta T, Kobayashi Y, Gotoh O, Takeda K, Kawajiri K . Molecular mechanism of nuclear translocation of an orphan nuclear receptor, SXR . Molecular Pharmacology . 63 . 3 . 524–31 . March 2003 . 12606758 . 10.1124/mol.63.3.524 . 6402235 .

External links

• • Nuclear Receptor Resource Page

Notes and References

1. https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=8856&ordinalpos=1&itool=EntrezSystem2.PEntrez.Gene.Gene_ResultsPanel.Gene_RVDocSum Entrez result for NR1I2
2. Lehmann JM, McKee DD, Watson MA, Willson TM, Moore JT, Kliewer SA . The human orphan nuclear receptor PXR is activated by compounds that regulate CYP3A4 gene expression and cause drug interactions . The Journal of Clinical Investigation . 102 . 5 . 1016–23 . September 1998 . 9727070 . 508967 . 10.1172/JCI3703 .
3. Bertilsson G, Heidrich J, Svensson K, Asman M, Jendeberg L, Sydow-Bäckman M, Ohlsson R, Postlind H, Blomquist P, Berkenstam A . Identification of a human nuclear receptor defines a new signaling pathway for CYP3A induction . Proceedings of the National Academy of Sciences of the United States of America . 95 . 21 . 12208–13 . October 1998 . 9770465 . 22810 . 10.1073/pnas.95.21.12208 . 1998PNAS...9512208B . free .
4. Kliewer SA, Goodwin B, Willson TM . The nuclear pregnane X receptor: a key regulator of xenobiotic metabolism . Endocrine Reviews . 23 . 5 . 687–702 . October 2002 . 12372848 . 10.1210/er.2001-0038 . free .
5. Web site: Entrez Gene: NR1I2 nuclear receptor subfamily 1, group I, member 2.
6. Ricketts ML, Boekschoten MV, Kreeft AJ, Hooiveld GJ, Moen CJ, Müller M, Frants RR, Kasanmoentalib S, Post SM, Princen HM, Porter JG, Katan MB, Hofker MH, Moore DD . The cholesterol-raising factor from coffee beans, cafestol, as an agonist ligand for the farnesoid and pregnane X receptors . Molecular Endocrinology . 21 . 7 . 1603–16 . July 2007 . 17456796 . 10.1210/me.2007-0133 . free .
7. Kaur J, Sodhi RK, Madan J, Chahal SK, Kumar R . Forskolin convalesces memory in high fat diet-induced dementia in wistar rats-Plausible role of pregnane x receptors . Pharmacological Reports . 70 . 1 . 161–171 . February 2018 . 29367103 . 10.1016/j.pharep.2017.07.009 . 3872389 .
8. Ding. X.. Induction of Drug Metabolism by Forskolin: The Role of the Pregnane X Receptor and the Protein Kinase A Signal Transduction Pathway. Journal of Pharmacology and Experimental Therapeutics. 312. 2. 2004. 849–856. 0022-3565. 10.1124/jpet.104.076331. 15459237. 8056821.
9. Li H, Dou W, Padikkala E, Mani S . Reverse yeast two-hybrid system to identify mammalian nuclear receptor residues that interact with ligands and/or antagonists . Journal of Visualized Experiments . 81 . e51085 . November 2013 . 24300333 . 3904218 . 10.3791/51085 .
10. Mani S, Dou W, Redinbo MR . PXR antagonists and implication in drug metabolism . Drug Metabolism Reviews . 45 . 1 . 60–72 . February 2013 . 23330542 . 3583015 . 10.3109/03602532.2012.746363 .
11. Lin W, Goktug AN, Wu J, Currier DG, Chen T . 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 . 15 . 8 . 383–394 . December 2017 . 29112465 . 5731549 . 10.1089/adt.2017.809 .
12. Lin W, Wang YM, Chai SC, Lv L, Zheng J, Wu J, Zhang Q, Wang YD, Griffin PR, Chen T . SPA70 is a potent antagonist of human pregnane X receptor . Nature Communications . 8 . 1 . 741 . September 2017 . 28963450 . 5622171 . 10.1038/s41467-017-00780-5 . 2017NatCo...8..741L .
13. Falkner KC, Pinaire JA, Xiao GH, Geoghegan TE, Prough RA . Regulation of the rat glutathione S-transferase A2 gene by glucocorticoids: involvement of both the glucocorticoid and pregnane X receptors . Molecular Pharmacology . 60 . 3 . 611–9 . September 2001 . 11502894 .
14. 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 . The nuclear receptor PXR is a lithocholic acid sensor that protects against liver toxicity . Proceedings of the National Academy of Sciences of the United States of America . 98 . 6 . 3369–74 . March 2001 . 11248085 . 30660 . 10.1073/pnas.051551698 . 2001PNAS...98.3369S . free .
15. Synold TW, Dussault I, Forman BM . The orphan nuclear receptor SXR coordinately regulates drug metabolism and efflux . Nature Medicine . 7 . 5 . 584–90 . May 2001 . 11329060 . 10.1038/87912 . 34155288 .
16. Geick A, Eichelbaum M, Burk O . Nuclear receptor response elements mediate induction of intestinal MDR1 by rifampin . The Journal of Biological Chemistry . 276 . 18 . 14581–7 . May 2001 . 11297522 . 10.1074/jbc.M010173200 . free .