Pregnane X receptor: Difference between revisions

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{{Infobox gene}}
{{Infobox gene}}


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.<ref>[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].</ref><ref name="pmid9727070">{{cite journal |vauthors=Lehmann JM, McKee DD, Watson MA, Willson TM, Moore JT, Kliewer SA | title = The human orphan nuclear receptor PXR is activated by compounds that regulate CYP3A4 gene expression and cause drug interactions | journal = J. Clin. Invest. | volume = 102 | issue = 5 | pages = 1016–23 |date=September 1998 | pmid = 9727070 | pmc = 508967 | doi = 10.1172/JCI3703 | url =  }}</ref><ref name="pmid9770465">{{cite journal |vauthors=Bertilsson G, Heidrich J, Svensson K, Asman M, Jendeberg L, Sydow-Bäckman M, Ohlsson R, Postlind H, Blomquist P, Berkenstam A | title = Identification of a human nuclear receptor defines a new signaling pathway for CYP3A induction | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 95 | issue = 21 | pages = 12208–13 |date=October 1998 | pmid = 9770465 | pmc = 22810 | doi = 10.1073/pnas.95.21.12208| url = http://www.pnas.org/cgi/pmidlookup?view=long&pmid=9770465 }}</ref>
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.<ref>[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].</ref><ref name="pmid9727070">{{cite journal | vauthors = Lehmann JM, McKee DD, Watson MA, Willson TM, Moore JT, Kliewer SA | title = The human orphan nuclear receptor PXR is activated by compounds that regulate CYP3A4 gene expression and cause drug interactions | journal = The Journal of Clinical Investigation | volume = 102 | issue = 5 | pages = 1016–23 | date = September 1998 | pmid = 9727070 | pmc = 508967 | doi = 10.1172/JCI3703 }}</ref><ref name="pmid9770465">{{cite journal | vauthors = Bertilsson G, Heidrich J, Svensson K, Asman M, Jendeberg L, Sydow-Bäckman M, Ohlsson R, Postlind H, Blomquist P, Berkenstam A | title = Identification of a human nuclear receptor defines a new signaling pathway for CYP3A induction | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 95 | issue = 21 | pages = 12208–13 | date = October 1998 | pmid = 9770465 | pmc = 22810 | doi = 10.1073/pnas.95.21.12208 | url = http://www.pnas.org/cgi/pmidlookup?view=long&pmid=9770465 }}</ref>


==Function==
== Function ==
PXR is a [[nuclear hormone receptor class|nuclear receptor]] whose primary function is to sense the presence of foreign toxic substances and in response [[downregulation and upregulation|up regulate]] the expression of proteins involved in the [[detoxification]] and clearance of these substances from the body.<ref name="Kliewer">{{cite journal |vauthors=Kliewer S, Goodwin B, Willson T |title=The nuclear pregnane X receptor: a key regulator of xenobiotic metabolism |journal=Endocr. Rev. |volume=23 |issue=5 |pages=687–702 |year=2002 |pmid=12372848 |doi=10.1210/er.2001-0038}}</ref>  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 [[Retinoid X receptor|RXR]]. It is activated by a range of compounds that induce CYP3A4, including [[dexamethasone]] and [[rifampicin]].<ref name="pmid9770465"/><ref name="entrez">{{cite web | title = Entrez Gene: NR1I2 nuclear receptor subfamily 1, group I, member 2| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=8856| accessdate = }}</ref>
PXR is a [[nuclear hormone receptor class|nuclear receptor]] whose primary function is to sense the presence of foreign toxic substances and in response [[downregulation and upregulation|up regulate]] the expression of proteins involved in the [[detoxification]] and clearance of these substances from the body.<ref name="Kliewer">{{cite journal | vauthors = Kliewer SA, Goodwin B, Willson TM | title = The nuclear pregnane X receptor: a key regulator of xenobiotic metabolism | journal = Endocrine Reviews | volume = 23 | issue = 5 | pages = 687–702 | date = October 2002 | pmid = 12372848 | doi = 10.1210/er.2001-0038 }}</ref>  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 [[Retinoid X receptor|RXR]]. It is activated by a range of compounds that induce CYP3A4, including [[dexamethasone]] and [[rifampicin]].<ref name="pmid9770465"/><ref name="entrez">{{cite web | title = Entrez Gene: NR1I2 nuclear receptor subfamily 1, group I, member 2| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=8856| access-date = }}</ref>


==Ligands==
==Ligands==


===Agonists===
===Agonists===
PXR is activated by a large number of [[endogenous]] and [[exogenous]] chemicals including [[steroid]]s (e.g., [[progesterone]], [[17α-hydroxyprogesterone]], [[17α-hydroxypregnenolone]], [[5α-dihydroprogesterone]], [[5β-dihydroprogesterone]], [[allopregnanolone]], [[corticosterone]], [[cyproterone acetate]], [[spironolactone]], [[dexamethasone]], [[mifepristone]]), [[antibiotic]]s (e.g., [[rifampicin]], [[rifaximin]]), [[antimycotic]]s, [[bile acid]]s, [[hyperforin]] (a constituent of the herbal antidepressant [[St. John's Wort]]), and many herbal and other compounds (e.g. [[meclizine]], [[paclitaxel]]).<ref name="Kliewer"/> [[Cafestol]] found in [[coffee]] is also an agonist.<ref>{{Cite journal|last=Ricketts|first=Marie-Louise|last2=Boekschoten|first2=Mark V.|last3=Kreeft|first3=Arja J.|last4=Hooiveld|first4=Guido J. E. J.|last5=Moen|first5=Corina J. A.|last6=Müller|first6=Michael|last7=Frants|first7=Rune R.|last8=Kasanmoentalib|first8=Soemini|last9=Post|first9=Sabine M.|date=July 2007|title=The cholesterol-raising factor from coffee beans, cafestol, as an agonist ligand for the farnesoid and pregnane X receptors|url=https://www.ncbi.nlm.nih.gov/pubmed/17456796|journal=Molecular Endocrinology (Baltimore, Md.)|volume=21|issue=7|pages=1603–1616|doi=10.1210/me.2007-0133|issn=0888-8809|pmid=17456796}}</ref>
PXR is activated by a large number of [[endogenous]] and [[exogenous]] chemicals including [[steroid]]s (e.g., [[progesterone]], [[17α-hydroxyprogesterone]], [[17α-hydroxypregnenolone]], [[5α-dihydroprogesterone]], [[5β-dihydroprogesterone]], [[allopregnanolone]], [[corticosterone]], [[cyproterone acetate]], [[spironolactone]], [[dexamethasone]], [[mifepristone]]), [[antibiotic]]s (e.g., [[rifampicin]], [[rifaximin]]), [[antimycotic]]s, [[bile acid]]s, [[hyperforin]] (a constituent of the herbal antidepressant [[St. John's Wort]]), and many herbal and other compounds (e.g. [[meclizine]], [[paclitaxel]]).<ref name="Kliewer"/> [[Cafestol]] found in [[coffee]] is also an agonist.<ref>{{cite journal | vauthors = 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 | title = The cholesterol-raising factor from coffee beans, cafestol, as an agonist ligand for the farnesoid and pregnane X receptors | journal = Molecular Endocrinology | volume = 21 | issue = 7 | pages = 1603–16 | date = July 2007 | pmid = 17456796 | doi = 10.1210/me.2007-0133 }}</ref>
 
[[Forskolin]] is another case example of a PXR agonist.<ref name="KaurSodhi2018">{{cite journal | vauthors = Kaur J, Sodhi RK, Madan J, Chahal SK, Kumar R | title = Forskolin convalesces memory in high fat diet-induced dementia in wistar rats-Plausible role of pregnane x receptors | journal = Pharmacological Reports | volume = 70 | issue = 1 | pages = 161–171 | date = February 2018 | pmid = 29367103 | doi = 10.1016/j.pharep.2017.07.009 }}</ref><ref name="Ding2004">{{cite journal|last1=Ding|first1=X.|title=Induction of Drug Metabolism by Forskolin: The Role of the Pregnane X Receptor and the Protein Kinase A Signal Transduction Pathway|journal=Journal of Pharmacology and Experimental Therapeutics|volume=312|issue=2|year=2004|pages=849–856|issn=0022-3565|doi=10.1124/jpet.104.076331}}</ref>


===Antagonists===
===Antagonists===
[[Ketoconazole]] is an example of one of the relatively few-known [[receptor antagonist|antagonist]]s of the PXR.<ref name="Li_2013">{{cite journal | vauthors = Li H, Dou W, Padikkala E, Mani S | title = Reverse yeast two-hybrid system to identify mammalian nuclear receptor residues that interact with ligands and/or antagonists | journal = J Vis Exp | volume = | issue = 81 | pages = e51085 | year = 2013 | pmid = 24300333 | pmc = 3904218 | doi = 10.3791/51085 }}</ref><ref name="Mani_2013">{{cite journal | vauthors = Mani S, Dou W, Redinbo MR | title = PXR antagonists and implication in drug metabolism | journal = Drug Metabolism Reviews | volume = 45 | issue = 1 | pages = 60–72 | year = 2013 | pmid = 23330542 | pmc = 3583015 | doi = 10.3109/03602532.2012.746363 }}</ref>  SPA70 (also known as LC-1) was recently identified and characterized as a potent and selective PXR antagonist.<ref name="Lin_2017a">{{cite journal | vauthors = Lin W, Goktug AN, Wu J, Currier DG, Chen T | title = High-Throughput Screening Identifies 1,4,5-Substituted 1,2,3-Triazole Analogs as Potent and Specific Antagonists of Pregnane X Receptor | journal = Assay and Drug Development Technologies | volume = | issue = | pages = | year = 2017 | pmid = 29112465 | doi = 10.1089/adt.2017.809 }}</ref><ref name="Lin_2017b">{{cite journal | vauthors = Lin W, Wang YM, Chai SC, Lv L, Zheng J, Wu J, Zhang Q, Wang YD, Griffin PR, Chen T | title = SPA70 is a potent antagonist of human pregnane X receptor | journal = Nature Communications | volume = 8 | issue = 1 | pages = 741 | year = 2017 | pmid = 28963450 | pmc = 5622171 | doi = 10.1038/s41467-017-00780-5 }}</ref>
[[Ketoconazole]] is an example of one of the relatively few-known [[receptor antagonist|antagonist]]s of the PXR.<ref name="Li_2013">{{cite journal | vauthors = Li H, Dou W, Padikkala E, Mani S | title = Reverse yeast two-hybrid system to identify mammalian nuclear receptor residues that interact with ligands and/or antagonists | journal = Journal of Visualized Experiments | volume = | issue = 81 | pages = e51085 | date = November 2013 | pmid = 24300333 | pmc = 3904218 | doi = 10.3791/51085 }}</ref><ref name="Mani_2013">{{cite journal | vauthors = Mani S, Dou W, Redinbo MR | title = PXR antagonists and implication in drug metabolism | journal = Drug Metabolism Reviews | volume = 45 | issue = 1 | pages = 60–72 | date = February 2013 | pmid = 23330542 | pmc = 3583015 | doi = 10.3109/03602532.2012.746363 }}</ref>  SPA70 (also known as LC-1) was recently identified and characterized as a potent and selective PXR antagonist.<ref name="Lin_2017a">{{cite journal | vauthors = Lin W, Goktug AN, Wu J, Currier DG, Chen T | title = High-Throughput Screening Identifies 1,4,5-Substituted 1,2,3-Triazole Analogs as Potent and Specific Antagonists of Pregnane X Receptor | journal = Assay and Drug Development Technologies | volume = 15 | issue = 8 | pages = 383–394 | date = December 2017 | pmid = 29112465 | pmc = 5731549 | doi = 10.1089/adt.2017.809 }}</ref><ref name="Lin_2017b">{{cite journal | vauthors = Lin W, Wang YM, Chai SC, Lv L, Zheng J, Wu J, Zhang Q, Wang YD, Griffin PR, Chen T | title = SPA70 is a potent antagonist of human pregnane X receptor | journal = Nature Communications | volume = 8 | issue = 1 | pages = 741 | date = September 2017 | pmid = 28963450 | pmc = 5622171 | doi = 10.1038/s41467-017-00780-5 }}</ref>


==Mechanism==
==Mechanism==
Like other [[Nuclear hormone receptor class#Type II|type II nuclear receptors]], when activated, it forms a hetero[[protein dimer|dimer]] with the [[retinoid X receptor]], and binds to [[hormone response element]]s on DNA which elicits expression of [[gene]] products.<ref name="Kliewer"/>
Like other [[Nuclear hormone receptor class#Type II|type II nuclear receptors]], when activated, it forms a hetero[[protein dimer|dimer]] with the [[retinoid X receptor]], and binds to [[hormone response element]]s on DNA which elicits expression of [[gene]] products.<ref name="Kliewer"/>


One of the primary targets of PXR activation is the induction of [[CYP3A4]], an important [[Metabolism#Xenobiotics and redox metabolism|phase I]] oxidative [[enzyme]] that is responsible for the [[metabolism]] of many [[drugs]].<ref name="pmid9727070"/><ref name="pmid9770465"/> In addition, PXR up regulates the expression of phase II conjugating enzymes such as [[glutathione S-transferase]]<ref name="pmid11502894">{{cite journal |vauthors=Falkner KC, Pinaire JA, Xiao GH, Geoghegan TE, Prough RA | title = Regulation of the rat glutathione S-transferase A2 gene by glucocorticoids: involvement of both the glucocorticoid and pregnane X receptors | journal = Mol. Pharmacol. | volume = 60 | issue = 3 | pages = 611–9 |date=September 2001 | pmid = 11502894 | doi = | url = http://molpharm.aspetjournals.org/cgi/pmidlookup?view=long&pmid=11502894 | issn = }}</ref> and phase III transport uptake and [[efflux (microbiology)|efflux]] proteins such as [[SLCO2A1|OATP2]]<ref name="pmid11248085">{{cite journal |vauthors=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 | title = The nuclear receptor PXR is a lithocholic acid sensor that protects against liver toxicity | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 98 | issue = 6 | pages = 3369–74 |date=March 2001 | pmid = 11248085 | pmc = 30660 | doi = 10.1073/pnas.051551698 | url =  }}</ref> and [[P-glycoprotein|MDR1]].<ref name="pmid11329060">{{cite journal |vauthors=Synold TW, Dussault I, Forman BM | title = The orphan nuclear receptor SXR coordinately regulates drug metabolism and efflux | journal = Nat. Med. | volume = 7 | issue = 5 | pages = 584–90 |date=May 2001 | pmid = 11329060 | doi = 10.1038/87912 | url =  }}</ref><ref name="pmid11297522">{{cite journal |vauthors=Geick A, Eichelbaum M, Burk O | title = Nuclear receptor response elements mediate induction of intestinal MDR1 by rifampin | journal = J. Biol. Chem. | volume = 276 | issue = 18 | pages = 14581–7 |date=May 2001 | pmid = 11297522 | doi = 10.1074/jbc.M010173200 | url =  }}</ref>
One of the primary targets of PXR activation is the induction of [[CYP3A4]], an important [[Metabolism#Xenobiotics and redox metabolism|phase I]] oxidative [[enzyme]] that is responsible for the [[metabolism]] of many [[drugs]].<ref name="pmid9727070"/><ref name="pmid9770465"/> In addition, PXR up regulates the expression of phase II conjugating enzymes such as [[glutathione S-transferase]]<ref name="pmid11502894">{{cite journal | vauthors = Falkner KC, Pinaire JA, Xiao GH, Geoghegan TE, Prough RA | title = Regulation of the rat glutathione S-transferase A2 gene by glucocorticoids: involvement of both the glucocorticoid and pregnane X receptors | journal = Molecular Pharmacology | volume = 60 | issue = 3 | pages = 611–9 | date = September 2001 | pmid = 11502894 | doi = | url = http://molpharm.aspetjournals.org/cgi/pmidlookup?view=long&pmid=11502894 }}</ref> and phase III transport uptake and [[efflux (microbiology)|efflux]] proteins such as [[SLCO2A1|OATP2]]<ref name="pmid11248085">{{cite journal | vauthors = 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 | title = The nuclear receptor PXR is a lithocholic acid sensor that protects against liver toxicity | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 98 | issue = 6 | pages = 3369–74 | date = March 2001 | pmid = 11248085 | pmc = 30660 | doi = 10.1073/pnas.051551698 }}</ref> and [[P-glycoprotein|MDR1]].<ref name="pmid11329060">{{cite journal | vauthors = Synold TW, Dussault I, Forman BM | title = The orphan nuclear receptor SXR coordinately regulates drug metabolism and efflux | journal = Nature Medicine | volume = 7 | issue = 5 | pages = 584–90 | date = May 2001 | pmid = 11329060 | doi = 10.1038/87912 }}</ref><ref name="pmid11297522">{{cite journal | vauthors = Geick A, Eichelbaum M, Burk O | title = Nuclear receptor response elements mediate induction of intestinal MDR1 by rifampin | journal = The Journal of Biological Chemistry | volume = 276 | issue = 18 | pages = 14581–7 | date = May 2001 | pmid = 11297522 | doi = 10.1074/jbc.M010173200 }}</ref>


==See also==
== See also ==
* [[Constitutive androstane receptor]]
* [[Constitutive androstane receptor]]
* [[Farnesoid X receptor]]
* [[Farnesoid X receptor]]


==References==
== References ==
{{Reflist|2}}
{{Reflist|2}}


==Further reading==
== Further reading ==
{{refbegin | 2}}
{{refbegin | 2}}
*{{cite journal |vauthors=Watkins RE, Noble SM, Redinbo MR |title=Structural insights into the promiscuity and function of the human pregnane X receptor. |journal=Current Opinion in Drug Discovery & Development |volume=5 |issue= 1 |pages= 150–8 |year= 2002 |pmid= 11865669 |doi=  }}
* {{cite journal | vauthors = Watkins RE, Noble SM, Redinbo MR | title = Structural insights into the promiscuity and function of the human pregnane X receptor | journal = Current Opinion in Drug Discovery & Development | volume = 5 | issue = 1 | pages = 150–8 | date = January 2002 | pmid = 11865669 | doi =  }}
*{{cite journal |vauthors=Maruyama K, Sugano S |title=Oligo-capping: a simple method to replace the cap structure of eukaryotic mRNAs with oligoribonucleotides. |journal=Gene |volume=138 |issue= 1-2 |pages= 171–4 |year= 1994 |pmid= 8125298 |doi=10.1016/0378-1119(94)90802-8 }}
* {{cite journal | vauthors = Maruyama K, Sugano S | title = Oligo-capping: a simple method to replace the cap structure of eukaryotic mRNAs with oligoribonucleotides | journal = Gene | volume = 138 | issue = 1-2 | pages = 171–4 | date = January 1994 | pmid = 8125298 | doi = 10.1016/0378-1119(94)90802-8 }}
*{{cite journal   |vauthors=Suzuki Y, Yoshitomo-Nakagawa K, Maruyama K, etal |title=Construction and characterization of a full length-enriched and a 5'-end-enriched cDNA library. |journal=Gene |volume=200 |issue= 1-2 |pages= 149–56 |year= 1997 |pmid= 9373149 |doi=10.1016/S0378-1119(97)00411-3 }}
* {{cite journal | vauthors = Suzuki Y, Yoshitomo-Nakagawa K, Maruyama K, Suyama A, Sugano S | title = Construction and characterization of a full length-enriched and a 5'-end-enriched cDNA library | journal = Gene | volume = 200 | issue = 1-2 | pages = 149–56 | date = October 1997 | pmid = 9373149 | doi = 10.1016/S0378-1119(97)00411-3 }}
*{{cite journal   |vauthors=Kliewer SA, Moore JT, Wade L, etal |title=An orphan nuclear receptor activated by pregnanes defines a novel steroid signaling pathway. |journal=Cell |volume=92 |issue= 1 |pages= 73–82 |year= 1998 |pmid= 9489701 |doi=10.1016/S0092-8674(00)80900-9 }}
* {{cite journal | vauthors = Kliewer SA, Moore JT, Wade L, Staudinger JL, Watson MA, Jones SA, McKee DD, Oliver BB, Willson TM, Zetterström RH, Perlmann T, Lehmann JM | title = An orphan nuclear receptor activated by pregnanes defines a novel steroid signaling pathway | journal = Cell | volume = 92 | issue = 1 | pages = 73–82 | date = January 1998 | pmid = 9489701 | doi = 10.1016/S0092-8674(00)80900-9 }}
*{{cite journal   |vauthors=Lehmann JM, McKee DD, Watson MA, etal |title=The human orphan nuclear receptor PXR is activated by compounds that regulate CYP3A4 gene expression and cause drug interactions. |journal=J. Clin. Invest. |volume=102 |issue= 5 |pages= 1016–23 |year= 1998 |pmid= 9727070 |doi=10.1172/JCI3703 | pmc=508967  }}
* {{cite journal | vauthors = Lehmann JM, McKee DD, Watson MA, Willson TM, Moore JT, Kliewer SA | title = The human orphan nuclear receptor PXR is activated by compounds that regulate CYP3A4 gene expression and cause drug interactions | journal = The Journal of Clinical Investigation | volume = 102 | issue = 5 | pages = 1016–23 | date = September 1998 | pmid = 9727070 | pmc = 508967 | doi = 10.1172/JCI3703 }}
*{{cite journal   |vauthors=Bertilsson G, Heidrich J, Svensson K, etal |title=Identification of a human nuclear receptor defines a new signaling pathway for CYP3A induction. |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=95 |issue= 21 |pages= 12208–13 |year= 1998 |pmid= 9770465 |doi=10.1073/pnas.95.21.12208 | pmc=22810  }}
* {{cite journal | vauthors = Bertilsson G, Heidrich J, Svensson K, Asman M, Jendeberg L, Sydow-Bäckman M, Ohlsson R, Postlind H, Blomquist P, Berkenstam A | title = Identification of a human nuclear receptor defines a new signaling pathway for CYP3A induction | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 95 | issue = 21 | pages = 12208–13 | date = October 1998 | pmid = 9770465 | pmc = 22810 | doi = 10.1073/pnas.95.21.12208 }}
*{{cite journal   |vauthors=Blumberg B, Sabbagh W, Juguilon H, etal |title=SXR, a novel steroid and xenobiotic-sensing nuclear receptor. |journal=Genes Dev. |volume=12 |issue= 20 |pages= 3195–205 |year= 1998 |pmid= 9784494 |doi=10.1101/gad.12.20.3195 | pmc=317212  }}
* {{cite journal | vauthors = Blumberg B, Sabbagh W, Juguilon H, Bolado J, van Meter CM, Ong ES, Evans RM | title = SXR, a novel steroid and xenobiotic-sensing nuclear receptor | journal = Genes & Development | volume = 12 | issue = 20 | pages = 3195–205 | date = October 1998 | pmid = 9784494 | pmc = 317212 | doi = 10.1101/gad.12.20.3195 }}
*{{cite journal |vauthors=Dotzlaw H, Leygue E, Watson P, Murphy LC |title=The human orphan receptor PXR messenger RNA is expressed in both normal and neoplastic breast tissue. |journal=Clin. Cancer Res. |volume=5 |issue= 8 |pages= 2103–7 |year= 1999 |pmid= 10473093 |doi=  }}
* {{cite journal | vauthors = Dotzlaw H, Leygue E, Watson P, Murphy LC | title = The human orphan receptor PXR messenger RNA is expressed in both normal and neoplastic breast tissue | journal = Clinical Cancer Research | volume = 5 | issue = 8 | pages = 2103–7 | date = August 1999 | pmid = 10473093 | doi =  }}
*{{cite journal |vauthors=Geick A, Eichelbaum M, Burk O |title=Nuclear receptor response elements mediate induction of intestinal MDR1 by rifampin. |journal=J. Biol. Chem. |volume=276 |issue= 18 |pages= 14581–7 |year= 2001 |pmid= 11297522 |doi= 10.1074/jbc.M010173200 }}
* {{cite journal | vauthors = Geick A, Eichelbaum M, Burk O | title = Nuclear receptor response elements mediate induction of intestinal MDR1 by rifampin | journal = The Journal of Biological Chemistry | volume = 276 | issue = 18 | pages = 14581–7 | date = May 2001 | pmid = 11297522 | doi = 10.1074/jbc.M010173200 }}
*{{cite journal   |vauthors=Watkins RE, Wisely GB, Moore LB, etal |title=The human nuclear xenobiotic receptor PXR: structural determinants of directed promiscuity. |journal=Science |volume=292 |issue= 5525 |pages= 2329–33 |year= 2001 |pmid= 11408620 |doi= 10.1126/science.1060762 }}
* {{cite journal | vauthors = Watkins RE, Wisely GB, Moore LB, Collins JL, Lambert MH, Williams SP, Willson TM, Kliewer SA, Redinbo MR | title = The human nuclear xenobiotic receptor PXR: structural determinants of directed promiscuity | journal = Science | volume = 292 | issue = 5525 | pages = 2329–33 | date = June 2001 | pmid = 11408620 | doi = 10.1126/science.1060762 }}
*{{cite journal   |vauthors=Zhang J, Kuehl P, Green ED, etal |title=The human pregnane X receptor: genomic structure and identification and functional characterization of natural allelic variants. |journal=Pharmacogenetics |volume=11 |issue= 7 |pages= 555–72 |year= 2001 |pmid= 11668216 |doi=10.1097/00008571-200110000-00003 }}
* {{cite journal | vauthors = 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 | title = The human pregnane X receptor: genomic structure and identification and functional characterization of natural allelic variants | journal = Pharmacogenetics | volume = 11 | issue = 7 | pages = 555–72 | date = October 2001 | pmid = 11668216 | doi = 10.1097/00008571-200110000-00003 }}
*{{cite journal |vauthors=Gonzalez MM, Carlberg C |title=Cross-repression, a functional consequence of the physical interaction of non-liganded nuclear receptors and POU domain transcription factors. |journal=J. Biol. Chem. |volume=277 |issue= 21 |pages= 18501–9 |year= 2002 |pmid= 11891224 |doi= 10.1074/jbc.M200205200 }}
* {{cite journal | vauthors = Gonzalez MM, Carlberg C | title = Cross-repression, a functional consequence of the physical interaction of non-liganded nuclear receptors and POU domain transcription factors | journal = The Journal of Biological Chemistry | volume = 277 | issue = 21 | pages = 18501–9 | date = May 2002 | pmid = 11891224 | doi = 10.1074/jbc.M200205200 }}
*{{cite journal |vauthors=Takeshita A, Taguchi M, Koibuchi N, Ozawa Y |title=Putative role of the orphan nuclear receptor SXR (steroid and xenobiotic receptor) in the mechanism of CYP3A4 inhibition by xenobiotics. |journal=J. Biol. Chem. |volume=277 |issue= 36 |pages= 32453–8 |year= 2002 |pmid= 12072427 |doi= 10.1074/jbc.M111245200 }}
* {{cite journal | vauthors = Takeshita A, Taguchi M, Koibuchi N, Ozawa Y | title = Putative role of the orphan nuclear receptor SXR (steroid and xenobiotic receptor) in the mechanism of CYP3A4 inhibition by xenobiotics | journal = The Journal of Biological Chemistry | volume = 277 | issue = 36 | pages = 32453–8 | date = September 2002 | pmid = 12072427 | doi = 10.1074/jbc.M111245200 }}
*{{cite journal   |vauthors=Frungieri MB, Weidinger S, Meineke V, etal |title=Proliferative action of mast-cell tryptase is mediated by PAR2, COX2, prostaglandins, and PPARgamma : Possible relevance to human fibrotic disorders. |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=99 |issue= 23 |pages= 15072–7 |year= 2003 |pmid= 12397176 |doi= 10.1073/pnas.232422999 | pmc=137545 }}
* {{cite journal | vauthors = Frungieri MB, Weidinger S, Meineke V, Köhn FM, Mayerhofer A | title = Proliferative action of mast-cell tryptase is mediated by PAR2, COX2, prostaglandins, and PPARgamma : Possible relevance to human fibrotic disorders | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 99 | issue = 23 | pages = 15072–7 | date = November 2002 | pmid = 12397176 | pmc = 137545 | doi = 10.1073/pnas.232422999 }}
*{{cite journal   |vauthors=Fukuen S, Fukuda T, Matsuda H, etal |title=Identification of the novel splicing variants for the hPXR in human livers. |journal=Biochem. Biophys. Res. Commun. |volume=298 |issue= 3 |pages= 433–8 |year= 2002 |pmid= 12413960 |doi=10.1016/S0006-291X(02)02469-5 }}
* {{cite journal | vauthors = Fukuen S, Fukuda T, Matsuda H, Sumida A, Yamamoto I, Inaba T, Azuma J | title = Identification of the novel splicing variants for the hPXR in human livers | journal = Biochemical and Biophysical Research Communications | volume = 298 | issue = 3 | pages = 433–8 | date = November 2002 | pmid = 12413960 | doi = 10.1016/S0006-291X(02)02469-5 }}
*{{cite journal   |vauthors=Strausberg RL, Feingold EA, Grouse LH, etal |title=Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=99 |issue= 26 |pages= 16899–903 |year= 2003 |pmid= 12477932 |doi= 10.1073/pnas.242603899  | pmc=139241 }}
* {{cite journal | vauthors = Chang TK, Bandiera SM, Chen J | title = Constitutive androstane receptor and pregnane X receptor gene expression in human liver: interindividual variability and correlation with CYP2B6 mRNA levels | journal = Drug Metabolism and Disposition | volume = 31 | issue = 1 | pages = 7–10 | date = January 2003 | pmid = 12485946 | doi = 10.1124/dmd.31.1.7 }}
*{{cite journal |vauthors=Chang TK, Bandiera SM, Chen J |title=Constitutive androstane receptor and pregnane X receptor gene expression in human liver: interindividual variability and correlation with CYP2B6 mRNA levels. |journal=Drug Metab. Dispos. |volume=31 |issue= 1 |pages= 7–10 |year= 2003 |pmid= 12485946 |doi=10.1124/dmd.31.1.7  }}
* {{cite journal | vauthors = Dussault I, Yoo HD, Lin M, Wang E, Fan M, Batta AK, Salen G, Erickson SK, Forman BM | title = Identification of an endogenous ligand that activates pregnane X receptor-mediated sterol clearance | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 100 | issue = 3 | pages = 833–8 | date = February 2003 | pmid = 12569201 | pmc = 298687 | doi = 10.1073/pnas.0336235100 }}
*{{cite journal   |vauthors=Dussault I, Yoo HD, Lin M, etal |title=Identification of an endogenous ligand that activates pregnane X receptor-mediated sterol clearance. |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=100 |issue= 3 |pages= 833–8 |year= 2003 |pmid= 12569201 |doi= 10.1073/pnas.0336235100  | pmc=298687 }}
* {{cite journal | vauthors = Kawana K, Ikuta T, Kobayashi Y, Gotoh O, Takeda K, Kawajiri K | title = Molecular mechanism of nuclear translocation of an orphan nuclear receptor, SXR | journal = Molecular Pharmacology | volume = 63 | issue = 3 | pages = 524–31 | date = March 2003 | pmid = 12606758 | doi = 10.1124/mol.63.3.524 }}
*{{cite journal  |vauthors=Kawana K, Ikuta T, Kobayashi Y, etal |title=Molecular mechanism of nuclear translocation of an orphan nuclear receptor, SXR. |journal=Mol. Pharmacol. |volume=63 |issue= 3 |pages= 524–31 |year= 2003 |pmid= 12606758 |doi=10.1124/mol.63.3.524 }}
{{refend}}
{{refend}}


==External links==
== External links ==
* {{MeshName|pregnane+X+receptor}}
* {{MeshName|pregnane+X+receptor}}
* [http://nrresource.org/nr_page_collection/nr1i2-pregnane-x-receptor.html Nuclear Receptor Resource Page]
* [http://nrresource.org/nr_page_collection/nr1i2-pregnane-x-receptor.html Nuclear Receptor Resource Page]

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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]

Forskolin is another case example of a PXR agonist.[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

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". The Journal of Clinical Investigation. 102 (5): 1016–23. doi:10.1172/JCI3703. PMC 508967. PMID 9727070.
  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". Proceedings of the National Academy of Sciences of the United States of America. 95 (21): 12208–13. doi:10.1073/pnas.95.21.12208. PMC 22810. PMID 9770465.
  4. ↑ 4.0 4.1 4.2 Kliewer SA, Goodwin B, Willson TM (October 2002). "The nuclear pregnane X receptor: a key regulator of xenobiotic metabolism". Endocrine Reviews. 23 (5): 687–702. doi:10.1210/er.2001-0038. PMID 12372848.
  5. ↑ "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 (July 2007). "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. doi:10.1210/me.2007-0133. PMID 17456796.
  7. ↑ Kaur J, Sodhi RK, Madan J, Chahal SK, Kumar R (February 2018). "Forskolin convalesces memory in high fat diet-induced dementia in wistar rats-Plausible role of pregnane x receptors". Pharmacological Reports. 70 (1): 161–171. doi:10.1016/j.pharep.2017.07.009. PMID 29367103.
  8. ↑ Ding, X. (2004). "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): 849–856. doi:10.1124/jpet.104.076331. ISSN 0022-3565.
  9. ↑ Li H, Dou W, Padikkala E, Mani S (November 2013). "Reverse yeast two-hybrid system to identify mammalian nuclear receptor residues that interact with ligands and/or antagonists". Journal of Visualized Experiments (81): e51085. doi:10.3791/51085. PMC 3904218. PMID 24300333.
  10. ↑ Mani S, Dou W, Redinbo MR (February 2013). "PXR antagonists and implication in drug metabolism". Drug Metabolism Reviews. 45 (1): 60–72. doi:10.3109/03602532.2012.746363. PMC 3583015. PMID 23330542.
  11. ↑ Lin W, Goktug AN, Wu J, Currier DG, Chen T (December 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. 15 (8): 383–394. doi:10.1089/adt.2017.809. PMC 5731549. PMID 29112465.
  12. ↑ Lin W, Wang YM, Chai SC, Lv L, Zheng J, Wu J, Zhang Q, Wang YD, Griffin PR, Chen T (September 2017). "SPA70 is a potent antagonist of human pregnane X receptor". Nature Communications. 8 (1): 741. doi:10.1038/s41467-017-00780-5. PMC 5622171. PMID 28963450.
  13. ↑ 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". Molecular Pharmacology. 60 (3): 611–9. PMID 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 (March 2001). "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. doi:10.1073/pnas.051551698. PMC 30660. PMID 11248085.
  15. ↑ Synold TW, Dussault I, Forman BM (May 2001). "The orphan nuclear receptor SXR coordinately regulates drug metabolism and efflux". Nature Medicine. 7 (5): 584–90. doi:10.1038/87912. PMID 11329060.
  16. ↑ Geick A, Eichelbaum M, Burk O (May 2001). "Nuclear receptor response elements mediate induction of intestinal MDR1 by rifampin". The Journal of Biological Chemistry. 276 (18): 14581–7. doi:10.1074/jbc.M010173200. PMID 11297522.

Further reading

External links

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

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