TABLE 3

PXR

Receptor Nomenclature NR1I2
Receptor code 4.10.1:XE:1:I2
Other names ONR1, BXR, PAR, PRR, PXR, SAR, PAR1, PAR2, PARq
Molecular information Hs: 434aa, O75469, chr. 3q12-q13.31–3
Rn: 431aa, Q9R1A7, chr. 11q214
Mm: 431aa, O54915, chr. 16 B33
DNA binding
   Structure Heterodimer, RXR partner
   HRE core sequence AGGTCA (DR-3, ER6, DR-4, ER8, IR0, PBRE)3,5–11
Partners PIT1 (physical): cellular localization12
Agonists Hyperforin (27 nM), SR12813 (200 nM), pregnenolone-16α-carbonitrile (300 nM), (+)-S20 (0.4 μM), dexamethasone (0.8 μM), schisandrins A and B (1.25–2 μM), rifampicin (0.8–3 μM), 5β -cholestane-3α, 7α, 12α -triol (3–5 μM), taxol (5 μM) [EC50]13–20; lithocholic acid (9–15 μM)* [IC50]11; vitamin K21
Antagonists Ecteinascidin 743 (3 nM)[IC50]18
Coactivators NCOA1, NRIP1, PGC-1, FOXO1, GRIP13,22–25
Corepressors SHP, NCOR218,26,2 7
Biologically important isoforms PXR1 {Hs}: main isoform1,2,5; PXR2 {Hs}: has a different 5′-UTR and encodes a single full-length product with an N-terminal extension not found in other isoforms; PXR3 {Hs}: has a different 5′-UTR and encodes an isoform lacking 39 N-terminal and 37 internal amino acids compared with PXR2—the reading frame is maintained, and it uses a non-AUG translation initiation codon
Tissue distribution Liver, intestine, kidney, lung {Hs, Mm} [Northern blot, Q-PCR, immunohistology]1–5,13
Functional assays Drug clearance by the liver following tribromoethanol-induced anaesthesia or zoxazolamine-induced paralysis {Mm}28; measurement of bile acid liver toxicity after PXR activation {Mm}13,29; bilirubin and corticosterone clearance {Mm}30; warfarin clearance from the liver by PXR-activating Chinese herb wu wei zi (Schisandra chinensis Baill) and gan cao (Glycyrrhiza uralensis Fisch) {Rn}20
Main target genes Activated: cytochrome P450 genes {Hs, Mm, Rn},1–3,10,11,18,28,31 OATP2 {Mm, Rn},32 MRP2 {Hs, Mm},7 UGT1A1 {Mm},30 SULT2A {Mm},8 MDR1 {Mm},6 ALAS-1 {Mm}33
Mutant phenotype 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 {Mm} [knockout]15,28,29; acquired responsiveness to human-specific ligands such as rifampicin, loss of responsiveness to rodent-specific ligands, such as PCN {Mm} [hPXR transgenic mice and hPXR transgenic with PXR knockout background]28; increased bilirubin and cortisone clearance, increased detoxification of bile acids, increased protection against xenobiotic toxicants, such as zoxazolamine and tribromoethanol {Mm} [transgenes of a constitutively actived hPXR into the liver]28–30
Human disease Breast cancer: levels of PXR mRNA in ER-positive tumors are significantly lower than those observed in ER-negative tumors34; a significant positive correlation was detected between SXR/hPXR labeling index and both the histologic grade and the lymph node status of the carcinomas35

  • aa, amino acids; chr., chromosome; HRE, hormone response element; PAR, proliferator-activated receptor; UTR, untranslated region; Q-PCR, quantitative polymerase chain reaction; h, human; ER, estrogen receptor; BXR, benzoate X receptor; PBRE, phenobarbital response element

  • ↵* Radioligand

  • ↵1. Bertilsson G, Heidrich J, Svensson K, Asman M, Jendeberg L, Sydow-Backman M, Ohlsson R, Postlind H, Blomquist P, and Berkenstam A (1998) Identification of a human nuclear receptor defines a new signaling pathway for CYP3A induction. Proc Natl Acad Sci USA 95: 12208-12213

  • ↵2. Blumberg B, Sabbagh W Jr, Juguilon H, Bolado J Jr, van Meter CM, Ong ES and Evans RM (1998) SXR, a novel steroid and xenobiotic-sensing nuclear receptor. Genes Dev 12: 3195-3205

  • ↵3. Kliewer SA, Moore JT, Wade L, Staudinger JL, Watson MA, Jones SA, McKee DD, Oliver BB, Willson TM, Zetterstrom RH, et al. (1998) An orphan nuclear receptor activated by pregnanes defines a novel steroid signaling pathway. Cell 92: 73-82

  • ↵4. Zhang H, LeCulyse E, Liu L, Hu M, Matoney L, Zhu W, and Yan B (1999) Rat pregnane X receptor: molecular cloning, tissue distribution, and xenobiotic regulation. Arch Biochem Biophys 368: 14-22

  • ↵5. Lehmann JM, McKee DD, Watson MA, Willson TM, Moore JT, and Kliewer SA (1998) The human orphan nuclear receptor PXR is activated by compounds that regulate CYP3A4 gene expression and cause drug interactions. J Clin Investig 102: 1016-1023

  • ↵6. Geick A, Eichelbaum M, and Burk O (2001) Nuclear receptor response elements mediate induction of intestinal MDR1 by rifampin. J Biol Chem 276: 14581-14587

  • ↵7. Kast HR, Goodwin B, Tarr PT, Jones SA, Anisfeld AM, Stoltz CM, Tontonoz P, Kliewer S, Willson TM, and 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: 2908-2915

  • ↵8. Sonoda J, Xie W, Rosenfeld JM, Barwick JL, Guzelian PS, and Evans RM (2002) Regulation of a xenobiotic sulfonation cascade by nuclear pregnane X receptor (PXR). Proc Natl Acad Sci USA 99: 13801-13806

  • ↵9. Xie W, Barwick JL, Simon CM, Pierce AM, Safe S, Blumberg B, Guzelian PS, and Evans RM (2000) Reciprocal activation of xenobiotic response genes by nuclear receptors SXR/PXR and CAR. Genes Dev 14: 3014-3023

  • ↵10. Goodwin B, Moore L B, Stoltz CM, McKee DD, and Kliewer SA (2001) Regulation of the human CYP2B6 gene by the nuclear pregnane X receptor. Mol Pharmacol 60: 427-431

  • ↵11. Ferguson SS, Chen Y, LeCluyse EL, Negishi M, and Goldstein JA (2005) Human CYP2C8 is transcriptionally regulated by the nuclear receptors constitutive androstane receptor, pregnane X receptor, glucocorticoid receptor, and hepatic nuclear factor 4α. Mol Pharmacol 68: 747-757

  • ↵12. Gonzalez MM and 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: 18501-18509

  • ↵13. Jones SA, Moore LB, Shenk JL, Wisely GB, Hamilton GA, McKee DD, Tomkinson NC, LeCluyse EL, Lambert MH, Willson TM, et al. (2000) The pregnane X receptor: a promiscuous xenobiotic receptor that has diverged during evolution. Mol Endocrinol 14: 27-39

  • ↵14. Moore LB, Goodwin B, Jones SA, Wisely GB, Serabjit-Singh CJ, Willson TM, Collins JL, and Kliewer SA (2000) St. John's wort induces hepatic drug metabolism through activation of the pregnane X receptor. Proc Natl Acad Sci USA 97: 7500-7502

  • ↵15. Staudinger JL, Goodwin B, Jones SA, Hawkins-Brown D, MacKenzie KI, LaTour A, Liu Y, Klaassen CD, Brown KK, Reinhard J, et al. (2001) The nuclear receptor PXR is a lithocholic acid sensor that protects against liver toxicity. Proc Natl Acad Sci USA 98: 3369-3374

  • ↵16. Dussault I, Yoo HD, Lin M, Wang E, Fan M, Batta AK, Salen G, Erickson SK, and Forman BM (2003) Identification of an endogenous ligand that activates pregnane X receptor-mediated sterol clearance. Proc Natl Acad Sci USA 100: 833-838

  • ↵17. Goodwin B, Gauthier KC, Umetani M, Watson MA, Lochansky MI, Collins JL, Leitersdorf E, Mangelsdorf DJ, Kliewer SA, and Repa JJ (2003) Identification of bile acid precursors as endogenous ligands for the nuclear xenobiotic pregnane X receptor. Proc Natl Acad Sci USA 100: 223-228

  • ↵18. Synold TW, Dussault I, and Forman BM (2001) The orphan nuclear receptor SXR coordinately regulates drug metabolism and efflux. Nat Med 7: 584-590

  • ↵19. Mu Y, Stephenson CRJ, Kendall C, Saini SPS, Toma D, Cai H, Strom S, Day BW, Wipf P, and Xie W (2005) A PXR agonist with unique species-dependent stereoselectivity and its implications in drug development. Mol Pharmacol 68: 403-413

  • ↵20. Mu Y, Zhang J, Zhang S, Zhou HH, Toma D, Ren S, Huang L, Yaramus M, Baum A, Venkataramanan R, and 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: 1369-1377

  • ↵21. Tabb MM, Sun A, Zhou C, Grun F, Errandi J, Romero K, Pham H, Inoue S, Mallick S, Lin M, et al. (2003) Vitamin K2 regulation of bone homeostasis is mediated by the steroid and xenobiotic receptor SXR. J Biol Chem 278: 43919-43927

  • ↵22. Cavailles V, Dauvois S, L'Horset F, Lopez G, Hoare S, Kushner PJ, and Parker MG (1995) Nuclear factor RIP140 modulates transcriptional activation by the estrogen receptor. EMBO (Eur Mol Biol Organ) J 14: 3741-3751

  • ↵23. Bhalla S, Ozalp C, Fang S, Xiang L, and Kemper JK (2004) Ligand-activated pregnane X receptor interferes with HNF-4 signaling by targeting a common coactivator PGC-1α : functional implications in hepatic cholesterol and glucose metabolism. J Biol Chem 279: 45139-45147

  • ↵24. Kodama S, Koike C, Negishi M, and 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: 7931-7940

  • ↵25. Sugatani J, Nishitani S, Yamakawa K, Yoshinari K, Sueyoshi T, Negishi M, and 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: 845-855

  • ↵26. Ourlin JC, Lasserre F, Pineau T, Fabre JM, Sa-Cunha A, Maurel P, Vilarem MJ, and Pascussi JM (2003) The small heterodimer partner interacts with the pregnane X receptor and represses its transcriptional activity. Mol Endocrinol 17: 1693-1703

  • ↵27. Takeshita A, Taguchi M, Koibuchi N, and Ozawa Y (2002) Putative role of the orphan nuclear receptor SXR (steroid and xenobiotic receptor) in the mechanism of CYP3A4 inhibition by xenobiotics. J Biol Chem 277: 32453-32458

  • ↵28. Xie W, Barwick JL, Downes M, Blumberg B, Simon CM, Nelson MC, Neuschwander-Tetri BA, Brunt EM, Guzelian PS, and Evans RM (2000) Humanized xenobiotic response in mice expressing nuclear receptor SXR. Nature (Lond) 406: 435-439

  • ↵29. Xie W, Radominska-Pandya A, Shi Y, Simon CM, Nelson MC, Ong ES, Waxman DJ, and Evans RM (2001) An essential role for nuclear receptors SXR/PXR in detoxification of cholestatic bile acids. Proc Natl Acad Sci USA 98: 3375-3380

  • ↵30. Xie W, Yeuh MF, Radominska-Pandya A, Saini SP, Negishi Y, Bottroff BS, Cabrera GY, Tukey RH, and Evans RM (2003) Control of steroid, heme, and carcinogen metabolism by nuclear pregnane X receptor and constitutive androstane receptor. Proc Natl Acad Sci USA 100: 4150-4155

  • ↵31. Chen Y, Kissling G, Negishi M, and Goldstein JA (2005) The nuclear receptors constitutive androstane receptor and pregnane X receptor cross-talk with hepatic nuclear factor 4α to synergistically activate the human CYP2C9 promoter. J Pharmacol Exp Ther 314: 1125-1133

  • ↵32. Guo GL, Staudinger J, Ogura K, and Klaassen CD (2002) Induction of rat organic anion transporting polypeptide 2 by pregnenolone-16α -carbonitrile is via interaction with pregnane X receptor. Mol Pharmacol 61: 832-839

  • ↵33. Fraser DJ, Zumsteg A, and 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: 39392-39401

  • ↵34. Dotzlaw H, Leygue E, Watson P and Murphy LC (1999) The human orphan receptor PXR messenger RNA is expressed in both normal and neoplastic breast tissue. Clin Cancer Res 5: 2103-2107

  • ↵35. Miki Y, Suzuki T, Kitada K, Yabuki N, Shibuya R, Moriya T, Ishida T, Ohuchi N, Blumberg B, and 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: 535-542