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Gene Review

NR1I2  -  nuclear receptor subfamily 1, group I,...

Homo sapiens

Synonyms: BXR, Nuclear receptor subfamily 1 group I member 2, ONR1, Orphan nuclear receptor PAR1, Orphan nuclear receptor PXR, ...
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Disease relevance of NR1I2


Psychiatry related information on NR1I2


High impact information on NR1I2


Chemical compound and disease context of NR1I2


Biological context of NR1I2


Anatomical context of NR1I2

  • We have examined the relationship between MDR1 and PXR mRNA in peripheral blood cells and demonstrate a significant correlation in 18 volunteers (R2=0.4; P<0.005) [21].
  • By contrast, parallel experiments in HepG2 cell lines co-transfected with an hPXR expression vector did not show increased reporter activity [22].
  • This is the first demonstration of the ability of blood-brain barrier PXR to alter the efficacy of a CNS-acting drug [20].
  • P-glycoprotein expression and transport activity in brain capillaries from transgenic mice was significantly increased when capillaries were exposed to the hPXR ligands, rifampin and hyperforin, in vitro and when the mice were dosed with rifampin in vivo [20].
  • Expression levels of nuclear receptors revealed high expression of PXR only in LS180 cells and exclusive expression of GR in Caco-2 cells [23].

Associations of NR1I2 with chemical compounds

  • Our results suggest that CAR, like PXR, is a steroid receptor that is capable of recognizing structurally diverse compounds [24].
  • The dexamethasone- and pregnenolone 16alpha-carbonitrile-dependent induction of MRP2 expression was not evident in hepatocytes derived from PXR null mice [25].
  • In contrast, induction of MRP2 by phenobarbital, an activator of CAR, was comparable in wild-type and PXR null mice [25].
  • Similarly, the PXR activator clotrimazole is a potent deactivator of hCAR [24].
  • In contrast, the CAR deactivator androstanol activates both mouse and human PXR [24].
  • This review is focused on recent observations showing that activation of CAR and PXR alters lipid metabolism, glucose homeostasis, and inflammation by interfering with HNF4alpha, FoxO1, FoxA2, PGC1alpha, or NFkB p65 [26].

Physical interactions of NR1I2

  • Electrophoretic mobility shift assay (EMSA) with a CYP3A4 ER6 probe demonstrated that relatively high molecular weight complex containing pregnane X receptor (PXR)/retinoid X receptor alpha(RXR alpha), compared with that in the monolayer culture, is possibly generated in the RFB culture of FLC-5 treated with rifampicin [27].
  • Chromatin immunoprecipitation assay revealed that PXR and PGC-1alpha bind to CYP2A6 chromatin [28].
  • These studies strongly support the hypothesis that there is cross talk between distal CAR/PXR sites and HNF4alpha binding sites in the CYP2C9 promoter and that the HNF4alpha sites are required for maximal induction of the CYP2C9 promoter [29].
  • We demonstrated that PXR binds to and transactivates the 2 proximal vitamin D-responsive elements of the human CYP24 promoter [4].
  • We present the 2.0A crystal structure of the human PXR ligand-binding domain (LBD) in complex with the cholesterol-lowering compound SR12813 and a 25 amino acid residue fragment of the human steroid receptor coactivator-1 (SRC-1) containing one LXXLL motif [30].

Regulatory relationships of NR1I2

  • Taken together, these observations demonstrate that the CYP2B6 gene is directly regulated by PXR and further establish this receptor as a key regulator of drug-metabolizing P450s [31].
  • The pregnane X receptor (PXR)/steroid and xenobiotic receptor (SXR) transcriptionally activates cytochrome P4503A4 (CYP3A4) when ligand activated by endobiotics and xenobiotics [32].
  • In conclusion, we found that CYP2A6 is induced via PXR and PGC-1alpha through the DR4-like element at the distal response region [28].
  • The objective of this study is to elucidate the mechanism by which PXR inhibits CYP7A1 gene transcription [33].
  • Overall, our novel findings indicate the upregulation of CYP1B1 by ATRA in HL-60 human promyelocytic leukemic cells shown for the first time to express PXR but not CAR mRNA [34].

Other interactions of NR1I2


Analytical, diagnostic and therapeutic context of NR1I2


  2. Ligand recognition by drug-activated nuclear receptors PXR and CAR: structural, site-directed mutagenesis and molecular modeling studies. Poso, A., Honkakoski, P. Mini reviews in medicinal chemistry. (2006) [Pubmed]
  3. The pregnane X receptor locus is associated with susceptibility to inflammatory bowel disease. Dring, M.M., Goulding, C.A., Trimble, V.I., Keegan, D., Ryan, A.W., Brophy, K.M., Smyth, C.M., Keeling, P.W., O'Donoghue, D., O'Sullivan, M., O'Morain, C., Mahmud, N., Wikström, A.C., Kelleher, D., McManus, R. Gastroenterology (2006) [Pubmed]
  4. Possible involvement of pregnane X receptor-enhanced CYP24 expression in drug-induced osteomalacia. Pascussi, J.M., Robert, A., Nguyen, M., Walrant-Debray, O., Garabedian, M., Martin, P., Pineau, T., Saric, J., Navarro, F., Maurel, P., Vilarem, M.J. J. Clin. Invest. (2005) [Pubmed]
  5. Nuclear receptors constitutive androstane receptor and pregnane X receptor ameliorate cholestatic liver injury. Stedman, C.A., Liddle, C., Coulter, S.A., Sonoda, J., Alvarez, J.G., Moore, D.D., Evans, R.M., Downes, M. Proc. Natl. Acad. Sci. U.S.A. (2005) [Pubmed]
  6. Expanding the roles for pregnane X receptor in cancer: proliferation and drug resistance in ovarian cancer. Gupta, D., Venkatesh, M., Wang, H., Kim, S., Sinz, M., Goldberg, G.L., Whitney, K., Longley, C., Mani, S. Clin. Cancer Res. (2008) [Pubmed]
  7. TOLL-like receptors linking innate and adaptive immune response. Werling, D., Jungi, T.W. Vet. Immunol. Immunopathol. (2003) [Pubmed]
  8. The orphan nuclear receptor HNF4alpha determines PXR- and CAR-mediated xenobiotic induction of CYP3A4. Tirona, R.G., Lee, W., Leake, B.F., Lan, L.B., Cline, C.B., Lamba, V., Parviz, F., Duncan, S.A., Inoue, Y., Gonzalez, F.J., Schuetz, E.G., Kim, R.B. Nat. Med. (2003) [Pubmed]
  9. The orphan nuclear receptor SXR coordinately regulates drug metabolism and efflux. Synold, T.W., Dussault, I., Forman, B.M. Nat. Med. (2001) [Pubmed]
  10. Humanized xenobiotic response in mice expressing nuclear receptor SXR. Xie, W., Barwick, J.L., Downes, M., Blumberg, B., Simon, C.M., Nelson, M.C., Neuschwander-Tetri, B.A., Brunt, E.M., Guzelian, P.S., Evans, R.M. Nature (2000) [Pubmed]
  11. An essential role for nuclear receptors SXR/PXR in detoxification of cholestatic bile acids. Xie, W., Radominska-Pandya, A., Shi, Y., Simon, C.M., Nelson, M.C., Ong, E.S., Waxman, D.J., Evans, R.M. Proc. Natl. Acad. Sci. U.S.A. (2001) [Pubmed]
  12. Expression and potential roles of pregnane X receptor in endometrial cancer. Masuyama, H., Hiramatsu, Y., Kodama, J., Kudo, T. J. Clin. Endocrinol. Metab. (2003) [Pubmed]
  13. Methylation-associated silencing of the nuclear receptor 1I2 gene in advanced-type neuroblastomas, identified by bacterial artificial chromosome array-based methylated CpG island amplification. Misawa, A., Inoue, J., Sugino, Y., Hosoi, H., Sugimoto, T., Hosoda, F., Ohki, M., Imoto, I., Inazawa, J. Cancer Res. (2005) [Pubmed]
  14. Digoxin up-regulates multidrug resistance transporter (MDR1) mRNA and simultaneously down-regulates steroid xenobiotic receptor mRNA. Takara, K., Takagi, K., Tsujimoto, M., Ohnishi, N., Yokoyama, T. Biochem. Biophys. Res. Commun. (2003) [Pubmed]
  15. Physiology and pathophysiology of proteinase-activated receptors (PARs): role of tryptase/PAR-2 in vascular endothelial barrier function. Itoh, Y., Sendo, T., Oishi, R. J. Pharmacol. Sci. (2005) [Pubmed]
  16. The human orphan nuclear receptor PXR is activated by compounds that regulate CYP3A4 gene expression and cause drug interactions. Lehmann, J.M., McKee, D.D., Watson, M.A., Willson, T.M., Moore, J.T., Kliewer, S.A. J. Clin. Invest. (1998) [Pubmed]
  17. Nuclear receptor response elements mediate induction of intestinal MDR1 by rifampin. Geick, A., Eichelbaum, M., Burk, O. J. Biol. Chem. (2001) [Pubmed]
  18. The pregnane X receptor regulates gene expression in a ligand- and promoter-selective fashion. Masuyama, H., Suwaki, N., Tateishi, Y., Nakatsukasa, H., Segawa, T., Hiramatsu, Y. Mol. Endocrinol. (2005) [Pubmed]
  19. Regulation of human CYP2C9 by the constitutive androstane receptor: discovery of a new distal binding site. Ferguson, S.S., LeCluyse, E.L., Negishi, M., Goldstein, J.A. Mol. Pharmacol. (2002) [Pubmed]
  20. In Vivo Activation of Human Pregnane X Receptor Tightens the Blood-Brain Barrier to Methadone through P-Glycoprotein Up-Regulation. Bauer, B., Yang, X., Hartz, A.M., Olson, E.R., Zhao, R., Kalvass, J.C., Pollack, G.M., Miller, D.S. Mol. Pharmacol. (2006) [Pubmed]
  21. Expression of pregnane-X-receptor transcript in peripheral blood mononuclear cells and correlation with MDR1 mRNA. Owen, A., Chandler, B., Back, D.J., Khoo, S.H. Antivir. Ther. (Lond.) (2004) [Pubmed]
  22. Human constitutive androstane receptor mediates induction of CYP2B6 gene expression by phenytoin. Wang, H., Faucette, S., Moore, R., Sueyoshi, T., Negishi, M., LeCluyse, E. J. Biol. Chem. (2004) [Pubmed]
  23. Effects of budesonide on P-glycoprotein expression in intestinal cell lines. Maier, A., Zimmermann, C., Beglinger, C., Drewe, J., Gutmann, H. Br. J. Pharmacol. (2007) [Pubmed]
  24. Orphan nuclear receptors constitutive androstane receptor and pregnane X receptor share xenobiotic and steroid ligands. Moore, L.B., Parks, D.J., Jones, S.A., Bledsoe, R.K., Consler, T.G., Stimmel, J.B., Goodwin, B., Liddle, C., Blanchard, S.G., Willson, T.M., Collins, J.L., Kliewer, S.A. J. Biol. Chem. (2000) [Pubmed]
  25. Regulation of multidrug resistance-associated protein 2 (ABCC2) by the nuclear receptors pregnane X receptor, farnesoid X-activated receptor, and constitutive androstane receptor. Kast, H.R., Goodwin, B., Tarr, P.T., Jones, S.A., Anisfeld, A.M., Stoltz, C.M., Tontonoz, P., Kliewer, S., Willson, T.M., Edwards, P.A. J. Biol. Chem. (2002) [Pubmed]
  26. Xenoreceptors CAR and PXR activation and consequences on lipid metabolism, glucose homeostasis, and inflammatory response. Moreau, A., Vilarem, M.J., Maurel, P., Pascussi, J.M. Mol. Pharm. (2008) [Pubmed]
  27. CYP3A4 inducible model for in vitro analysis of human drug metabolism using a bioartificial liver. Iwahori, T., Matsuura, T., Maehashi, H., Sugo, K., Saito, M., Hosokawa, M., Chiba, K., Masaki, T., Aizaki, H., Ohkawa, K., Suzuki, T. Hepatology (2003) [Pubmed]
  28. Induction of Human CYP2A6 Is Mediated by the Pregnane X Receptor with Peroxisome Proliferator-Activated Receptor-{gamma} Coactivator 1{alpha}. Itoh, M., Nakajima, M., Higashi, E., Yoshida, R., Nagata, K., Yamazoe, Y., Yokoi, T. J. Pharmacol. Exp. Ther. (2006) [Pubmed]
  29. The nuclear receptors constitutive androstane receptor and pregnane X receptor cross-talk with hepatic nuclear factor 4alpha to synergistically activate the human CYP2C9 promoter. Chen, Y., Kissling, G., Negishi, M., Goldstein, J.A. J. Pharmacol. Exp. Ther. (2005) [Pubmed]
  30. Coactivator binding promotes the specific interaction between ligand and the pregnane X receptor. Watkins, R.E., Davis-Searles, P.R., Lambert, M.H., Redinbo, M.R. J. Mol. Biol. (2003) [Pubmed]
  31. Regulation of the human CYP2B6 gene by the nuclear pregnane X receptor. Goodwin, B., Moore, L.B., Stoltz, C.M., McKee, D.D., Kliewer, S.A. Mol. Pharmacol. (2001) [Pubmed]
  32. The human pregnane X receptor: genomic structure and identification and functional characterization of natural allelic variants. Zhang, J., Kuehl, P., Green, E.D., Touchman, J.W., Watkins, P.B., Daly, A., Hall, S.D., Maurel, P., Relling, M., Brimer, C., Yasuda, K., Wrighton, S.A., Hancock, M., Kim, R.B., Strom, S., Thummel, K., Russell, C.G., Hudson, J.R., Schuetz, E.G., Boguski, M.S. Pharmacogenetics (2001) [Pubmed]
  33. Mechanism of rifampicin and pregnane X receptor inhibition of human cholesterol 7 alpha-hydroxylase gene transcription. Li, T., Chiang, J.Y. Am. J. Physiol. Gastrointest. Liver Physiol. (2005) [Pubmed]
  34. Transcript profiling of cytochrome P450 genes in HL-60 human leukemic cells: upregulation of CYP1B1 by all-trans-retinoic acid. Kawai, M., Chen, J., Cheung, C.Y., Chang, T.K. Mol. Cell. Biochem. (2003) [Pubmed]
  35. Sex is a major determinant of CYP3A4 expression in human liver. Wolbold, R., Klein, K., Burk, O., Nüssler, A.K., Neuhaus, P., Eichelbaum, M., Schwab, M., Zanger, U.M. Hepatology (2003) [Pubmed]
  36. The induction of cytochrome P450 3A5 (CYP3A5) in the human liver and intestine is mediated by the xenobiotic sensors pregnane X receptor (PXR) and constitutively activated receptor (CAR). Burk, O., Koch, I., Raucy, J., Hustert, E., Eichelbaum, M., Brockmöller, J., Zanger, U.M., Wojnowski, L. J. Biol. Chem. (2004) [Pubmed]
  37. Ketoconazole and miconazole are antagonists of the human glucocorticoid receptor: consequences on the expression and function of the constitutive androstane receptor and the pregnane X receptor. Duret, C., Daujat-Chavanieu, M., Pascussi, J.M., Pichard-Garcia, L., Balaguer, P., Fabre, J.M., Vilarem, M.J., Maurel, P., Gerbal-Chaloin, S. Mol. Pharmacol. (2006) [Pubmed]
  38. Cyclin-dependent kinase 2 negatively regulates human pregnane X receptor-mediated CYP3A4 gene expression in HepG2 liver carcinoma cells. Lin, W., Wu, J., Dong, H., Bouck, D., Zeng, F.Y., Chen, T. J. Biol. Chem. (2008) [Pubmed]
  39. Activation of the steroid and xenobiotic receptor (human pregnane X receptor) by nontaxane microtubule-stabilizing agents. Mani, S., Huang, H., Sundarababu, S., Liu, W., Kalpana, G., Smith, A.B., Horwitz, S.B. Clin. Cancer Res. (2005) [Pubmed]
  40. Dexamethasone induces pregnane X receptor and retinoid X receptor-alpha expression in human hepatocytes: synergistic increase of CYP3A4 induction by pregnane X receptor activators. Pascussi, J.M., Drocourt, L., Fabre, J.M., Maurel, P., Vilarem, M.J. Mol. Pharmacol. (2000) [Pubmed]
  41. Regulation of drug and bile salt transporters in liver and intestine. Kullak-Ublick, G.A., Becker, M.B. Drug Metab. Rev. (2003) [Pubmed]
  42. Steroid and xenobiotic receptor (SXR), cytochrome P450 3A4 and multidrug resistance gene 1 in human adult and fetal tissues. Miki, Y., Suzuki, T., Tazawa, C., Blumberg, B., Sasano, H. Mol. Cell. Endocrinol. (2005) [Pubmed]
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