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Gene Review

Nr1i2  -  nuclear receptor subfamily 1, group I,...

Mus musculus

Synonyms: Nuclear receptor subfamily 1 group I member 2, Orphan nuclear receptor PXR, PXR, PXR.1, PXR.2, ...
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Disease relevance of Nr1i2


High impact information on Nr1i2


Chemical compound and disease context of Nr1i2

  • To test whether up-regulation of CAR represents a means of protection against bile acid toxicity to compensate for the loss of FXR and PXR, animals were pretreated with CAR activators, phenobarbital or 1,4-bis[2-(3,5-dichlorpyridyloxy)]benzene (TCPOBOP), followed by the CA diet [1].
  • In conclusion, administration of specific CAR or PXR ligands results in coordinated stimulation of major hepatic bile acid/bilirubin metabolizing and detoxifying enzymes and hepatic key alternative efflux systems, effects that are predicted to counteract cholestasis [7].
  • As previously observed with PXR (Xie, W., Radominska-Pandya, A., Shi, Y., Simon, C. M., Nelson, M. C., Ong, E. S., Waxman, D. J., and Evans, R. M. (2001) Proc. Natl. Acad. Sci. U. S. A. 98, 3375-3380), pharmacologic activation of CAR induces multiple LCA detoxifying enzymes and provides strong protection against LCA toxicity [8].
  • Enhanced acetaminophen toxicity by activation of the pregnane X receptor [9].
  • The antagonism of LPS against dexamethasone-mediated CYP3A induction suggests that endotoxemia minimizes the inducibility of PXR target genes [10].

Biological context of Nr1i2


Anatomical context of Nr1i2


Associations of Nr1i2 with chemical compounds

  • In summary, the current study demonstrates a critical and combined role of FXR and PXR in maintaining not only bile acid but also cholesterol and lipid homeostasis in vivo [1].
  • We investigated whether quantitative and functional changes in CAR and PXR could affect bilirubin detoxification in chronic arthritis [19].
  • In addition, we observed a concomitant decrease in RXR (retinoid X receptor) mRNA levels, the obligatory partner of both CAR and PXR for high affinity binding to DNA [20].
  • NP is an environmental estrogen that also activates the pregnane X-receptor (PXR) and in turn induces P450s [21].
  • LPS treatment also reversed the up-regulation of Cyp3a in mice pre-treated with PXR ligand RU486 [20].

Regulatory relationships of Nr1i2


Other interactions of Nr1i2


Analytical, diagnostic and therapeutic context of Nr1i2


  1. Complementary roles of farnesoid X receptor, pregnane X receptor, and constitutive androstane receptor in protection against bile acid toxicity. Guo, G.L., Lambert, G., Negishi, M., Ward, J.M., Brewer, H.B., Kliewer, S.A., Gonzalez, F.J., Sinal, C.J. J. Biol. Chem. (2003) [Pubmed]
  2. Dual role of orphan nuclear receptor pregnane X receptor in bilirubin detoxification in mice. Saini, S.P., Mu, Y., Gong, H., Toma, D., Uppal, H., Ren, S., Li, S., Poloyac, S.M., Xie, W. Hepatology (2005) [Pubmed]
  3. Activation of pregnane x receptor disrupts glucocorticoid and mineralocorticoid homeostasis. Zhai, Y., Pai, H.V., Zhou, J., Amico, J.A., Vollmer, R.R., Xie, W. Mol. Endocrinol. (2007) [Pubmed]
  4. An orphan nuclear receptor activated by pregnanes defines a novel steroid signaling pathway. Kliewer, S.A., Moore, J.T., Wade, L., Staudinger, J.L., Watson, M.A., Jones, S.A., McKee, D.D., Oliver, B.B., Willson, T.M., Zetterström, R.H., Perlmann, T., Lehmann, J.M. Cell (1998) [Pubmed]
  5. Reciprocal activation of xenobiotic response genes by nuclear receptors SXR/PXR and CAR. Xie, W., Barwick, J.L., Simon, C.M., Pierce, A.M., Safe, S., Blumberg, B., Guzelian, P.S., Evans, R.M. Genes Dev. (2000) [Pubmed]
  6. Benefit of farnesoid X receptor inhibition in obstructive cholestasis. Stedman, C., Liddle, C., Coulter, S., Sonoda, J., Alvarez, J.G., Evans, R.M., Downes, M. Proc. Natl. Acad. Sci. U.S.A. (2006) [Pubmed]
  7. CAR and PXR agonists stimulate hepatic bile acid and bilirubin detoxification and elimination pathways in mice. Wagner, M., Halilbasic, E., Marschall, H.U., Zollner, G., Fickert, P., Langner, C., Zatloukal, K., Denk, H., Trauner, M. Hepatology (2005) [Pubmed]
  8. The constitutive androstane receptor and pregnane X receptor function coordinately to prevent bile acid-induced hepatotoxicity. Zhang, J., Huang, W., Qatanani, M., Evans, R.M., Moore, D.D. J. Biol. Chem. (2004) [Pubmed]
  9. Enhanced acetaminophen toxicity by activation of the pregnane X receptor. Guo, G.L., Moffit, J.S., Nicol, C.J., Ward, J.M., Aleksunes, L.A., Slitt, A.L., Kliewer, S.A., Manautou, J.E., Gonzalez, F.J. Toxicol. Sci. (2004) [Pubmed]
  10. Lipopolysaccharide and cecal ligation/puncture differentially affect the subcellular distribution of the pregnane X receptor but consistently cause suppression of its target genes CYP3A. Sachdeva, K., Yan, B., Chichester, C.O. Shock (2003) [Pubmed]
  11. Xenobiotic- and vitamin D-responsive induction of the steroid/bile acid-sulfotransferase Sult2A1 in young and old mice: The role of a gene enhancer in the liver chromatin. Seo, Y.K., Chung, Y.T., Kim, S., Echchgadda, I., Song, C.S., Chatterjee, B. Gene (2007) [Pubmed]
  12. Identification of a human nuclear receptor defines a new signaling pathway for CYP3A induction. Bertilsson, G., Heidrich, J., Svensson, K., Asman, M., Jendeberg, L., Sydow-Bäckman, M., Ohlsson, R., Postlind, H., Blomquist, P., Berkenstam, A. Proc. Natl. Acad. Sci. U.S.A. (1998) [Pubmed]
  13. Role of the hepatocyte nuclear factor 4alpha in control of the pregnane X receptor during fetal liver development. Kamiya, A., Inoue, Y., Gonzalez, F.J. Hepatology (2003) [Pubmed]
  14. Phenobarbital regulates nuclear expression of HNF-4alpha in mouse and rat hepatocytes independent of CAR and PXR. Bell, A.W., Michalopoulos, G.K. Hepatology (2006) [Pubmed]
  15. Regulation of mRNA expression of xenobiotic transporters by the pregnane x receptor in mouse liver, kidney, and intestine. Cheng, X., Klaassen, C.D. Drug Metab. Dispos. (2006) [Pubmed]
  16. Cytoplasmic localization of pregnane X receptor and ligand-dependent nuclear translocation in mouse liver. Squires, E.J., Sueyoshi, T., Negishi, M. J. Biol. Chem. (2004) [Pubmed]
  17. Kupffer cells and reactive oxygen species partially mediate lipopolysaccharide-induced downregulation of nuclear receptor pregnane x receptor and its target gene CYP3a in mouse liver. Xu, D.X., Wei, W., Sun, M.F., Wu, C.Y., Wang, J.P., Wei, L.Z., Zhou, C.F. Free Radic. Biol. Med. (2004) [Pubmed]
  18. 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]
  19. Effects of Alterations in CAR on Bilirubin Detoxification in Mouse Collagen-Induced Arthritis. Kawase, A., Tsunokuni, Y., Iwaki, M. Drug Metab. Dispos. (2007) [Pubmed]
  20. Reduction in cytochrome P-450 enzyme expression is associated with repression of CAR (constitutive androstane receptor) and PXR (pregnane X receptor) in mouse liver during the acute phase response. Beigneux, A.P., Moser, A.H., Shigenaga, J.K., Grunfeld, C., Feingold, K.R. Biochem. Biophys. Res. Commun. (2002) [Pubmed]
  21. Gender-specific induction of cytochrome P450s in nonylphenol-treated FVB/NJ mice. Hernandez, J.P., Chapman, L.M., Kretschmer, X.C., Baldwin, W.S. Toxicol. Appl. Pharmacol. (2006) [Pubmed]
  22. Repression of PXR-mediated induction of hepatic CYP3A gene expression by protein kinase C. Ding, X., Staudinger, J.L. Biochem. Pharmacol. (2005) [Pubmed]
  23. The contribution of hepatic steroid metabolism to serum estradiol and estriol concentrations in nonylphenol treated MMTVneu mice and its potential effects on breast cancer incidence and latency. Acevedo, R., Parnell, P.G., Villanueva, H., Chapman, L.M., Gimenez, T., Gray, S.L., Baldwin, W.S. Journal of applied toxicology : JAT. (2005) [Pubmed]
  24. Development of the fetal intestine in mice lacking the glucocorticoid receptor (GR). Gartner, H., Graul, M.C., Oesterreicher, T.J., Finegold, M.J., Henning, S.J. J. Cell. Physiol. (2003) [Pubmed]
  25. Microarray-based compendium of hepatic gene expression profiles for prototypical ADME gene-inducing compounds in rats and mice in vivo. Slatter, J.G., Cheng, O., Cornwell, P.D., De Souza, A., Rockett, J., Rushmore, T., Hartley, D., Evers, R., He, Y., Dai, X., Hu, R., Caguyong, M., Roberts, C.J., Castle, J., Ulrich, R.G. Xenobiotica (2006) [Pubmed]
  26. Gene expression profiling in the liver of CD-1 mice to characterize the hepatotoxicity of triazole fungicides. Goetz, A.K., Bao, W., Ren, H., Schmid, J.E., Tully, D.B., Wood, C., Rockett, J.C., Narotsky, M.G., Sun, G., Lambert, G.R., Thai, S.F., Wolf, D.C., Nesnow, S., Dix, D.J. Toxicol. Appl. Pharmacol. (2006) [Pubmed]
  27. Identification of bile acid precursors as endogenous ligands for the nuclear xenobiotic pregnane X receptor. Goodwin, B., Gauthier, K.C., Umetani, M., Watson, M.A., Lochansky, M.I., Collins, J.L., Leitersdorf, E., Mangelsdorf, D.J., Kliewer, S.A., Repa, J.J. Proc. Natl. Acad. Sci. U.S.A. (2003) [Pubmed]
  28. Nuclear receptors constitutive androstane receptor and pregnane X receptor activate a drug-responsive enhancer of the murine 5-aminolevulinic acid synthase gene. Fraser, D.J., Zumsteg, A., Meyer, U.A. J. Biol. Chem. (2003) [Pubmed]
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