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Gene Review

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

Rattus norvegicus

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


High impact information on Nr1i2

  • Thus, EDC-occupied PXR may regulate its specific gene expression through the receptor-coactivator interaction [2].
  • In this paper, we demonstrated that phthalic acid and nonylphenol, endocrine-disrupting chemicals (EDCs), stimulated PXR-mediated transcription at concentrations comparable to those at which they activate estrogen receptor-mediated transcription using a transient reporter gene expression assay in COS-7 cells [2].
  • These data suggest that EDCs may affect endocrine functions by altering steroid hormone metabolism through PXR [2].
  • Endocrine disrupting chemicals, phthalic acid and nonylphenol, activate Pregnane X receptor-mediated transcription [2].
  • In the yeast two-hybrid protein interaction assay, PXR interacted with two nuclear receptor coactivator proteins, steroid hormone receptor coactivator-1 and receptor interacting protein 140, in the presence of phthalic acid or nonylphenol [2].

Biological context of Nr1i2

  • In this study, the gene expression of 40 CYPs and 2 orphan nuclear receptors for CYP inducers, that is, Nr1i2 (CYP3A subfamily inducible by PCN) and Nr1i3 (CYP2B subfamily inducible by PB), in pregnant rat's liver, fetal liver, and placenta was investigated at one time [3].
  • In receptor transactivation assays, both CAR and PXR transcriptional activities were significantly enhanced by DDE [4].
  • In contrast, RT-PCR analysis revealed marked down-regulation of the nuclear receptors RXRalpha, PXR, FXR, LXR, PPARalpha and CAR [5].
  • Pregnane X receptor (PXR) is a nuclear receptor that regulates the expression of genes for cytochrome P450 3A (CYP3A), multidrug resistance 1 (MDR1), and organic anion-transporting peptide 2 (OATP2) [6].
  • Such data indicate that AAF up-regulates CYP3A23 through PXR activation but does not require PXR for exerting its carcinogenic promoting properties based on inhibition of cell growth [7].

Anatomical context of Nr1i2


Associations of Nr1i2 with chemical compounds

  • The expression of Nr1i2 gene was significantly elevated only in dam's liver of PCN group, while the expression of Nr1i3 gene showed no changes in all groups [3].
  • However, bisphenol A, another EDC, had no effect on PXR-mediated transcription, although this chemical significantly enhanced ER-mediated transcription [2].
  • These data support the idea that induction of hepatic 3A1 and 2B1 by DDE is mediated through the activation of CAR and PXR [4].
  • Clofibrate and perfluorodecanoate both upregulate the expression of the pregnane X receptor but oppositely affect its ligand-dependent induction on cytochrome P450 3A23 [10].
  • Oatp2 mRNA levels, determined by the bDNA technique, generally did not show a correlation with the altered oatp2 protein levels, e.g., among PXR ligands, only PCN increased oatp2 mRNA levels, but spironolactone and dexamethasone did not [11].

Other interactions of Nr1i2


Analytical, diagnostic and therapeutic context of Nr1i2

  • 2(S)-((3,5-bis(Trifluoromethyl)benzyl)-oxy)-3(S)phenyl-4-((3-oxo-1,2,4-triazol-5-yl)methyl)morpholine (L-742694) is a potent activator of the rat PXR and was characterized for its effects on hepatic and intestinal gene expression in female Sprague-Dawley rats by DNA microarray analysis [9].
  • Results from electrophoretic mobility shift assays showed that the PXR-retinoid X receptor alpha heterodimer binds to the DR3-2 with the highest affinity, to the DR3-4 and DR3-1 with a lower affinity, and weakly or not at all to the DR3-3 [12].
  • Oatp2 protein levels determined by Western blot were decreased 56 to 72% by the AhR ligands, increased 84 to 132% by the CAR ligands, and increased 230 to 360% by PXR ligands [11].
  • We used mRNA differential display to define further the domain of genes under the control of PCN/PXR [14].


  1. Postnatal expression and induction by pregnenolone-16alpha-carbonitrile of the organic anion-transporting polypeptide 2 in rat liver. Guo, G.L., Johnson, D.R., Klaassen, C.D. Drug Metab. Dispos. (2002) [Pubmed]
  2. Endocrine disrupting chemicals, phthalic acid and nonylphenol, activate Pregnane X receptor-mediated transcription. Masuyama, H., Hiramatsu, Y., Kunitomi, M., Kudo, T., MacDonald, P.N. Mol. Endocrinol. (2000) [Pubmed]
  3. Microarray analysis on CYPs expression in pregnant rats after treatment with pregnenolone-16alpha-carbonitrile and phenobarbital. Ejiri, N., Katayama, K., Kiyosawa, N., Baba, Y., Doi, K. Exp. Mol. Pathol. (2005) [Pubmed]
  4. The environmental pollutant 1,1-dichloro-2,2-bis (p-chlorophenyl)ethylene induces rat hepatic cytochrome P450 2B and 3A expression through the constitutive androstane receptor and pregnane X receptor. Wyde, M.E., Bartolucci, E., Ueda, A., Zhang, H., Yan, B., Negishi, M., You, L. Mol. Pharmacol. (2003) [Pubmed]
  5. Hepatic expression of multiple acute phase proteins and down-regulation of nuclear receptors after acute endotoxin exposure. Fang, C., Yoon, S., Tindberg, N., Järveläinen, H.A., Lindros, K.O., Ingelman-Sundberg, M. Biochem. Pharmacol. (2004) [Pubmed]
  6. Endocrine disruptors induce cytochrome P450 by affecting transcriptional regulation via pregnane X receptor. Mikamo, E., Harada, S., Nishikawa, J., Nishihara, T. Toxicol. Appl. Pharmacol. (2003) [Pubmed]
  7. Pregnane X receptor-dependent and -independent effects of 2-acetylaminofluorene on cytochrome P450 3A23 expression and liver cell proliferation. Sparfel, L., Payen, L., Gilot, D., Sidaway, J., Morel, F., Guillouzo, A., Fardel, O. Biochem. Biophys. Res. Commun. (2003) [Pubmed]
  8. Induction of Rat UDP-Glucuronosyltransferases in Liver and Duodenum by Microsomal Enzyme Inducers That Activate Various Transcriptional Pathways. Shelby, M.K., Klaassen, C.D. Drug Metab. Dispos. (2006) [Pubmed]
  9. Activators of the rat pregnane X receptor differentially modulate hepatic and intestinal gene expression. Hartley, D.P., Dai, X., He, Y.D., Carlini, E.J., Wang, B., Huskey, S.E., Ulrich, R.G., Rushmore, T.H., Evers, R., Evans, D.C. Mol. Pharmacol. (2004) [Pubmed]
  10. Clofibrate and perfluorodecanoate both upregulate the expression of the pregnane X receptor but oppositely affect its ligand-dependent induction on cytochrome P450 3A23. Ma, Y., Sachdeva, K., Liu, J., Song, X., Li, Y., Yang, D., Deng, R., Chichester, C.O., Yan, B. Biochem. Pharmacol. (2005) [Pubmed]
  11. Induction profile of rat organic anion transporting polypeptide 2 (oatp2) by prototypical drug-metabolizing enzyme inducers that activate gene expression through ligand-activated transcription factor pathways. Guo, G.L., Choudhuri, S., Klaassen, C.D. J. Pharmacol. Exp. Ther. (2002) [Pubmed]
  12. Induction of rat organic anion transporting polypeptide 2 by pregnenolone-16alpha-carbonitrile is via interaction with pregnane X receptor. Guo, G.L., Staudinger, J., Ogura, K., Klaassen, C.D. Mol. Pharmacol. (2002) [Pubmed]
  13. Regulation of rat hepatic hydroxysteroid sulfotransferase (SULT2-40/41) gene expression by glucocorticoids: evidence for a dual mechanism of transcriptional control. Runge-Morris, M., Wu, W., Kocarek, T.A. Mol. Pharmacol. (1999) [Pubmed]
  14. Identification by differential display of the IF1 inhibitor peptide of ATP synthase/ATPase as a gene inducible in rat liver by pregnenolone 16alpha-carbonitrile. Jiménez, B.D., Quattrochi, L.C., Yockey, C.B., Guzelian, P.S. Life Sci. (2000) [Pubmed]
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