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Review Article

Xenobiotic-sensing nuclear receptors involved in drug metabolism: a structural perspective

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Pages 79-100 | Received 31 Aug 2012, Accepted 09 Oct 2012, Published online: 05 Dec 2012

References

  • Aleksunes, L. M., Manautou, J. E. (2007). Emerging role of Nrf2 in protecting against hepatic and gastrointestinal disease. Toxicol Pathol 35:459–473.
  • Alnouti, Y., Klaassen, C. D. (2008). Regulation of sulfotransferase enzymes by prototypical microsomal enzyme inducers in mice. J Pharmacol Exp Ther 324:612–621.
  • André, E., Gawlas, K., Becker-André, M. (1998). A novel isoform of the orphan nuclear receptor RORbeta is specifically expressed in pineal gland and retina. Gene 216:277–283.
  • Arita, K., Nanda, A., Wessagowit, V., Akiyama, M., Alsaleh, Q. A., McGrath, J. A. (2008). A novel mutation in the VDR gene in hereditary vitamin D-resistant rickets. Br J Dermatol 158:168–171.
  • Arnold, K. A., Eichelbaum, M., Burk, O. (2004). Alternative splicing affects the function and tissue-specific expression of the human constitutive androstane receptor. Nucl Recept 2:1.
  • Auerbach, S. S., Dekeyser, J. G., Stoner, M. A., Omiecinski, C. J. (2007). CAR2 displays unique ligand binding and RXRalpha heterodimerization characteristics. Drug Metab Dispos 35:428–439.
  • Auerbach, S. S., Ramsden, R., Stoner, M. A., Verlinde, C., Hassett, C., Omiecinski, C. J. (2003). Alternatively spliced isoforms of the human constitutive androstane receptor. Nucleic Acids Res 31:3194–3207.
  • Auerbach, S. S., Stoner, M. A., Su, S., Omiecinski, C. J. (2005). Retinoid X receptor-alpha-dependent transactivation by a naturally occurring structural variant of human constitutive androstane receptor (NR1I3). Mol Pharmacol 68:1239–1253.
  • Baba, T., Mimura, J., Nakamura, N., Harada, N., Yamamoto, M., Morohashi, K., et al. (2005). Intrinsic function of the aryl hydrocarbon (dioxin) receptor as a key factor in female reproduction. Mol Cell Biol 25:10040–10051.
  • Baes, M., Gulick, T., Choi, H. S., Martinoli, M. G., Simha, D., Moore, D. D. (1994). A new orphan member of the nuclear hormone receptor superfamily that interacts with a subset of retinoic acid response elements. Mol Cell Biol 14:1544–1522.
  • Barbier, O., Duran-Sandoval, D., Pineda-Torra, I., Kosykh, V., Fruchart, J. C., Staels, B. (2003a). Peroxisome proliferator-activated receptor alpha induces hepatic expression of the human bile acid glucuronidating UDP-glucuronosyltransferase 2B4 enzyme. J Biol Chem 278:32852–32860.
  • Barbier, O., Torra, I. P., Sirvent, A., Claudel, T., Blanquart, C., Duran-Sandoval, D., et al. (2003b). FXR induces the UGT2B4 enzyme in hepatocytes: a potential mechanism of negative feedback control of FXR activity. Gastroenterology 124:1926–1940.
  • Baskin-Bey, E. S., Huang, W., Ishimura, N., Isomoto, H., Bronk, S. F., Braley, K., et al. (2006). Constitutive androstane receptor (CAR) ligand, TCPOBOP, attenuates Fas-induced murine liver injury by altering Bcl-2 proteins. Hepatology 44:252–262.
  • Bauer, B., Hartz, A. M., Fricker, G., Miller, D. S. (2004). Pregnane X receptor up-regulation of P-glycoprotein expression and transport function at the blood-brain barrier. Mol Pharmacol 66:413–419.
  • Bélanger, A., Pelletier, G., Labrie, F., Barbier, O., Chouinard, S. (2003). Inactivation of androgens by UDP-glucuronosyltransferase enzymes in humans. Trends Endocrinol Metab 14:473–479.
  • Bertilsson, G., Heidrich, J., Svensson, K., Asman, M., Jendeberg, L., Sydow-Bäckman, M., et al. (1998). Identification of a human nuclear receptor defines a new signaling pathway for CYP3A induction. Proc Natl Acad Sci U S A 95:12208–12213.
  • Binkowski, T. A., Naghibzadeh, S., Liang, J. (2003). CASTp: Computed Atlas of Surface Topography of proteins. Nucleic Acids Res 31:3352–3355.
  • Bishop-Bailey, D., Walsh, D. T., Warner, T. D. (2004). Expression and activation of the farnesoid X receptor in the vasculature. Proc Natl Acad Sci U S A 101:3668–3673.
  • Blattler, S. M., Rencurel, F., Kaufmann, M.R., Meyer, U. A. (2007). In the regulation of cytochrome P450 genes, phenobarbital targets LKB1 for necessary activation of AMP-activated protein kinase. Proc Natl Acad Sci U S A 104:1045–1050.
  • Blumberg, B., Sabbagh, W., Jr., Juguilon, H., Bolado, J., Jr., van Meter, C. M., Ong, S., et al. (1998). SXR, a novel steroid and xenobiotic-sensing nuclear receptor. Genes Dev 12:3195–3205.
  • Brobst, D. E., Ding, X., Creech, K. L., Goodwin, B., Kelley, B., Staudinger, J. L. (2004). Guggulsterone activates multiple nuclear receptors and induces CYP3A gene expression through the pregnane X receptor. J Pharmacol Exp Ther 310:528–535.
  • Brown, J. D., Plutzky, J. (2007). Peroxisome proliferator-activated receptors as transcriptional nodal points and therapeutic targets. Circulation 115:518–533.
  • Brzozowski, A. M., Pike, A. C., Dauter, Z., Hubbard, R. E., Bonn, T., Engström, O., et al. (1997). Molecular basis of agonism and antagonism in the oestrogen receptor. Nature 389:753–758.
  • Buckley, D. B., Klaassen, C. D. (2009). Induction of mouse UDP-glucuronosyltransferase mRNA expression in liver and intestine by activators of aryl-hydrocarbon receptor, constitutive androstane receptor, pregnane X receptor, peroxisome proliferator-activated receptor alpha, and nuclear factor erythroid 2-related factor 2. Drug Metab Dispos 37:847–856.
  • Burbach, K. M., Poland, A., Bradfield, C. A. (1992). Cloning of the Ah-receptor cDNA reveals a distinctive ligand-activated transcription factor. Proc Natl Acad Sci U S A 89:8185–8189.
  • Cai, S. Y., He, H., Nguyen, T., Mennone, A., Boyer, J. L. (2010). Retinoic acid represses CYP7A1 expression in human hepatocytes and HepG2 cells by FXR/RXR-dependent and independent mechanisms. J Lipid Res 51:2265–2274.
  • Campbell, M. J., Adorini, L. (2006). The vitamin D receptor as a therapeutic target. Expert Opin Ther Targets 10:735–748.
  • Carlberg, C., Hooft van Huijsduijnen, R., Staple, J. K., DeLamarter, J. F., Becker-André, M. (1994). RZRs, a new family of retinoid-related orphan receptors that function as both monomers and homodimers. Mol Endocrinol 8:757–770.
  • Cermenati, G., Abbiati, F., Cermenati, S., Brioschi, E., Volonterio, A., Cavaletti, G., et al. (2012). Diabetes-induced myelin abnormalities are associated with an altered lipid pattern: protective effects of LXR activation. J Lipid Res 53:300–310.
  • Chandra, V., Huang, P., Hamuro, Y., Raghuram, S., Wang, Y., Burris, T. P., et al. (2008). Structure of the intact PPAR-gamma-RXR- nuclear receptor complex on DNA. Nature 456:350–356.
  • Chang, T. K. (2009). Activation of pregnane X receptor (PXR) and constitutive androstane receptor (CAR) by herbal medicines. AAPS J 11:590–601.
  • Chen, X., Zhang, J., Baker, S. M., Chen, G. (2007). Human constitutive androstane receptor mediated methotrexate induction of human dehydroepiandrosterone sulfotransferase (hSULT2A1). Toxicology 231:224–233.
  • Cheng, J., Ma, X., Krausz, K. W., Idle, J. R., Gonzalez, F. J. (2009). Rifampicin-activated human pregnane X receptor and CYP3A4 induction enhance acetaminophen-induced toxicity. Drug Metab Dispos 37:1611–1621.
  • Cheng, Y., Redinbo, M. R. (2011). Activation of the human nuclear xenobiotic receptor PXR by the reverse transcriptase-targeted anti-HIV drug PNU-142721. Protein Sci 20:1713–1719.
  • Chiang, J. Y. (2009). Hepatocyte nuclear factor 4alpha regulation of bile acid and drug metabolism. Expert Opin Drug Metab Toxicol 5:137–147.
  • Choi, H. S., Chung, M., Tzameli, I., Simha, D., Lee, Y. K., Seol, W., et al. (1997). Differential transactivation by two isoforms of the orphan nuclear hormone receptor. CAR J Biol Chem 272:23565–23571.
  • Chrencik, J. E., Orans, J., Moore, L. B., Xue, Y., Peng, L., Collins, J. L., et al. (2005). Structural disorder in the complex of human pregnane X receptor and the macrolide antibiotic rifampicin. Mol Endocrinol 19:1125–1134.
  • Cieśla, W. (2001). Can melatonin regulate the expression of prohormone convertase 1 and 2 genes via monomeric and dimeric forms of RZR/ROR nuclear receptor, and can melatonin influence the processes of embryogenesis or carcinogenesis by disturbing the proportion of cAMP and cGMP concentrations? Theoretic model of controlled apoptosis. Med Hypotheses 56:181–193.
  • Conde, I., Lobo, M. V., Zamora, J., Pérez, J., González, F. J., Alba, E., et al. (2008). Human pregnane X receptor is expressed in breast carcinomas, potential heterodimers formation between hPXR and RXR-alpha. BMC Cancer 8:174.
  • Delerive, P., Monté, D., Dubois, G., Trottein, F., Fruchart-Najib, J., Mariani, J., et al. (2001). The orphan nuclear receptor ROR alpha is a negative regulator of the inflammatory response. EMBO Rep 2:42–48.
  • Delvecchio, C. J., Bilan, P., Nair, P., Capone, J. P. (2008). LXR-induced reverse cholesterol transport in human airway smooth muscle is mediated exclusively by ABCA1. Am J Physiol Lung Cell Mol Physiol 295:L949–L957.
  • Denison, M. S., Nagy, S. R. (2003). Activation of the aryl hydrocarbon receptor by structurally diverse exogenous and endogenous chemicals. Annu Rev Pharmacol Toxicol 43:309–334.
  • Denison, M. S., Pandini, A., Nagy, S. R., Baldwin, E. P., Bonati, L. (2002). Ligand binding and activation of the Ah receptor. Chem Biol Interact 141:3–24.
  • di Masi, A., De Marinis, E., Ascenzi, P., Marino, M. (2009). Nuclear receptors CAR and PXR: Molecular, functional, and biomedical aspects. Mol Aspects Med 30:297–343.
  • Ding, X., Lichti, K., Kim, I., Gonzalez, F. J., Staudinger, J. L. (2006). Regulation of constitutive androstane receptor and its target genes by fasting, cAMP, hepatocyte nuclear factor alpha, and the coactivator peroxisome proliferator-activated receptor gamma coactivator-1alpha. J Biol Chem 281:26540–26551.
  • Dong, B., Qatanani, M., Moore, D. D. (2009). Constitutive androstane receptor mediates the induction of drug metabolism in mouse models of type 1 diabetes. Hepatology 50:622–629.
  • Drocourt, L., Ourlin, J. C., Pascussi, J. M., Maurel, P., Vilarem, M. J. (2002). Expression of CYP3A4, CYP2B6, and CYP2C9 is regulated by the vitamin D receptor pathway in primary human hepatocytes. J Biol Chem 277:25125–25132.
  • Dundas, J., Ouyang, Z., Tseng, J., Binkowski, A., Turpaz, Y., Liang, J. (2006). CASTp: computed atlas of surface topography of proteins with structural and topographical mapping of functionally annotated residues. Nucleic Acids Res 34:W116–W118.
  • Dushkin, M. I., Khoshchenko, O. M., Chasovsky, M. A., Pivovarova, E. N. (2009). The content of PPAR, LXR, and RXR and the PPAR DNA-binding activity in macrophages over the course of inflammation in mice. Bull Exp Biol Med 147:345–348.
  • Dussault, I., Lin, M., Hollister, K., Fan, M., Termini, J., Sherman, M. A., et al. (2002). A structural model of the constitutive androstane receptor defines novel interactions that mediate ligand-independent activity. Mol Cell Biol 22:5270–5280.
  • Ebisawa, T., Tojo, K., Tajima, N., Kamio, M., Oki, Y., Ono, K., et al. (2008). Immunohistochemical analysis of 11-beta-hydroxysteroid dehydrogenase type 2 and glucocorticoid receptor in subclinical Cushing’s disease due to pituitary macroadenoma. Endocr Pathol 19:252–260.
  • Echchgadda, I., Song, C. S., Oh, T., Ahmed, M., De La Cruz, I. J., Chatterjee, B. (2007). The xenobiotic-sensing nuclear receptors pregnane X receptor, constitutive androstane receptor, and orphan nuclear receptor hepatocyte nuclear factor 4alpha in the regulation of human steroid-/bile acid-sulfotransferase. Mol Endocrinol 21:2099–2111.
  • Echchgadda, I., Song, C. S., Roy, A. K., Chatterjee, B. (2004). Dehydroepiandrosterone sulfotransferase is a target for transcriptional induction by the vitamin D receptor. Mol Pharmacol 65:720–729.
  • Einstein, M., Greenlee, M., Rouen, G., Sitlani, A., Santoro, J., Wang, C., et al. (2004). Selective glucocorticoid receptor nonsteroidal ligands completely antagonize the dexamethasone mediated induction of enzymes involved in gluconeogenesis and glutamine metabolism. J Steroid Biochem Mol Biol 92:345–356.
  • Ekins, S., Mirny, L., Schuetz, E. G. (2002). A ligand-based approach to understanding selectivity of nuclear hormone receptors PXR, CAR, FXR, LXRalpha, and LXRbeta. Pharm Res 19:1788–1800.
  • Evans, W. E., Relling, M. V. (1999). Pharmacogenomics: translating functional genomics into rational therapeutics. Science 286:487–491.
  • Fang, H. L., Strom, S. C., Cai, H., Falany, C. N., Kocarek, T. A., Runge-Morris, M. (2005). Regulation of human hepatic hydroxysteroid sulfotransferase gene expression by the peroxisome proliferator-activated receptor alpha transcription factor. Mol Pharmacol 67:1257–1267.
  • Fiorucci, S., Zampella, A., Distrutti, E. (2012). Development of FXR, PXR and CAR agonists and antagonists for treatment of liver disorders. Curr Top Med Chem 12:605–624.
  • Forman, B. M., Tzameli, I., Choi, H. S., Chen, J., Simha, D., Seol, W., et al. (1998). Androstane metabolites bind to and deactivate the nuclear receptor CAR-beta. Nature 395:612–615.
  • Fujii-Kuriyama, Y., Mimura, J. (2005). Molecular mechanisms of AhR functions in the regulation of cytochrome P450 genes. Biochem Biophys Res Commun 338:311–317.
  • Fukunaga, B. N., Probst, M. R., Reisz-Porszasz, S., Hankinson, O. (1995). Identification of functional domains of the aryl hydrocarbon receptor. J Biol Chem 270:29270–29278.
  • Gascon-Barré, M., Demers, C., Mirshahi, A., Néron, S., Zalzal, S., Nanci, A. (2003). The normal liver harbors the vitamin D nuclear receptor in nonparenchymal and biliary epithelial cells. Hepatology 37:1034–1042.
  • Girroir, E. E., Hollingshead, H. E., He, P., Zhu, B., Perdew, G. H., Peters, J. M. (2008). Quantitative expression patterns of peroxisome proliferator-activated receptor-beta/delta (PPARbeta/delta) protein in mice. Biochem Biophys Res Commun 371:456–461.
  • Glatt, H. (2000). Sulfotransferases in the bioactivation of xenobiotics. Chem Biol Interact 129:141–170.
  • Gnerre, C., Blattler, S., Kaufmann, M. R., Looser, R., Meyer, U. A. (2004). Regulation of CYP3A4 by the bile acid receptor FXR: evidence for functional binding sites in the CYP3A4 gene. Pharmacogenetics 14:635–645.
  • Goodwin, B., Hodgson, E., Liddle, C. (1999). The orphan human pregnane X receptor mediates the transcriptional activation of CYP3A4 by rifampicin through a distal enhancer module. Mol Pharmacol 56:1329–1339.
  • Goodwin, B., Redinbo, M. R., Kliewer, S. A. (2002). Regulation of cyp3a gene transcription by the pregnane x receptor. Annu Rev Pharmacol Toxicol 42:1–23.
  • Gonzalez, F. J. (1988). The molecular biology of cytochrome P450s. Pharmacol Rev 40:243–288.
  • Gronemeyer, H., Gustafsson, J. A., Laudet, V. (2004). Principles for modulation of the nuclear receptor superfamily. Nat Rev Drug Discov 3:950–964.
  • Haimeur, A., Conseil, G., Deeley, R. G., Cole, S. P. (2004). The MRP-related and BCRP/ABCG2 multidrug resistance proteins: biology, substrate specificity and regulation. Curr Drug Metab 5:21–53.
  • Hamilton, B. A. Frankel, W. N., Kerrebrock, A. W., Hawkins, T. L., FitzHugh, W., Kusumi, K., et al. (1996). Disruption of the nuclear hormone receptor RORalpha in staggerer mice. Nature 379:736–739.
  • Handschin, C., Meyer, U. A. (2003). Induction of drug metabolism: the role of nuclear receptors. Pharmacol Rev 55:649–673.
  • He, Y. W., Deftos, M. L., Ojala, E. W., Bevan, M. J. (1998). RORgamma t, a novel isoform of an orphan receptor, negatively regulates Fas ligand expression and IL-2 production in T cells. Immunity 9:797–806.
  • Holm, L., Kääriäinen, S., Rosenstrom, P., Schenkel, A. (2008). Searching protein structure databases with DaliLite v.3. Bioinformatics 24:2780–2781.
  • Hong, C., Tontonoz, P. (2008). Coordination of inflammation and metabolism by PPAR and LXR nuclear receptors. Curr Opin Genet Dev 18:461–467.
  • Honjo, Y., Sasaki, S., Kobayashi, Y., Misawa, H., Nakamura, H. (2006). 1,25-dihydroxyvitamin D3 and its receptor inhibit the chenodeoxycholic acid-dependent transactivation by farnesoid X receptor. J Endocrinol 188:635–643.
  • Huber, R. M., Murphy, K., Miao, B., Link, J. R., Cunningham, M. R., Rupar, M. J., et al. (2002). Generation of multiple farnesoid-X-receptor isoforms through the use of alternative promoters. Gene 290:35–43.
  • Huss, J. M., Kasper, C. B. (2000). Two-stage glucocorticoid induction of CYP3A23 through both the glucocorticoid and pregnane X receptors. Mol Pharmacol 58:48–57.
  • Ingraham, H. A., Redinbo, M. R. (2005). Orphan nuclear receptors adopted by crystallography. Curr Opin Struct Biol 15:708–715.
  • Itoh, K., Chiba, T., Takahashi, S., Ishii, T., Igarashi, K., Katoh, Y., et al. (1997). An Nrf2/small Maf heterodimer mediates the induction of phase II detoxifying enzyme genes through antioxidant response elements. Biochem Biophys Res Commun 236:313–322.
  • Itoh, K., Wakabayashi, N., Katoh, Y., Ishii, T., Igarashi, K., Engel, J. D., et al. (1999). Keap1 represses nuclear activation of antioxidant responsive elements by Nrf2 through binding to the amino-terminal Neh2 domain. Genes Dev 13:76–86.
  • Janowski, B. A., Willy, P. J., Devi, T. R., Falck, J. R., Mangelsdorf, D. J. (1996). An oxysterol signalling pathway mediated by the nuclear receptor LXR alpha. Nature 383:728–731.
  • Jetten, A. M., Kurebayashi, S., Ueda, E. (2001). The ROR nuclear orphan receptor subfamily: critical regulators of multiple biological processes. Prog Nucleic Acid Res Mol Biol 69:205–247.
  • Jin, L., Martynowski, D., Zheng, S., Wada, T., Xie, W., Li, Y. (2010). Structural basis for hydroxycholesterols as natural ligands of orphan nuclear receptor RORgamma. Mol Endocrinol 24:923–929.
  • Johansson, L., Båvner, A., Thomsen, J. S., Färnegårdh, M., Gustafsson, A., Treuter, E. (2000). The orphan nuclear receptor SHP utilizes conserved LXXLL-related motifs for interactions with ligand-activated estrogen receptors. Mol Cell Biol 20:1124–1133.
  • Jover, R., Bort, R., Gómez-Lechón, M. J., Castell, J. V. (2001). Cytochrome P450 regulation by hepatocyte nuclear factor 4 in human hepatocytes: a study using adenovirus-mediated antisense targeting. Hepatology 33:668–675.
  • Jyrkkärinne, J., Windshügel, B., Rönkkö, T., Tervo, A. J., Küblbeck, J., Lahtela-Kakkonen, M., et al. (2008). Insights into ligand-elicited activation of human constitutive androstane receptor based on novel agonists and three-dimensional quantitative structure-activity relationship. J Med Chem 51:7181–7192.
  • Kachaylo, E. M., Pustylnyak, V. O., Lyakhovich, V. V., Gulyaeva, L. F. (2011). Constitutive androstane receptor (CAR) is a xenosensor and target for therapy. Biochemistry (Mosc) 76:1087–1097.
  • Kallen, J. A., Schlaeppi, J. M., Bitsch, F., Geisse, S., Geiser, M., Delhon, I., et al. (2002). X-ray structure of the hRORalpha LBD at 1.63 A: structural and functional data that cholesterol or a cholesterol derivative is the natural ligand of RORalpha. Structure 10:1697–1707.
  • Kamiya, A., Inoue, Y., Gonzalez, F. J. (2003). Role of the hepatocyte nuclear factor 4alpha in control of the pregnane X receptor during fetal liver development. Hepatology 37:1375–1384.
  • Kang, H. S., Angers, M., Beak, J. Y., Wu, X., Gimble, J. M., Wada, T., et al. (2007). Gene expression profiling reveals a regulatory role for ROR alpha and ROR gamma in phase I and phase II metabolism. Physiol Genomics 31:281–294.
  • Kang, M. I., Kobayashi, A., Wakabayashi, N., Kim, S. G., Yamamoto, M. (2004). Scaffolding of Keap1 to the actin cytoskeleton controls the function of Nrf2 as key regulator of cytoprotective phase 2 genes. Proc Natl Acad Sci U S A 101:2046–2051.
  • Kast, H. R., Goodwin, B., Tarr, P. T., Jones, S. A., Anisfield, A. M., Stoltz, C. M., et al. (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.
  • Kawamoto, T., Sueyoshi, T., Zelko, I., Moore, R., Washburn, K., Negishi, M. (1999). Phenobarbital-responsive nuclear translocation of the receptor CAR in induction of the CYP2B gene. Mol Cell Biol 19:6318–6322.
  • Kawano, S., Kumagai, S. (2007). Diagnosis and treatment of glucocorticoid-induced osteoporosis in collagen vascular disease. [Article in Japanese]. Nihon Rinsho 65(Suppl 9):504–507.
  • Khan, A. A., Chow, E. C., van Loenen-Weemaes, A. M., Porte, R. J., Pang, K. S., Groothuis, G. M. (2009). Comparison of effects of VDR versus PXR, FXR and GR ligands on the regulation of CYP3A isozymes in rat and human intestine and liver. Eur J Pharm Sci 37:115–125.
  • Kliewer, S. A., Goodwin, B., Willson, T. M. (2002). The nuclear pregnane X receptor: a key regulator of xenobiotic metabolism. Endocr Rev 23:687–702.
  • Kliewer, S. A., Moore, J. T., Wade, L., Staudinger, J. L., Watson, M. A., Jones, S. A., et al. (1998). An orphan nuclear receptor activated by pregnanes defines a novel steroid signaling pathway. Cell 92:73–82.
  • Kliewer, S. A., Willson, T. M. (2002). Regulation of xenobiotic and bile acid metabolism by the nuclear pregnane X receptor. J Lipid Res 43:359–364.
  • Kobayashi, K., Sueyoshi, T., Inoue, K., Moore, R., Negishi, M. (2003). Cytoplasmic accumulation of the nuclear receptor CAR by a tetratricopeptide repeat protein in HepG2 cells. Mol Pharmacol 64:1069–1075.
  • Köhle, C., Bock, K. W. (2007). Coordinate regulation of phase I and II xenobiotic metabolisms by the Ah receptor and Nrf2. Biochem Pharmacol 73:1853–1862.
  • Köhle, C., Bock, K. W. (2009). Coordinate regulation of human drug-metabolizing enzymes, and conjugate transporters by the Ah receptor, pregnane X receptor and constitutive androstane receptor. Biochem Pharmacol 77:689–699.
  • Korf, H., Vander Beken, S., Romano, M., Steffensen, K. R., Stijlemans, B., Gustafsson, J. A., et al. (2009). Liver X receptors contribute to the protective immune response against Mycobacterium tuberculosis in mice. J Clin Invest 119:1626–1637.
  • Koyano, S., Kurose, K., Saito, Y., Ozawa, S., Hasegawa, R., Komamura, K., et al. (2004). Functional characterization of four naturally occurring variants of human pregnane X receptor (PXR): one variant causes dramatic loss of both DNA binding activity and the transactivation of the CYP3A4 promoter/enhancer region. Drug Metab Dispos 32:149–154.
  • Kurebayashi, S., Ueda, E., Sakaue, M., Patel, D. D., Medvedev, A., Zhang, F., et al. (2000). Retinoid-related orphan receptor gamma (RORgamma) is essential for lymphoid organogenesis and controls apoptosis during thymopoiesis. Proc Natl Acad Sci U S A 97:10132–10137.
  • Ladias, J. A., Hadzopoulou-Cladaras, M., Kardassis, D., Cardot, P., Cheng, J., Zannis, V., et al. (1992). Transcriptional regulation of human apolipoprotein genes ApoB, ApoCIII, and ApoAII by members of the steroid hormone receptor superfamily HNF-4, ARP-1, EAR-2, and EAR-3. J Biol Chem 267:15849–15860.
  • Laffitte, B. A., Kast, H. R., Nguyen, C. M., Zavacki, A. M., Moore, D. D., Edwards, P. A. (2000). Identification of the DNA binding specificity and potential target genes for the farnesoid X-activated receptor. J Biol Chem 275:10638–10647.
  • Lamba, J., Lamba, V., Schuetz, E. (2005). Genetic variants of PXR (NR1I2) and CAR (NR1I3) and their implications in drug metabolism and pharmacogenetics. Curr Drug Metab 6:369–383.
  • Lamba, J. K., Lamba, V., Yasuda, K., Lin, Y. S., Assem, M., Thompson, E., et al. (2004). Expression of constitutive androstane receptor splice variants in human tissues and their functional consequences. J Pharmacol Exp Ther 311:811–821.
  • Lamba, V., Yasuda, K., Lamba, J. K., Assem, M., Davila, J., Strom, S., et al. (2004). PXR (NR1I2): splice variants in human tissues, including brain, and identification of neurosteroids and nicotine as PXR activators. Toxicol Appl Pharmacol 199:251–265.
  • Larrede, S., Quinn, C. M., Jessup, W., Frisdal, E., Olivier, M., Hsieh, V., et al. (2009). Stimulation of cholesterol efflux by LXR agonists in cholesterol-loaded human macrophages is ABCA1-dependent but ABCG1-independent. Arterioscler Thromb Vasc Biol 29:1930–1936.
  • Larrieu, G., Galtier, P. (1988). A comparative study of some oxidative and conjugative drug metabolizing enzymes in liver, lung and kidney of sheep. Comp Biochem Physiol C 89:225–228.
  • Laue, L., Kawai, S., Brandon, D. D., Brightwell, D., Barnes, K., Knazek, R. A., et al. (1988). Receptor-mediated effects of glucocorticoids on inflammation: enhancement of the inflammatory response with a glucocorticoid antagonist. J Steroid Biochem 29:591–598.
  • Lee, H. K., Lee, Y. K., Park, S. H., Kim, Y. S., Park, S. H., Lee, J. W., et al. (1998). Structure and expression of the orphan nuclear receptor SHP gene. J Biol Chem 273:14398–14402.
  • Lehmann, J. M., Kliewer, S. A., Moore, L. B., Smith-Oliver, T. A., Oliver, B. B., Su, J. L., et al. (1997). Activation of the nuclear receptor LXR by oxysterols defines a new hormone response pathway. J Biol Chem 272:3137–3140.
  • Lehmann, J. M., McKee, D. D., Watson, M. A., Willson, T. M., Moore, J. T., Kliewer, S. A. (1998). The human orphan nuclear receptor PXR is activated by compounds that regulate CYP3A4 gene expression and cause drug interactions. J Clin Invest 102:1016–1023.
  • Lin, Y. S., Yasuda, K., Assem, M., Cline, C., Barber, J., Li, C. W., et al. (2009). The major human pregnane X receptor (PXR) splice variant, PXR.2, exhibits significantly diminished ligand-activated transcriptional regulation. Drug Metab Dispos 37:1295–1304.
  • Lu, T. T., Repa, J. J., Mangelsdorf, D. J. (2001). Orphan nuclear receptors as eLiXiRs and FiXeRs of sterol metabolism. J Biol Chem 276:37735–37738.
  • Lu, Y., Heydel, J. M., Li, X., Bratton, S., Lindblom, T., Radominska-Pandya, A. (2005). Lithocholic acid decreases expression of UGT2B7 in Caco-2 cells: a potential role for a negative farnesoid X receptor response element. Drug Metab Dispos 33:937–946.
  • Luci, S., Geissler, S., König, B., Koch, A., Stangl, G. I., Hirche, F., et al. (2006). PPARalpha agonists up-regulate organic cation transporters in rat liver cells. Biochem Biophys Res Commun 350:704–708.
  • Mader, S., Chen, J. Y., Chen, Z., White, J., Chambon, B., Gronemeyer, H. (1993). The patterns of binding of RAR, RXR and TR homo- and heterodimers to direct repeats are dictated by the binding specificites of the DNA binding domains. EMBO J 12:5029–5041.
  • Maglich, J. M., Stoltz, C. M., Goodwin, B., Hawkins-Brown, D., Moore, J. T., Kliewer, S. A. (2002). Nuclear pregnane x receptor and constitutive androstane receptor regulate overlapping but distinct sets of genes involved in xenobiotic detoxification. Mol Pharmacol 62:638–646.
  • Makishima, M., Lu, T. T., Xie, W., Whitfield, G. K., Domoto, H., Evans, R. M., et al. (2002). Vitamin D receptor as an intestinal bile acid sensor. Science 296:1313–1316.
  • Makishima, M., Okamoto, A. Y., Repa, J. J., Tu, H., Learned, R. M., Luk, A., et al. (1999). Identification of a nuclear receptor for bile acids. Science 284:1362–1365.
  • Malloy, P. J., Wang, J., Peng, L., Nayak, S., Sisk, J. M., Thompson, C. C., et al. (2007). A unique insertion/duplication in the VDR gene that truncates the VDR causing hereditary 1,25-dihydroxyvitamin D-resistant rickets without alopecia. Arch Biochem Biophys 460:285–292.
  • Mangelsdorf, D. J., Evans, R. M. (1995). The RXR heterodimers and orphan receptors. Cell 83:841–850.
  • Mangelsdorf, D. J., Ong, E. S., Dyck, J. A., Evans, R. M. (1990). Nuclear receptor that identifies a novel retinoic acid response pathway. Nature 345:224–229.
  • Martin, H., Sarsat, J. P., de Waziers, I., Housset, C., Balladur, P., Beaune, P., et al. (2003). Induction of cytochrome P450 2B6 and 3A4 expression by phenobarbital and cyclophosphamide in cultured human liver slices. Pharm Res 20:557–568.
  • Matic, M., Mahns, A., Tsoli, M., Corradin, A., Polly, P., Robertson, G. R. (2007). Pregnane X receptor: promiscuous regulator of detoxification pathways. Int J Biochem Cell Biol 39:478–483.
  • Matsui, T. (1997). Orphan nuclear receptor ROR alpha in cerebellum. [Article in Japanese]. Tanpakushitsu Kakusan Koso 42:2039–2048.
  • McMahon, M., Thomas, N., Itoh, K., Yamamoto, M., Hayes, J. D. (2004). Redox-regulated turnover of Nrf2 is determined by at least two separate protein domains, the redox-sensitive Neh2 degron and the redox-insensitive Neh6 degron. J Biol Chem 279:31556–31567
  • Medvedev, A., Yan, Z. H., Hirose, T., Giguère, V., Jetten, A. M. (1996). Cloning of a cDNA encoding the murine orphan receptor RZR/ROR gamma and characterization of its response element. Gene 181:199–206.
  • Meyer, M. B., Goetsch, P. D., Pike, J. W. (2012). VDR/RXR and TCF4/beta-catenin cistromes in colonic cells of colorectal tumor origin: impact on c-FOS and c-MYC gene expression. Mol Endocrinol 26:37–51.
  • Miao, J., Choi, S. E., Seok, S. M., Yang, L., Zuercher, W. J., Xu, Y., et al. (2011). Ligand-dependent regulation of the activity of the orphan nuclear receptor, small heterodimer partner (SHP), in the repression of bile acid biosynthetic CYP7A1 and CYP8B1 genes. Mol Endocrinol 25:1159–1169.
  • Miller, R. T., Willson, T. M. (2001). Regulation of xenobiotic metabolism by orphan nuclear receptors. Toxicol Pathol 29:3–5.
  • Miquerol, L., Lopez, S., Cartier, N., Tulliez, M., Raymondjean, M., Kahn, A. (1994). Expression of the L-type pyruvate kinase gene and the hepatocyte nuclear factor 4 transcription factor in exocrine and endocrine pancreas. J Biol Chem 269:8944–8951.
  • Missbach, M., Jagher, B., Sigg, I., Nayeri, S., Carlberg, C., Weisenberg, I. (1996). Thiazolidine diones, specific ligands of the nuclear receptor retinoid Z receptor/retinoid acid receptor-related orphan receptor alpha with potent antiarthritic activity. J Biol Chem 271:13515–13522.
  • Miyata, M., Matsuda, Y., Tsuchiya, H., Kitada, H., Akase, T., Shimada, M., et al. (2006). Chenodeoxycholic acid-mediated activation of the farnesoid X receptor negatively regulates hydroxysteroid sulfotransferase. Drug Metab Pharmacokinet 21:315–323.
  • Modica, S., Bellafante, E., Moschetta, A. (2009). Master regulation of bile acid and xenobiotic metabolism via the FXR, PXR and CAR trio. Front Biosci 14:4719–4745.
  • Moi, P., Chan, K., Asunis, I., Cao, A., Kan, Y. W. (1994). Isolation of NF-E2-related factor 2 (Nrf2), a NF-E2-like basic leucine zipper transcriptional activator that binds to the tandem NF-E2/AP1 repeat of the beta-globin locus control region. Proc Natl Acad Sci U S A 91:9926–9930.
  • Moore, D. D. (2001). Regulation of drug transport by new xenobiotic receptors. Pharmacogenomics J 1:224–225.
  • Moore, L. B., Maglich, J. M., McKee, D. D., Wisely, B., Willson, T. M., Kliewer, S. A., et al. (2002). Pregnane X receptor (PXR), constitutive androstane receptor (CAR), and benzoate X receptor (BXR) define three pharmacologically distinct classes of nuclear receptors. Mol Endocrinol 16:977–986.
  • Moore, L. B., Parks, D. J., Jones, S. A., Bledsoe, R. K., Consler, T. G., Stimmel, J. B., et al. (2000). Orphan nuclear receptors constitutive androstane receptor and pregnane X receptor share xenobiotic and steroid ligands. J Biol Chem 275:15122–15127.
  • Motohashi, H., Katsuoka, F., Engel, J. D., Yamamoto, M. (2004). Small Maf proteins serve as transcriptional cofactors for keratinocyte differentiation in the Keap1-Nrf2 regulatory pathway. Proc Natl Acad Sci U S A 101:6379–6384.
  • Motohashi, H., Yamamoto, M. (2004). Nrf2-Keap1 defines a physiologically important stress response mechanism. Trends Mol Med 10:549–557.
  • Munck, A., Wira, C., Young, D. A., Mosher, K. M., Hallahan, C., Bell, P. A. (1972). Glucocorticoid-receptor complexes and the earliest steps in the action of glucocorticoids on thymus cells. J Steroid Biochem 3:567–578.
  • Nannelli, A., Chirulli, V., Longo, V., Gervasi, P. G. (2008). Expression and induction by rifampicin of CAR- and PXR-regulated CYP2B and CYP3A in liver, kidney and airways of pig. Toxicology 252:105–112.
  • Ng, M. K., Celermajer, D. S. (2004). Glucocorticoid treatment and cardiovascular disease. Heart 90:829–830.
  • Nioi, P., Nguyen, T., Sherratt, P. J., Pickett, C. B. (2005). The carboxy-terminal Neh3 domain of Nrf2 is required for transcriptional activation. Mol Cell Biol 25:10895–10906.
  • Noble, S. M., Carnahan, V. E., Moore, L. B., Luntz, T., Wang, H., Ittoop, O. R., et al. (2006). Human PXR forms a tryptophan zipper-mediated homodimer. Biochemistry 45:8579–8589.
  • Nowell, S., Falany, C. N. (2006). Pharmacogenetics of human cytosolic sulfotransferases. Oncogene 25:1673–1678.
  • Omiecinski, C. J., Vanden Heuvel, J. P., Perdew, G. H., Peters, J. M. (2011). Xenobiotic metabolism, disposition, and regulation by receptors: from biochemical phenomenon to predictors of major toxicities. Toxicol Sci 120(Suppl 1):S49–S75.
  • Orans, J., Teotico, D. G., Redinbo, M. R. (2005). The nuclear xenobiotic receptor pregnane X receptor: recent insights and new challenges. Mol Endocrinol 19:2891–2900.
  • Orlov, I., Rochel, N., Moras, D., Klaholz, B. P. (2011). Structure of the full human RXR/VDR nuclear receptor heterodimer complex with its DR3 target DNA. EMBO J 31:291–300.
  • Ortlund, E. A., Lee, Y., Solomon, I. H., Hager, J. M., Safi, R., Choi, Y., et al. (2005). Modulation of human nuclear receptor LRH-1 activity by phospholipids and SHP. Nat Struct Mol Biol 12:357–363.
  • Ouvrier, A., Cadet, R., Lobaccaro, J. M., Drevet, J. R., Saez, F. (2009a). LXR regulate cholesterol homeostasis in the proximal mouse epididymis. Folia Histochem Cytobiol 47:S75–S79.
  • Ouvrier, A., Cadet, R., Vernet, P., Laillet, B., Chardigny, J. M., Lobaccaro, J. M., et al. (2009b). LXR and ABCA1 control cholesterol homeostasis in the proximal mouse epididymis in a cell-specific manner. J Lipid Res 50:1766–1775.
  • Parks, D. J., Blanchard, S. G., Bledsoe, R. K., Chandra, G., Consler, T. G., Kliewer, S. A., et al. (1999). Bile acids: natural ligands for an orphan nuclear receptor. Science 284:1365–1368.
  • Pascussi, J. M., Drocourt, L., Fabre, J. M., Maurel, P., Vilarem, M. J. (2000). Dexamethasone induces pregnane X receptor and retinoid X receptor-alpha expression in human hepatocytes: synergistic increase of CYP3A4 induction by pregnane X receptor activators. Mol Pharmacol 58:361–372.
  • Pascussi, J. M., Gerbal-Chaloin, S., Drocourt, L., Maurel, P., Vilarem, M. J. (2003). The expression of CYP2B6, CYP2C9 and CYP3A4 genes: a tangle of networks of nuclear and steroid receptors. Biochim Biophys Acta 1619:243–253.
  • Peet, D. J., Turley, S. D., Ma, W., Janowski, B. A., Lobaccaro, J. M., Hammer, R. E., et al. (1998). Cholesterol and bile acid metabolism are impaired in mice lacking the nuclear oxysterol receptor LXR alpha. Cell 93:693–704.
  • Pergola, P. E., Raskin, P., Toto, R. D., Meyer, C. J., Huff, J. W., Grossman, E. B., et al. (2011). Bardoxolone methyl and kidney function in CKD with type 2 diabetes. N Engl J Med 365:327–336.
  • Pool-Zobel, B., Veeriah, S., Böhmer, F. D. (2005). Modulation of xenobiotic metabolising enzymes by anticarcinogens—focus on glutathione S-transferases and their role as targets of dietary chemoprevention in colorectal carcinogenesis. Mutat Res 591:74–92.
  • Popowski, K., Eloranta, J. J., Saborowski, M., Fried, M., Meier, P. J., Kullak-Ublick, G. A. (2005). The human organic anion transporter 2 gene is transactivated by hepatocyte nuclear factor-4 alpha and suppressed by bile acids. Mol Pharmacol 67:1629–1638.
  • Raddatz, D., Middel, P., Bockemühl, M., Benöhr, P., Wissmann, C., Schwörer, H., et al. (2004). Glucocorticoid receptor expression in inflammatory bowel disease: evidence for a mucosal down-regulation in steroid-unresponsive ulcerative colitis. Aliment Pharmacol Ther 19:47–61.
  • Rauch, A., Seitz, S., Baschant, U., Schilling, A. F., Illing, A., Stride, B., et al. (2010). Glucocorticoids suppress bone formation by attenuating osteoblast differentiation via the monomeric glucocorticoid receptor. Cell Metab 11:517–531.
  • Ray, A., Siegel, M. D., Prefontaine, K. E., Ray, P. (1995). Anti-inflammation: direct physical association and functional antagonism between transcription factor NF-KB and the glucocorticoid receptor. Chest 107:139S.
  • Reisman, S. A., Chertow, G. M., Hebbar, S., Vaziri, N. D., Ward, K. W., Meyer, C. J. (2012). Bardoxolone methyl decreases megalin and activates Nrf2 in the kidney. J Am Soc Nephrol 23:1663–1673.
  • Remmer, H. (1972). Induction of drug metabolizing enzyme system in the liver. Eur J Clin Pharmacol 5:116–136.
  • Reschly, E. J., Krasowski, M. D. (2006). Evolution and function of the NR1I nuclear hormone receptor subfamily (VDR, PXR, and CAR) with respect to metabolism of xenobiotics and endogenous compounds. Curr Drug Metab 7:349–365.
  • Reschly, E. J., Ai, N., Ekins, S., Welsh, W. J., Hagey, L. R., Hofmann, A. F., et al. (2008). Evolution of the bile salt nuclear receptor FXR in vertebrates. J Lipid Res 49:1577–1587.
  • Ricketts, M. L., Boekschoten, M. V., Kreeft, A. J., Hooiveld, G. J., Moen, C. J., Müller, M., et al. (2007). The cholesterol-raising factor from coffee beans, cafestol, as an agonist ligand for the farnesoid and pregnane X receptors. Mol Endocrinol 21:1603–1616.
  • Rizzo, G., Disante, M., Mencarelli, A., Renga, B., Gioiello, A., Pellicciari, R., et al. (2006). The farnesoid X receptor promotes adipocyte differentiation and regulates adipose cell function in vivo. Mol Pharmacol 70:1164–1173.
  • Saborowski, M., Kullak-Ublick, G. A., Eloranta, J. J. (2006). The human organic cation transporter-1 gene is transactivated by hepatocyte nuclear factor-4alpha. J Pharmacol Exp Ther 317:778–785.
  • Sakai, H., Iwata, H., Kim, E. Y., Tsydenova, O., Miyazaki, N., Petrov, E. A., et al. (2006). Constitutive androstane receptor (CAR) as a potential sensing biomarker of persistent organic pollutants (POPs) in aquatic mammal: molecular characterization, expression level, and ligand profiling in Baikal seal (Pusa sibirica). Toxicol Sci 94:57–70.
  • Sashihara, S., Felts, P. A., Waxman, S. G., Matsui, T. (1996). Orphan nuclear receptor ROR alpha gene: isoform-specific spatiotemporal expression during postnatal development of brain. Brain Res Mol Brain Res 42:109–117.
  • Scheper, R. J., Broxterman, H. J., Scheffer, G. L., Meijer, C. J., Pinedo, H. M. (1992). Drug-transporter proteins in clinical multidrug resistance. Clin Chim Acta 206:25–32.
  • Schwabe, K., Vacca, G., Duck, R., Gillissen, A. (2009). Glucocorticoid receptor gene polymorphisms and potential association to chronic obstructive pulmonary disease susceptibility and severity. Eur J Med Res 14(Suppl 4):210–215.
  • Selye, H. (1971). Hormones and resistance. J Pharm Sci 60:1.
  • Seol, W., Choi, H. S., Moore, D. D. (1996). An orphan nuclear hormone receptor that lacks a DNA binding domain and heterodimerizes with other receptors. Science 272:1336–1339.
  • Shan, L., Vincent, J., Brunzelle, J. S., Dussault, I., Lin, M., Ianculescu, I., et al. (2004). Structure of the murine constitutive androstane receptor complexed to androstenol: a molecular basis for inverse agonism. Mol Cell 16:907–917.
  • Shi, D., Yang, D., Yan, B. (2010). Dexamethasone transcriptionally increases the expression of the pregnane X receptor and synergistically enhances pyrethroid esfenvalerate in the induction of cytochrome P450 3A23. Biochem Pharmacol 80:1274–1283.
  • Shindo, S., Numazawa, S., Yoshida, T. (2007). A physiological role of AMP-activated protein kinase in phenobarbital-mediated constitutive androstane receptor activation and CYP2B induction. Biochem J 401:735–741.
  • Shulman, A. I., Larson, C., Mangelsdorf, D. J., Ranganathan, R. (2004). Structural determinants of allosteric ligand activation in RXR heterodimers. Cell 116:417–429.
  • Sladek, F. M., Zhong, W. M., Lai, E., Darnell, J. E., Jr. (1990). Liver-enriched transcription factor HNF-4 is a novel member of the steroid hormone receptor superfamily. Genes Dev 4:2353–2365.
  • Son, Y. L., Lee, Y. C. (2009). Molecular determinants of the interactions between LXR/RXR heterodimers and TRAP220. Biochem Biophys Res Commun 384:389–393.
  • Song, C. S., Echchgadda, I., Baek, B. S., Ahn, S. C., Oh, T., Roy, A. K., et al. (2001). Dehydroepiandrosterone sulfotransferase gene induction by bile acid activated farnesoid X receptor. J Biol Chem 276:42549–42556.
  • Song, C., Hiipakka, R. A., Kokontis, J. M., Liao, S. (1995). Ubiquitous receptor: structures, immunocytochemical localization, and modulation of gene activation by receptors for retinoic acids and thyroid hormones. Ann N Y Acad Sci 761:38–49.
  • Song, C., Kokontis, J. M., Hiipakka, R. A., Liao, S. (1994). Ubiquitous receptor: a receptor that modulates gene activation by retinoic acid and thyroid hormone receptors. Proc Natl Acad Sci U S A 91:10809–10813.
  • Sonoda, J., Chong, L. W., Downes, M., Barish, G. D., Coulter, S., Liddle, C., et al. (2005). Pregnane X receptor prevents hepatorenal toxicity from cholesterol metabolites. Proc Natl Acad Sci U S A 102:2198–2203.
  • Sonoda, J., Evans, R. (2003). Biological function and mode of action of nuclear xenobiotic receptors. Pure Appl Chem 75:1733–1742.
  • Stanley, L. A., Horsburgh, B. C., Ross, J., Scheer, N., Wolf, C. R. (2006). PXR and CAR: nuclear receptors which play a pivotal role in drug disposition and chemical toxicity. Drug Metab Rev 38:515–597.
  • Sueyoshi, T., Kawamoto, T., Zelko, I., Honkakoski, P., Negishi, M. (1999). The repressed nuclear receptor CAR responds to phenobarbital in activating the human. CYP2B6 gene J Biol Chem 274:6043–6046.
  • Suino, K., Peng, L., Reynolds, R., Li, Y., Cha, J. Y., Repa, J. J., et al. (2004). The nuclear xenobiotic receptor CAR: structural determinants of constitutive activation and heterodimerization. Mol Cell 16:893–905.
  • Svec, F., Rudis, M. (1981). Glucocorticoids regulate the glucocorticoid receptor in the AtT-20 cell. J Biol Chem 256:5984–5987.
  • Swales, K., Negishi, M. (2004). CAR, driving into the future. Mol Endocrinol 18:1589–1598
  • Szatmari, I., Vámosi, G., Brazda, P., Balint, B. L., Benko, S., Széles, L., et al. (2006). Peroxisome proliferator-activated receptor gamma-regulated ABCG2 expression confers cytoprotection to human dendritic cells. J Biol Chem 281:23812–23823.
  • Takeshita, A., Koibuchi, N., Oka, J., Taguchi, M., Shishiba, Y., Ozawa, Y. (2001). Bisphenol-A, an environmental estrogen, activates the human orphan nuclear receptor, steroid and xenobiotic receptor-mediated transcription. Eur J Endocrinol 145:513–517.
  • Teotico, D. G., Bischof, J. J., Peng, L., Kliewer, S. A., Redinbo, M. R. (2008). Structural basis of human pregnane X receptor activation by the hops constituent colupulone. Mol Pharmacol 74:1512–1520.
  • Timsit, Y. E., Negishi, M. (2007). CAR and PXR: the xenobiotic-sensing receptors. Steroids 72:231–246.
  • Tirona, R. G., Lee, W., Leake, B. F., Lan, L. B., Cline, C. B., Lamba, V., et al. (2003). The orphan nuclear receptor HNF4alpha determines PXR- and CAR-mediated xenobiotic induction of CYP3A4. Nat Med 9:220–224.
  • Uppal, H., Saini, S. P., Moschetta, A., Mu, Y., Zhou, J., Gong, H., et al. (2007). Activation of LXRs prevents bile acid toxicity and cholestasis in female mice. Hepatology 45:422–432.
  • Uppal, H., Toma, D., Saini, S. P., Ren, S., Jones, T. J., Xie, W. (2005). Combined loss of orphan receptors PXR and CAR heightens sensitivity to toxic bile acids in mice. Hepatology 41:168–176.
  • Urizar, N. L., Dowhan, D. H., Moore, D. D. (2000). The farnesoid X-activated receptor mediates bile acid activation of phospholipid transfer protein gene expression. J Biol Chem 275:39313–39317.
  • Valrance, M. E., Brunet, A. H., Acosta, A., Welsh, J. (2007). Dissociation of growth arrest and CYP24 induction by VDR ligands in mammary tumor cells. J Cell Biochem 101:505–1519.
  • van den Akker, E. L., Koper, J. W., van Rossum, E. F., Dekker, M. J., Russcher, H., de Jong, F. H., et al. (2008). Glucocorticoid receptor gene and risk of cardiovascular disease. Arch Intern Med 168:33–39.
  • van der Vaart, M., Schaaf, M. J. (2009). Naturally occurring C-terminal splice variants of nuclear receptors. Nucl Recept Signal 7:e007.
  • Villey, I., de Chasseval, R., de Villartay, J. P. (1999). RORgammaT, a thymus-specific isoform of the orphan nuclear receptor RORgamma / TOR, is up-regulated by signaling through the pre-T cell receptor and binds to the TEA promoter. Eur J Immunol 29:4072–4080.
  • Wang, H., Chen, J., Hollister, K., Sowers, L. C., Forman, B. M. (1999). Endogenous bile acids are ligands for the nuclear receptor FXR/BAR. Mol Cell 3:543–553.
  • Wang, W., Prosise, W. W., Chen, J., Taremi, S. S., Le, H. V., Madison, V., et al. (2008). Construction and characterization of a fully active PXR/SRC-1 tethered protein with increased stability. Protein Eng Des Sel 21:425–433.
  • Wang, Y., Kumar, N., Solt, L. A., Richardson, T. I., Helvering, L. M., Crumbley, C., et al. (2010). Modulation of retinoic acid receptor-related orphan receptor alpha and gamma activity by 7-oxygenated sterol ligands. J Biol Chem 285:5013–5025.
  • Watkins, R. E., Davis-Searles, P. R., Lambert, M. H., Redinbo, M. R. (2003). Coactivator binding promotes the specific interaction between ligand and the pregnane X receptor. J Mol Biol 331:815–828.
  • Watkins, R. E., Maglich, J. M., Moore, L. B., Wisely, G. B., Noble, S. M., Davis-Searles, P. R., et al. (2003). 2.1 A crystal structure of human PXR in complex with the St. John’s wort compound hyperforin. Biochemistry 42:1430–1438.
  • Watkins, R. E., Wisely, G. B., Moore, L. B., Collins, J. L., Lambert, M. H., Williams, S. P., et al. (2001). The human nuclear xenobiotic receptor PXR: structural determinants of directed promiscuity. Science 292:2329–2333.
  • Waxman, D. J., Azaroff, L. (1992). Phenobarbital induction of cytochrome P-450 gene expression. Biochem J 281:577–592.
  • Wei, P., Zhang, J., Egan-Hafley, M., Liang, S., Moore, D. D. (2000). The nuclear receptor CAR mediates specific xenobiotic induction of drug metabolism. Nature 407:920–923.
  • Weinshilboum, R. M. (2006). Pharmacogenomics: catechol O-methyltransferase to thiopurine S-methyltransferase. Cell Mol Neurobiol 26:539–561.
  • Wells, P. G., Mackenzie, P. I., Chowdhury, J. R., Guillemette, C., Gregory, P. A., Ishii, Y., et al. (2004). Glucuronidation and the UDP-glucuronosyltransferases in health and disease. Drug Metab Dispos 32:281–290.
  • Wiesenberg, I., Missbach, M., Kahlen, J. P., Schräder, M., Carlberg, C. (1995). Transcriptional activation of the nuclear receptor RZR alpha by the pineal gland hormone melatonin and identification of CGP 52608 as a synthetic ligand. Nucleic Acids Res 23:327–333.
  • Willson, T. M., Brown, P. J., Sternbach, D. D., Henke, B. R. (2000). The PPARs: from orphan receptors to drug discovery. J Med Chem 43:527–550.
  • Willy, P. J., Umesono, K., Ong, E. S., Evans, R. M., Heyman, R. A., Mangelsdorf, D. J. (1995). LXR, a nuclear receptor that defines a distinct retinoid response pathway. Genes Dev 9:1033–1045.
  • Windshügel, B., Jyrkkärinne, J., Poso, A., Honkakoski, P., Sippl, W. (2005). Molecular dynamics simulations of the human CAR ligand-binding domain: deciphering the molecular basis for constitutive activity. J Mol Model 11:69–79.
  • Windshügel, B., Jyrkkärinne, J., Vanamo, J., Poso, A., Honkakoski, P., Sippl, W. (2007). Comparison of homology models and X-ray structures of the nuclear receptor CAR: assessing the structural basis of constitutive activity. J Mol Graph Model 25:644–657.
  • Windshügel, B., Poso, A. (2007). Constitutive activity and ligand-dependent activation of the nuclear receptor CAR-insights from molecular dynamics simulations. J Mol Recognit 24:875–882.
  • Wira, C., Munck, A. (1970). Specific glucocorticoid receptors in thymus cells. Localization in the nucleus and extraction of the cortisol-receptor complex. J Biol Chem 245:3436–3438.
  • Xia, J., Kemper, B. (2005). Structural determinants of constitutive androstane receptor required for its glucocorticoid receptor interacting protein-1-mediated nuclear accumulation. J Biol Chem 280:7285–7293.
  • Xia, Z., Correa, R. G., Das, J. K., Farhana, L., Castro, D. J., Yu, J., et al. (2012). Analogues of orphan nuclear receptor small heterodimer partner ligand and apoptosis inducer (E)-4-[3-(1-adamantyl)-4-hydroxyphenyl]-3-chlorocinnamic acid. 2. Impact of 3-chloro group replacement on inhibition of proliferation and induction of apoptosis of leukemia and cancer cell lines. J Med Chem 55:233–249.
  • Xia, Z., Farhana, L., Correa, R. G., Das, J. K., Castro, D. J., Yu, J., et al. (2011). Heteroatom-substituted analogues of orphan nuclear receptor small heterodimer partner ligand and apoptosis inducer (E)-4-[3-(1-Adamantyl)-4-hydroxyphenyl]-3-chlorocinnamic acid. J Med Chem 54:3793–3816.
  • Xie, W., Barwick, J. L., Simon, C. M., Pierce, A. M., Safe, S., Blumberg, B., et al. (2000). Reciprocal activation of xenobiotic response genes by nuclear receptors SXR/PXR and CAR. Genes Dev 14:3014–3023.
  • Xie, W., Evans, R. M. (2001). Orphan nuclear receptors: the exotics of xenobiotics. J Biol Chem 276:37739–37742.
  • Xie, W., Uppal, H., Saini, S. P., Mu, Y., Little, J. M., Radominska-Pandya, A., et al. (2004). Orphan nuclear receptor-mediated xenobiotic regulation in drug metabolism. Drug Discov Today 9:442–449.
  • Xu, C., Wang, X., Staudinger, J. L. (2009). Regulation of tissue-specific carboxylesterase expression by pregnane x receptor and constitutive androstane receptor. Drug Metab Dispos 37:1539–1547.
  • Xu, H. E., Stanley, T. B., Montana, V. G., Lambert, M. H., Shearer, B. G., Cobb, J. E., et al. (2002). Structural basis for antagonist-mediated recruitment of nuclear co-repressors by PPARalpha. Nature 415:813–817.
  • Xu, R. X., Lambert, M. H., Wisely, B. B., Warren, E. M., Weinert, E. E., Waitt, G. M., et al. (2004). A structural basis for constitutive activity in the human CAR/RXRalpha heterodimer. Mol Cell 16:919–928.
  • Xue, Y., Moore, L. B., Orans, J., Peng, L., Bencharit, S., Kliewer, S. A., et al. (2007). Crystal structure of the pregnane X receptor-estradiol complex provides insights into endobiotic recognition. Mol Endocrinol 21:1028–1038.
  • Yanagiba, Y., Ito, Y., Kamijima, M., Gonzalez, F. J., Nakajima, T. (2009). Octachlorostyrene induces cytochrome P450, UDP-glucuronosyltransferase, and sulfotransferase via the aryl hydrocarbon receptor and constitutive androstane receptor. Toxicol Sci 111:19–26.
  • Yu, J., Huang, L., Zhao, A., Metzger, E., Adams, A., Meinke, P. T., et al. (2002). Lithocholic acid decreases expression of bile salt export pump through farnesoid X receptor antagonist activity. J Biol Chem 277:31441–31447.
  • Yueh, M. F., Tukey, R. H. (2007). Nrf2-Keap1 signaling pathway regulates human UGT1A1 expression in vitro and in transgenic UGT1 mice. J Biol Chem 282:8749–8758.
  • Zamek-Gliszczynski, M. J., Hoffmaster, K. A., Nezasa, K., Tallman, M. N., Brouwer, K. L. (2006). Integration of hepatic drug transporters and phase II metabolizing enzymes: mechanisms of hepatic excretion of sulfate, glucuronide, and glutathione metabolites. Eur J Pharm Sci 27:447–486.
  • Zechel, C., X. Shen, X. Q., Chambon, P., Gronemeyer, H. (1994). Dimerization interfaces formed between the DNA binding domains determine the cooperative binding of RXR/RAR and RXR/TR heterodimers to DR5 and DR4 elements. EMBO J 13:1414–1424.
  • Zelcer, N., Hong, C., Boyadjian, R., Tontonoz, P. (2009). LXR regulates cholesterol uptake through Idol-dependent ubiquitination of the LDL receptor. Science 325:100–104.
  • Zelko, I., Negishi, M. (2000). Phenobarbital-elicited activation of nuclear receptor CAR in induction of cytochrome P450 genes. Biochem Biophys Res Commun 277:1–6.
  • Zhang, H., Chen, L., Chen, J., Jiang, H., Shen, X. (2011). Structural basis for retinoic X receptor repression on the tetramer. J Biol Chem 286:24593–24598.
  • Zhang, Q., Bae, Y., Kemper, J. K., Kemper, B. (2006). Analysis of multiple nuclear receptor binding sites for CAR/RXR in the phenobarbital responsive unit of CYP2B2. Arch Biochem Biophys 451:119–127.
  • Zhang, X. Y., Guan, Y. F. (2007). Farnesoid X receptor (FXR): a novel regulative factor involved in metabolism. [Article in Chinese]. Sheng Li Ke Xue Jin Zhan 38:219–223.
  • Zhang, Y., Ge, X., Heemstra, L. A., Chen, W. D., Xu, J., Smith, J. L., et al. (2012). Loss of FXR protects against diet-induced obesity and accelerates liver carcinogenesis in ob/ob mice. Mol Endocrinol 26:272–280.
  • Zhang, Y., Hagedorn, C. H., Wang, L. (2011). Role of nuclear receptor SHP in metabolism and cancer. Biochim Biophys Acta 1812:893–908.
  • Zhong, W., Mirkovitch, J., Darnell, J. E., Jr. (1994). Tissue-specific regulation of mouse hepatocyte nuclear factor 4 expression. Mol Cell Biol 14:7276–7284.
  • Zintzaras, E., Rodopoulou, P., Koukoulis, G. N. (2006). BsmI, TaqI, ApaI and FokI polymorphisms in the vitamin D receptor (VDR) gene and the risk of osteoporosis: a meta-analysis. Dis Markers 22:317–326.

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