Skip to main content
Log in

A Ligand-Based Approach to Understanding Selectivity of Nuclear Hormone Receptors PXR, CAR, FXR, LXRα, and LXRβ

  • Published:
Pharmaceutical Research Aims and scope Submit manuscript

Abstract

In recent years discussion of nuclear hormone receptors, transporters, and drug-metabolizing enzymes has begun to take place as our knowledge of the overlapping ligand specificity of each of these proteins has deepened. This ligand specificity is potentially valuable information for influencing future drug design, as it is important to avoid certain enzymes or transporters in order to circumvent potential drug–drug interactions. Similarly, it is critical that the induction of these same proteins via nuclear hormone receptors is avoided, as this can result in further toxicities. Using a ligand-based approach in this review we describe new and previously published computational models for PXR, CAR, FXR, LXRα, and LXRβ that may help in understanding the complexity of interactions between transporters and enzymes. The value of these types of models is that they may enable us to design molecules to selectively modulate pathways for therapeutic effect and in addition predict the potential for drug interactions more reliably. Simultaneously, we might learn which came first: the transporter, the enzyme, or the nuclear hormone receptor?

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

REFERENCES

  1. D. R. Nelson, L. Koymans, T. Kamataki, J. J. Stegeman, R. Feyereisen, D. J. Waxman, M. R. Waterman, O. Gotoh, M. J. Coon, R. W. Estabrook, I. C. Gunsalus, and D. W. Nebert. P450 superfamily: update on new sequences, gene mapping, accession numbers and nomenclature. Pharmacogenetics 6:1–42 (1996).

    Google Scholar 

  2. R. Kim, M. F. Fromm, C. Wandel, B. Leake, A. J. Wood, D. M. Roden, and G. R. Wilkinson. The drug transporter Pglycoprotein limits oral absorption and brain entry of HIV-1 protease inhibitors. J. Clin. Invest. 101:289–294 (1998).

    Google Scholar 

  3. R. B. Kim, C. Wandel, B. Leake, M. Cvetkovic, M. F. Fromm, P. J. Dempsey, M. M. Roden, F. Belas, A. K. Chaudhary, D. M. Roden, A. J. J. Wood, and G. R. Wilkinson. Interrelationship between substrates and inhibitiors of human CYP3A and Pglycoprotein. Pharm. Res. 16:408–414 (1999).

    Google Scholar 

  4. E. G. Scheutz, W. T. Beck, and J. D. Scheutz. Modulators and substrates of P-glycoprotein and cytochrome P4503A coordinately up-regulate these proteins in human colon carcinoma cells. Mol. Pharmacol. 49:311–318 (1996).

    Google Scholar 

  5. E. G. Schuetz, A. H. Schinkel, M. V. Relling, and J. D. Schuetz. P-glycoprotein: A major determinant of rifampicin-inducible expression of cytochrome P4503A in mice and humans. Proc. Natl. Acad. Sci. USA 93:4001–4005 (1996).

    Google Scholar 

  6. V. J. Wacher, C. Y. Wu, and L. Z. Benet. Overlapping substrate specificities and tissue distribution of cytochrome P450 3A and Selectivity of Nuclear Hormone Receptors 1797 P-glycoprotein: implications for drug delivery and activity in cancer chemotherapy. Mol. Carcinogen. 13:129–134 (1995).

    Google Scholar 

  7. M. F. Paine, M. Khalighi, J. M. Fisher, D. D. Shen, K. L. Kunze, C. L. Marsh, J. D. Perkins, and K. E. Thummel. Characterization of interintestinal and intraintestinal variations in human CYP3A-dependent metabolism. J. Pharmacol. Exp. Ther. 283: 1552–1562 (1997).

    Google Scholar 

  8. J. Grober, I. Zaghini, H. Fujii, S. A. Jones, S. A. Kliewer, T. M. Willson, T. Ono, and P. Besnard. Identification of a bile acidresponsive element in the human ileal bile acid-binding protein gene. Involvement of the farnesoid X receptor/9-cis-retinoic acid receptor heterodimer. J. Biol. Chem. 274:29749–29754 (1999).

    Google Scholar 

  9. M. Makishima, A. Y. Okamoto, J. J. Repa, H. Tu, R. M. Learned, A. Luk, M. V. Hull, K. D. Lustig, D. J. Mangelsdorf, and B. Shan. Identification of a nuclear receptor for bile acids. Science 284:1362–1365 (1999).

    Google Scholar 

  10. D. J. Parks, S. G. Blanchard, R. K. Bledsoe, G. Chandra, T. G. Consler, S. A. Kliewer, J. B. Stimmel, T. M. Willson, A. M. Zavacki, D. D. Moore, and J. M. Lehmann. Bile acids: natural ligands for an orphan nuclear receptor. Science 284:1365–1368 (1999).

    Google Scholar 

  11. E. Y. Zhang, M. A. Phelps, C. Cheng, S. Ekins, and P. W. Swaan. Modeling of active transport systems. Adv. Drug Deliv. Rev. 54:329–354 (2002).

    Google Scholar 

  12. A. R. Tall, N. Wang, and P. Mucksavage. Is it time to modify the reverse cholesterol transport model? J. Clin. Invest. 108:1273–1275 (2001).

    Google Scholar 

  13. D. W. Russell. Nuclear orphan receptors control cholesterol catabolism. Cell 97:539–542 (1999).

    Google Scholar 

  14. J. T. Moore and S. A. Kliewer. Use of the nuclear receptor PXR to predict drug interactions. Toxicology 153:1–10 (2000).

    Google Scholar 

  15. B. Blumberg and R. M. Evans. Orphan nuclear receptors-new ligands and new possibilities. Genes Dev. 12:3149–3155 (1998).

    Google Scholar 

  16. D. J. Waxman. P450 gene induction by structurally diverse xenochemicals: central role of nuclear receptors CAR, PXR, and PPAR. Arch. Biochem. Biophys. 369:11–23 (1999).

    Google Scholar 

  17. W. Xie and R. M. Evans. Orphan nuclear receptors: the exotics of xenobiotics. J. Biol. Chem. 276:37739–37742 (2001).

    Google Scholar 

  18. P. A. Edwards, H. R. Kast, and A. M. Anisfeld. BAREing it all. The adoption of lxr and fxr and their roles in lipid homeostasis. J. Lipid Res. 43:2–12 (2002).

    Google Scholar 

  19. A. Chawla, J. J. Repa, R. M. Evans, and D. J. Manglesdorf. Nuclear receptors and lipid physiology: opening the X-files. Science 294:1866–1870 (2001).

    Google Scholar 

  20. S. A. Kliewer, J. M. Lehmann, and T. M. Willson. Orphan nuclear receptors: shifting endocrinology into reverse. Science 284:757–760 (1999).

    Google Scholar 

  21. S. A. Kliewer and T. M. Willson. Regulation of xenobiotic and bile acid metabolism by the nuclear pregnane X receptor. J. Lipid Res. 43:359–364 (2002).

    Google Scholar 

  22. Y. Zhang and D. J. Mangelsdorf. LuXuRies of Lipid Homeostasis. Mol. Intervent. 2:78–87 (2002).

    Google Scholar 

  23. S. Ekins, B. J. Ring, G. Bravi, J. H. Wikel, and S. A. Wrighton. Predicting drug-drug interactions in silico using pharmacophores: A paradigm for the next millenium. In O. F. Guner (ed.), Pharmacophore, Perception, Development, and Use in Drug Design, University International Line, San Diego, California, 2000, pp. 269–299.

    Google Scholar 

  24. S. Ekins, C. L. Waller, P. W. Swaan, G. Cruciani, S. A. Wrighton, and J. H. Wikel. Progress in predicting human ADME parameters in silico. J. Pharmcol. Toxicol. Methods 44:251–272 (2000).

    Google Scholar 

  25. S. A. Wrighton, E. G. Schuetz, K. E. Thummel, D. D. Shen, K. R. Korzekwa, and P. B. Watkins. The human CYP3A subfamily: practical considerations. Drug Metab. Rev. 32:339–361 (2000).

    Google Scholar 

  26. S. Ekins, G. Bravi, J. H. Wikel, and S. A. Wrighton. Three dimensional quantitative structure activty relationship (3DQSAR) analysis of CYP3A4 substrates. J. Pharmacol. Exp. Ther. 291:424–433 (1999).

    Google Scholar 

  27. S. Ekins, G. Bravi, S. Binkley, J. S. Gillespie, B. J. Ring, J. H. Wikel, and S. A. Wrighton. Three dimensional-quantitative structure activity relationship (3D-QSAR) analyses of inhibitors for CYP3A4. J. Pharmacol. Exp. Ther. 290:429–438 (1999).

    Google Scholar 

  28. P. Kuehl, J. Zhang, Y. Lin, J. Lamba, M. Assem, J. Schuetz, P. B. Watkins, A. Daly, S. A. Wrighton, S. D. Hall, P. Maurel, M. Relling, C. Brimer, K. Yasuda, R. Venkataramanan, S. Strom, K. Thummel, M. S. Boguski, and E. Schuetz. Sequence diversity in CYP3A promotors and characterization of the genetic basis of polymorphic CYP3A5 expression. Nature Genet. 27:383–391 (2001).

    Google Scholar 

  29. F. Ruschitzka, P. J. Meier, M. Turina, T. F. Luscher, and G. Noll. Acute heart transplant rejection due to Saint John's wort. Lancet 355:548–549 (2000).

    Google Scholar 

  30. S. C. Piscatelli, A. H. Burstein, D. Chaitt, R. M. Alfaro, and J. Falloon. Indinavir concentrations and St. John's wort. Lancet 355:547–548 (2000).

    Google Scholar 

  31. E. A. Rekka and P. N. Kourounakis. An approach to QSAR of 16-substituted pregnenolones as microsomal enzyme inducers. Eur. J. Drug Metab. Pharmacokinet. 21:7–11 (1996).

    Google Scholar 

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

    Google Scholar 

  33. B. Blumberg, W. J. Sabbagh, H. Juguilon, J. J. Bolado, C. M. van Meter, E. S. Ong, and R. M. Evans. SXR, a novel steroid and xenobiotic-sensing nuclear receptor. Genes Dev. 12:3195–3205 (1998).

    Google Scholar 

  34. S. A. Kliewer, J. T. Moore, L. Wade, J. L. Staudinger, M. A. Watson, S. A. Jones, D. D. McKee, B. B. Oliver, T. M. Willson, R. H. Zetterstrom, T. Perlmann, and J. M. Lehmann. An orphan nuclear receptor activated by pregnanes defines a novel steroid signaling pathway. Cell 92:73–82 (1998).

    Google Scholar 

  35. T. W. Synold, I. Dussault, and B. M. Forman. The orphan nuclear receptor SXR coordinately regulates drug metabolism and efflux. Nature Med. 7:584–590 (2001).

    Google Scholar 

  36. E. Schuetz and S. Strom. Promiscuous regulator of xenobiotic removal. Nature Med. 7:536–537 (2001).

    Google Scholar 

  37. J. Zhang, P. Kuehl, E. D. Green, J. W. Touchman, P. B. Watkins, A. Daly, S. D. Hall, P. Maurel, M. Relling, C. Brimer, K. Yasuda, S. A. Wrighton, M. Hancock, R. B. Kim, S. Strom, K. Thummel, C. G. Russell, J. R. Hudson Jr., E. G. Schuetz, and M. S. Boguski. The human pregnane X receptor: genomic structure and identification and functional characterization of natural allelic variants. Pharmacogenetics 11:555–572 (2001).

    Google Scholar 

  38. B. M. Forman. Polymorphisms in promiscuous PXR: an explanation for interindividual differences in drug clearance? Pharmacogenetics 11:551–552 (2001).

    Google Scholar 

  39. J. L. Staudinger, B. Goodwin, S. A. Jones, D. Hawkins-Brown, K. I. Mackenzie, A. LaTour, Y. Liu, C. D. Klaassen, K. K. Brown, J. Reinhard, T. M. Willson, B. H. Koller, and S. A. Kliewer. The nuclear receptor PXR is a lithocholic acid sensor that protects against liver toxicity. Proc. Natl. Acad. Sci. USA 98:3369–3374 (2001).

    Google Scholar 

  40. R. E. Watkins, G. B. Wisely, L. B. Moore, J. L. Collins, M. H. Lambert, S. P. Williams, T. M. Willson, S. A. Kliewer, and M. R. Redinbo. The human nuclear xenobiotic receptor PXR: structural determinants of directed promiscuity. Science 292:2329–2333 (2001).

    Google Scholar 

  41. W. Xie, J. L. Barwick, M. Downes, B. Blumberg, C. M. Simon, M. C. Nelson, B. A. Neuschwander-Tetri, E. M. Brunt, P. S. Guzelian, and R. M. Evans. Humanized xenobiotic response in mice expressing nuclear receptor SXR. Nature 406:435–439 (2000).

    Google Scholar 

  42. J. Staudinger, Y. Liu, A. Madan, S. Habeebu, and C. D. Klaassen. Coordinate regulation of xenobiotic and bile acid homeostasis by pregnane X receptor. Drug Metab. Dispos. 29:1467–1472 (2001).

    Google Scholar 

  43. W. El-Sankary, G. G. Gibson, A. Ayrton, and N. Plant. Use of a reporter gene assay to predict and rank the potency and efficacy of CYP3A4 inducers. Drug Metab. Dispos. 29:1499–1504 (2001).

    Google Scholar 

  44. J. M. Wentworth, M. Agostini, J. Love, J. W. Schwabe, and V. K. Chatterjee. St. John's wort, a herbal antidepressant, activates the steroid X receptor. J. Endocrinol. 166:R11–R16 (2000).

    Google Scholar 

  45. L. B. Moore, B. Goodwin, S. A. Jones, G. B. Wisely, C. J. Serabijt-Singh, T. M. Willson, J. L. Collins, and S. A. Kliewer. St. John's wort induces hepatic drug metabolism through acti-Ekins, Mirny, and Schuetz 1798 vation of the pregnane X receptor. Proc. Natl. Acad. Sci. USA 97:7500–7502 (2000).

    Google Scholar 

  46. I. Dussault, M. Lin, K. Hollister, E. H. Wang, T. W. Synold, and B. M. Forman. Peptide mimetic HIV protease inhibitors are ligands for the orphan receptor SXR. J. Biol. Chem. 276:33309–33312 (2001).

    Google Scholar 

  47. L. Drocourt, J. M. Pascussi, E. Assenat, J. M. Fabre, P. Maurel, and M. J. Vilarem. Calcium channel modulators of the dihydropyridine family are human pregnane X receptor activators and inducers of CYP3A, CYP2B, and CYP2C in human hepatocytes. Drug Metab. Dispos. 29:1325–1331 (2001).

    Google Scholar 

  48. L. B. Moore, D. J. Parks, S. A. Jones, R. K. Bledsoe, T. G. Consler, J. B. Stimmel, B. Goodwin, C. Liddle, S. G. Blanchard, T. M. Willson, J. L. Collins, and S. A. Kliewer. Orphan nuclear receptors constitutive androstane receptor and pregnane X receptor share xenobiotic and steroid ligands. J. Biol. Chem. 275: 15122–15127 (2000).

    Google Scholar 

  49. A. Takeshita, N. Koibuchi, J. Oka, M. Taguchi, Y. Shishiba, and Y. Ozawa. Bisphenol-A, an environmental estrogen, activates the human orphan nuclear receptor, steroid and xenobiotic receptor-mediated transcription. Eur. J. Endocrinol. 145:513–517 (2001).

    Google Scholar 

  50. H. Masuyama, H. Inoshita, Y. Hiramatsu, and T. Kudo. Ligands have various potential effects on the degradation of pregnane X receptor by proteasome. Endocrinology 143:55–61 (2002).

    Google Scholar 

  51. H. Masuyama, Y. Hiramatsu, M. Kunitomi, T. Kudo, and P. N. MacDonald. Endocrine disrupting chemicals, phthalic acid and nonylphenol, activate pregnane X receptor-mediated transcription. Mol. Endocrinol. 14:421–428 (2000).

    Google Scholar 

  52. S. Ekins and J. A. Erickson. A pharmacophore for human pregnane X receptor ligands. Drug Metab. Dispos. 30:96–99 (2002).

    Google Scholar 

  53. S. A. Kliewer, J. T. Moore, L. Wade, J. L. Staudinger, M. A. Watson, S. A. Jones, D. D. McKee, B. B. Oliver, T. M. Willson, R. H. Zetterstrom, T. Perlmann, and J. M. Lehmann. An orphan nuclear receptor activated by pregnanes defines a novel steroid signaling pathway. Cell 92:73–82 (1998).

    Google Scholar 

  54. J. M. Lehmann, D. D. McKee, M. A. Watson, T. M. Willson, J. T. Moore, and S. A. Kliewer. 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 (1998).

    Google Scholar 

  55. R. E. Watkins, S. M. Noble, and M. R. Redinbo. Structural insights into the promiscuity and function of the human pregnane X receptor. Curr. Opin. Drug Discov. Dev. 5:150–158 (2002).

    Google Scholar 

  56. S. Ekins, M. de Groot, and J. P. Jones. Pharmacophore and three dimensional quantitative structure activity relationship methods for modeling cytochrome P450 active sites. Drug Metab. Dispos. 29:936–944 (2001).

    Google Scholar 

  57. S. Ekins, R. B. Kim, B. F. Leake, A. H. Dantzig, E. Schuetz, L.-B. Lan, K. Yasuda, R. L. Shepard, M. A. Winter, J. D. Schuetz, J. H. Wikel, and S. A. Wrighton. Application of three dimensional quantitative structure-activity relationships of P-glycoprotein inhibitors and substrates. Mol. Pharmacol. 61:974–981 (2002).

    Google Scholar 

  58. S. Ekins, R. B. Kim, B. F. Leake, A. H. Dantzig, E. Schuetz, L.-B. Lan, K. Yasuda, R. L. Shepard, M. A. Winter, J. D. Schuetz, J. H. Wikel, and S. A. Wrighton. Three dimensional quantitative structure-activity relationships of inhibitors of P-glycoprotein. Mol. Pharmacol. 61:964–973 (2002).

    Google Scholar 

  59. K. R. Korzekwa, N. Krishnamachary, M. Shou, A. Ogai, R. A. Parise, A. E. Rettie, and F. J. Gonzalez. Evaluation of atypical cytochrome P450 kinetics with two-substrate-models: evidence that multiple substrates can simultaneously bind to cytochrome P450 active sites. Biochemistry 37:4137–4147 (1998).

    Google Scholar 

  60. S. Ekins, B. J. Ring, S. N. Binkley, S. D. Hall, and S. A. Wrighton. Autoactivation and activation of cytochrome P450s. Int. J. Clin. Pharmacol. Ther. 36:642–651 (1998).

    Google Scholar 

  61. C. Martin, G. Berridge, C. F. Higgins, P. Mistry, P. Charlton, and R. Callaghan. Communication between multiple drug binding sites on P-glycoprotein. Mol. Pharmacol. 58:624–632 (2000).

    Google Scholar 

  62. S. Ekins and S. A. Wrighton. The role of CYP2B6 in human xenobiotic metabolism. Drug Metab. Rev. 31:719–754 (1999).

    Google Scholar 

  63. B. Goodwin, L. B. Moore, C. M. Stoltz, D. D. McKee, and S. A. Kliewer. Regulation of the human CYP2B6 gene by the nuclear pregnane X receptor. Mol. Pharmacol. 60:427–431 (2001).

    Google Scholar 

  64. B. E. Daikh, J. M. Lasker, J. L. Raucy, and D. R. Koop. Regioand stereoselective epoxidation of arachidonic acid by human cytochromes P450 2C8 and 2C9. J. Pharmacol. Exp. Ther. 271: 1427–1433 (1994).

    Google Scholar 

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

    Google Scholar 

  66. H. M. Kauffmann, S. Pfannschmidt, H. Zoller, A. Benz, B. Vorderstemann, J. I. Webster, and D. Schrenk. Influence of redox-active compounds and PXR-activators on human MRP1 and MRP2 gene expression. Toxicology 171:137–146 (2002).

    Google Scholar 

  67. A. Toell, K. D. Kroncke, H. Kleinert, and C. Carlberg. Orphan nuclear receptor binding site in the human inducible nitric oxide synthase promoter mediates responsiveness to steroid and xenobiotic ligands. J. Cell. Biochem. 85:72–82 (2002).

    Google Scholar 

  68. S. A. Jones, L. B. Moore, J. L. Shenk, G. B. Wisely, G. A. Hamilton, D. D. McKee, N. C. Tomkinson, E. L. LeCluyse, M. H. Lambert, T. M. Willson, S. A. Kliewer, and J. T. Moore. The pregnane X receptor: A promiscuous xenobiotic receptor that has diverged during evolution. Mol. Endocrinol. 14:27–39 (2000).

    Google Scholar 

  69. G. I. Murray, W. T. Melvin, W. F. Greenlee, and M. D. Burke. Regulation, function, and tissue-specific expression of cytochrome P450 CYP1B1. Annu. Rev. Pharmacol. Toxicol. 41:297–316 (2001).

    Google Scholar 

  70. I. Stoilov. Cytochrome P450s: coupling development and environment. Trends Genet. 17:629–632 (2001).

    Google Scholar 

  71. B. M. Forman, I. Tzameli, H. S. Choi, J. Chen, D. Simha, W. Seol, R. M. Evans, and D. D. Moore. Androstane metabolites bind to and deactivate the nuclear receptor CAR-beta. Nature 395:612–615 (1998).

    Google Scholar 

  72. D. Picard. Two orphans find a home. Nature 395:543–544 (1998).

    Google Scholar 

  73. I. Zelko and M. Negishi. Phenobarbital-elicited activation of nuclear receptor CAR in induction of cytochrome P450 genes. Biochem. Biophys. Res. Commun. 277:1–6 (2000).

    Google Scholar 

  74. T. Sueyoshi, T. Kawamato, I. Zelko, P. Honkakoski, and M. Negishi. The repressed nuclear receptor CAR responds to Phenobarbital in activating the Human CYP2B6 gene. J. Biol. Chem. 274:6043–6046 (1999).

    Google Scholar 

  75. P. Honkakoski, I. Jaaskelainen, M. Kortelahti, and A. Urtti. A novel drug-regulated gene expression system based on the nuclear receptor constitutive androstane receptor (CAR). Pharm. Res. 18:146–150 (2001).

    Google Scholar 

  76. P. Wei, J. Zhang, M. Egan-Hafley, S. Liang, and D. D. Moore. The nuclear receptor CAR mediates specific xenobiotic induction of drug metabolism. Nature 407:920–923 (2000).

    Google Scholar 

  77. E. L. LeCluyse. Pregnane X receptor: molecular basis for species differences in CYP3A induction by xenobiotics. Chem. Biol. Interact. 134:283–289 (2001).

    Google Scholar 

  78. I. Tzameli and D. D. Moore. Role reversal: new insights from new ligands for the xenobiotic receptor CAR. Trends Endocrinol. Metab. 12:7–10 (2001).

    Google Scholar 

  79. P. Honkakoski, I. Zelko, T. Sueyoshi, and M. Negishi. The nuclear orphan receptor CAR-retinoid x receptor heterodimer activates the phenobarbital-responsive enhancer module of the CYP2B gene. Mol. Cell Biol. 18:5652–5658 (1998).

    Google Scholar 

  80. S. Ekins, G. Bravi, B. J. Ring, T. A. Gillespie, J. S. Gillespie, M. VandenBranden, S. A. Wrighton, and J. H. Wikel. Three dimensional-quantitative structure activity relationship (3DQSAR) analyses of substrates for CYP2B6. J. Pharmacol. Exp. Ther. 288:21–29 (1999).

    Google Scholar 

  81. S. Ekins and E. Schuetz. The PXR crystal structure: the end of the beginning. Trends Pharmacol. Sci. 23:49–50 (2002).

    Google Scholar 

  82. J. M. Pascussi, L. Drocourt, J. M. Fabre, P. Maurel, and M. J. Vilarem. 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 (2000).

    Google Scholar 

  83. J. M. Pascussi, S. Gerbal-Chaloin, J. M. Fabre, P. Maurel, and M. J. Vilarem. Dexamethasone enhances constitutive androstane receptor expression in human hepatocytes: consequences on cytochrome P450 gene regulation. Mol. Pharmacol. 58:1441–1450 (2000).

    Google Scholar 

  84. J. M. Pascussi, L. Drocourt, S. Gerbal-Chaloin, J. M. Fabre, P. Maurel, and M. J. Vilarem. Dual effect of dexamethasone on CYP3A4 gene expression in human hepatocytes. Sequential role of glucocorticoid receptor and pregnane X receptor. Eur. J. Biochem. 268:6346–6358 (2001).

    Google Scholar 

  85. W. Xie, J. L. Barwick, C. D. Simon, A. M. Pierce, S. Safe, B. Blumberg, P. S. Guzelian, and R. M. Evans. Reciprocal activation of xenobiotic response genes by nuclear receptors SXR/ PXR and CAR. Genes Dev. 14:3014–3023 (2000).

    Google Scholar 

  86. P. W. Swaan, F. C. J. Szoka, and S. Oie. Molecular modeling of the intestinal bile acid carrier: a comparative molecular field analysis study. J. Comput. Aided Mol. Des. 11:581–588 (1997).

    Google Scholar 

  87. K. H. Baringhaus, H. Matter, S. Stenglin, and W. Kramer. Substrate specificity of the ileal and the hepatic Na(+)/bile acid cotransporters of the rabbit. II. A reliable 3D QSAR pharmacophore model for the ileal Na(+)/bile acid cotransporter. J. Lipid Res. 40:2158–2168 (1999).

    Google Scholar 

  88. M. Ananthanarayanan, N. Balasubramanian, M. Makishima, D. J. Mangelsdorf, and F. J. Suchy. Human bile salt export pump promoter is transactivated by the farnesoid X receptor/bile acid receptor. J. Biol. Chem. 276:28857–28865 (2001).

    Google Scholar 

  89. E. G. Schuetz, S. Strom, K. Yasuda, V. Lecureur, M. Assem, C. Brimer, J. Lamba, R. B. Kim, V. Ramachandran, B. J. Komoroski, R. Venkataramanan, H. Cai, C. J. Sinal, F. J. Gonzalez, and J. D. Schuetz. Disrupted bile acid homeostasis reveals an unexpected interaction among nuclear hormone receptors, transporters, and cytcochrome P450. J. Biol. Chem. 276:39411–39418 (2001).

    Google Scholar 

  90. R. B. Kim, B. Leake, M. Cvetkovic, M. M. Roden, J. Nadeau, A. Walubo, and G. R. Wilkinson. Modulation by drugs of human hepatic sodium-dependent bile acid transporter (sodium taurocholate cotransporting polypeptide) activity. J. Pharmacol. Exp. Ther. 291:1204–1209 (1999).

    Google Scholar 

  91. N. L. Urizar, A. B. Liverman, D. T. Dodds, F. V. Silva, P. Ordentlich, Y. Yan, F. J. Gonzalez, R. A. Heyman, D. J. Mangelsdorf, and D. D. Moore. A natural product that lowers cholesterol as an antagonist ligand for FXR. Science 296:1703–1706 (2002).

    Google Scholar 

  92. P. J. Willy, K. Umesono, E. S. Ong, R. M. Evans, R. A. Heyman, and D. J. Mangelsdorf. LXR, a nuclear receptor that defines a distinct retinoid response pathway. Genes Dev. 9:1033–1045 (1995).

    Google Scholar 

  93. B. A. Janowski, P. J. Willy, T. R. Devi, J. R. Falck, and D. J. Mangelsdorf. An oxysterol signalling pathway mediated by the nuclear receptor LXR alpha. Nature 383:728–731 (1996).

    Google Scholar 

  94. J. M. Lehmann, S. A. Kliewer, L. B. Moore, T. A. Smith-Oliver, B. B. Oliver, J. L. Su, S. S. Sundseth, D. A. Winegar, D. E. Blanchard, T. A. Spencer, and T. M. Willson. Activation of the nuclear receptor LXR by oxysterols defines a new hormone response pathway. J. Biol. Chem. 272:3137–3140 (1997).

    Google Scholar 

  95. X. Fu, J. G. Menke, Y. Chen, G. Zhou, K. L. MacNaul, S. D. Wright, C. P. Sparrow and E. G. Lund. 27-Hydroxycholesterol is an endogenous ligand for the liver X receptor in cholesterolloaded cells. J. Biol. Chem. 276:38378–38387 (2001).

    Google Scholar 

  96. B. A. Janowski, M. J. Grogan, S. A. Jones, G. B. Wisely, S. A. Kliewer, E. J. Corey, and D. J. Mangelsdorf. Structural requirements of ligands for the oxysterol liver X receptors LXRalpha and LXRbeta. Proc. Natl. Acad. Sci. USA 96:266–271 (1999).

    Google Scholar 

  97. T. A. Spencer, D. Li, J. S. Russel, J. L. Collins, R. K. Bledsoe, T. G. Consler, L. B. Moore, C. M. Galaradi, D. D. McKee, J. T. Moore, M. A. Watson, D. J. Parks, M. H. Lambert, and T. M. Willson. Pharmacophore analysis of the nuclear oxysterol receptor LXR?. J. Med. Chem. 44:886–897 (2001).

    Google Scholar 

  98. J. L. Collins, A. M. Fivush, M. A. Watson, C. M. Galardi, C. L. Michael, L. B. Moore, D. J. Parks, J. G. Wilson, T. K. Tippin, J. G. Binz, K. D. Plunkett, D. G. Morgan, E. J. Beaudet, K. D. Whitney, S. A. Kliewer, and T. M. Willson. Identification of a nonsteroidal liver X receptor agonist through parallel array synthesis of tertiary amines. J. Med. Chem. 45:1963–1966 (2002).

    Google Scholar 

  99. J. J. Repa, S. D. Turley, J. A. Lobaccaro, J. Medina, L. Li, K. Lustig, B. Shan, R. A. Heyman, J. M. Dietschy, and D. J. Mangelsdorf. Regulation of absorption and ABC1-mediated efflux of cholesterol by RXR heterodimers. Science 289:1524–1529 (2000).

    Google Scholar 

  100. P. Costet, Y. Luo, N. Wang, and A. R. Tall. Sterol-dependent transactivation of the ABC1 promoter by the liver X receptor/retinoid X receptor. J. Biol. Chem. 275:28240–28245 (2000).

    Google Scholar 

  101. M. A. Kennedy, A. Venkateswaran, P. T. Tarr, I. Xenarios, J. Kudo, H. N. Shimizu, and P. A. Edwards. Characterization of the human ABCG1 gene: liver X receptor activates an internal promoter that produces a novel transcript encoding an alternative form of the protein. J. Biol. Chem. 276:39438–39447 (2001).

    Google Scholar 

  102. A. Venkateswaran, J. J. Repa, J. M. Lobaccaro, A. Bronson, D. J. Mangelsdorf, and P. A. Edwards. Human white/murine ABC8 mRNA levels are highly induced in lipid-loaded macrophages. A transcriptional role for specific oxysterols. J. Biol. Chem. 275: 14700–14707 (2000).

    Google Scholar 

  103. K. E. Berge, H. Tian, G. A. Graf, L. Yu, N. V. Grishin, J. Schultz, P. Kwiterovich, B. Shan, R. Barnes, and H. H. Hobbs. Accumulation of dietary cholesterol in sitosterolemia caused by mutations in adjacent ABC transporters. Science 290:1771–1775 (2000).

    Google Scholar 

  104. J. J. Repa, K. E. Berge, C. Pomajke, J. A. Richarardson, H. Hobbs, and D. J. Mangelsdorf. Regulation of ATP-binding cassette sterol transporters, ABCG5 and ABCG8, by the oxysterol receptors J. Biol. Chem. (2002).

  105. H. R. Kast, B. Goodwin, P. T. Tarr, S. A. Jones, A. M. Anisfeld, C. M. Stoltz, P. Tontonoz, S. Kliewer, T. M. Willson, and P. A. Edwards. 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 (2002).

    Google Scholar 

  106. H. H. Bock and F. Lammert. Nuclear xeno-sensors as receptors for cholestatic bile acids: the second line of defense. Hepatology 35:232–234 (2002).

    Google Scholar 

  107. M. Makishima, T. T. Lu, W. Xie, G. K. Whitfield, H. Domoto, R. M. Evans, M. R. Haussler, and D. J. Manglesdorf. Vitamin D receptor as an intestinal bile acid sensor. Science 296:1313–1316 (2002).

    Google Scholar 

  108. L. Drocourt, J. C. Ourlin, J. M. Pascussi, P. Maurel, and M. J. Vilarem. Expression of CYP3A4, CYP2B6 and CYP2C9 is regulated by the vitamin D receptor pathway in primary human hepatocytes. J. Biol. Chem. (2002).

  109. K. Yamamoto, H. Masuno, M. Choi, K. Nakashima, T. Taga, H. Ooizumi, K. Umesono, W. Sicinska, J. VanHooke, H. F. De-Luca, and S. Yamada. Three dimensional modeling of and ligand docking to vitamin D receptor ligand binding domain. Proc. Natl. Acad. Sci. USA 97:1467–1472 (2000).

    Google Scholar 

  110. G. Tocchini-Valenti, N. Roche, J. M. Wurtz, A. Mitschler, and D. Moras. Crystal structures of the vitamin D receptor complexed to superagonist 20-epi ligands. Proc. Natl. Acad. Sci. USA 98:5491–5496 (2001).

    Google Scholar 

  111. R. E. Ostlund Jr., S. B. Racette, A. Okeke, and W. F. Stenson. Phytosterols that are naturally present in commercial corn oil significantly reduce cholesterol absorption in humans. Am. J. Clin. Nutr. 75:1000–1004 (2002).

    Google Scholar 

  112. R. Kaaks. Nutrition, hormones, and breast cancer: is insulin the missing link? Cancer Causes Control 7:605–625 (1996).

    Google Scholar 

  113. Y. M. Mu, T. Yanase, Y. Nishi, N. Waseda, T. Oda, A. Tanaka, R. Takayanagi, and H. Nawata. Insulin sensitizer, troglitazone, directly inhibits aromatase in human ovarian granulosa cells. Biochem. Biophys. Res. Commun. 271:710–713 (2000).

    Google Scholar 

  114. S. Ekins, B. Boulanger, P. W. Swaan, and M. A. Z. Hupcey. Towards a new age of virtual ADME/TOX and multidimensional drug discovery. J. Computer Aided Mol. Des. (in press).

  115. N. P. Brown, C. Leroy, and C. Sander. MView: a web-compatible database search or multiple alignment viewer. Bioinformatics 14:380–381 (1998).

    Google Scholar 

  116. D. G. Higgins, J. D. Thompson, and T. J. Gibson. Using CLUSTAL for multiple sequence alignments. Methods Enzymol. 266:383–402 (1996).

    Google Scholar 

  117. J. D. Retief. Phylogenetic analysis using PHYLIP. Methods Mol. Biol. 132:243–258 (2000).

    Google Scholar 

  118. T. Schwede, A. Diemand, N. Guex, and M. C. Peitsch. Protein structure computing in the genomic era. Res. Microbiol. 151: 107–112 (2000).

    Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Rights and permissions

Reprints and permissions

About this article

Cite this article

Ekins, S., Mirny, L. & Schuetz, E.G. A Ligand-Based Approach to Understanding Selectivity of Nuclear Hormone Receptors PXR, CAR, FXR, LXRα, and LXRβ. Pharm Res 19, 1788–1800 (2002). https://doi.org/10.1023/A:1021429105173

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1023/A:1021429105173

Navigation