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Constitutive androstane receptor (CAR) is a xenosensor and target for therapy

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Abstract

Constitutive androstane receptor (CAR, NR1I3), which is under consideration in this review, is a member of the superfamily of nuclear receptors. However, certain features distinguish CAR from the variety of nuclear receptors. First, this receptor has structural features that allow it to display constitutive activity in the absence of a ligand and to interact in a species-specific manner with a huge number of ligands diverse in chemical structure and origin. Second, recently many researchers are focused on CAR because the significance is increasingly shown of its influence on a variety of physiological functions, such as gluconeogenesis, metabolism of xenobiotics, fatty acids, bilirubin, and bile acids, hormonal regulation, etc. In addition to the fundamental scientific interest, the study of CAR is of practical importance because changes in CAR activity can lead to disorders in physiological processes, which finally can result in changes in pathological states. However, despite intensive studies, many mechanisms are still unclear, which makes it difficult to understand the role of CAR in the overall picture of molecular regulation of physiological processes. This review analyzes the features and diversity of the functions of CAR.

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Abbreviations

CAR:

constitutive androstane receptor

DBD:

DNA-binding domain

LBD:

ligand-binding domain

NR:

nuclear receptor

PB:

phenobarbital

RXR:

retinoic acid receptor

SRC:

steroid receptor coactivator

XRE:

xenobiotic-responsive element

References

  1. Committee Nuclear Receptors Nomenclature (1999) Cell, 97, 161–163.

    Article  Google Scholar 

  2. Sonoda, J., Pei, L., and Evans, R. (2008) FEBS Lett., 582, 2–9.

    Article  PubMed  CAS  Google Scholar 

  3. Wei, P., Zhang, J., Egan-Hafley, M., Liang, S., and Moore, D. (2000) Nature, 407, 920–923.

    Article  PubMed  CAS  Google Scholar 

  4. Ueda, A., Hamadeh, H. K., Webb, H. K., Yamamoto, Y., Sueyoshi, T., Afshari, C. A., Lehmann, J. M., and Negishi, M. (2002) Mol. Pharmacol., 61, 1–6.

    Article  PubMed  CAS  Google Scholar 

  5. Kassam, A., Winrow, C. J., Fernandez-Rachubinski, F., Capone, J. P., and Rachubinski, R. A. (2000) J. Biol. Chem., 275, 4345–4350.

    Article  PubMed  CAS  Google Scholar 

  6. Sugatani, J., Yamakawa, K., Yoshinari, K., Machida, T., Takagi, H., Mori, M., Kakizaki, S., Sueyoshi, T., Negishi, M., and Miwa, M. (2002) Biochem. Biophys. Res. Commun., 292, 492–497.

    Article  PubMed  CAS  Google Scholar 

  7. Eloranta, J. J., and Kullak-Ublick, G. A. (2005) Arch. Biochem. Biophys., 433, 397–412.

    Article  PubMed  CAS  Google Scholar 

  8. Baes, M., Gulick, T., Choi, H. S., Martinoli, M. G., Simha, D., and Moore, D. D. (1994) Mol. Cell. Biol., 14, 1544–1552.

    PubMed  CAS  Google Scholar 

  9. Forman, B. M., Tzameli, I., Choi, H. S., Chen, J., Simha, D., Seol, W., Evans, R. M., and Moore, D. D. (1998) Nature, 395, 612–615.

    Article  PubMed  CAS  Google Scholar 

  10. Timsit, Y. E., and Negishi, M. (2007) Steroids, 72, 231–246.

    Article  PubMed  CAS  Google Scholar 

  11. Pustylnyak, V. O., Gulyaeva, L. F., and Lyakhovich, V. V. (2007) Biochemistry (Moscow), 72, 608–617.

    Article  CAS  Google Scholar 

  12. Kanno, Y., Suzuki, M., Miyazaki, Y., Matsuzaki, M., Nakahama, T., Kurose, K., Sawada, J., and Inouye, Y. (2007) Biochim. Biophys. Acta, 1773, 934–944.

    Article  PubMed  CAS  Google Scholar 

  13. Smirnov, A. N. (2002) Biochemistry (Moscow), 67, 957–977.

    Article  CAS  Google Scholar 

  14. Kishimoto, M., Fujiki, R., Takezawa, S., Sassaki, Y., Nakamura, T., Yamaoka, K., Kitagawa, H., and Kato, S. (2006) Endocrine J., 53, 157–172.

    Article  CAS  Google Scholar 

  15. Li, H., and Wang, H. (2010) Expert. Opin. Drug. Metab. Toxicol., 6, 409–426.

    Article  PubMed  CAS  Google Scholar 

  16. Xu, R. X., Lambert, M. H., Wisely, B. B., Warren, E. N., Weinert, E. E., Waitt, G. M., Williams, J. D., Collins, J. L., Moore, L. B., Willson, T. M., and Moore, J. T. (2004) Mol. Cell, 16, 919–928.

    Article  PubMed  CAS  Google Scholar 

  17. Aranda, A., and Pascual, A. (2001) Physiol. Rev., 81, 1270–1304.

    Google Scholar 

  18. Wright, E., Busby, S. A., Wisecarver, S., Vincent, J., Griffin, P. R., and Fernandez, E. J. (2011) Structure, 19, 37–44.

    Article  PubMed  CAS  Google Scholar 

  19. Honkakoski, P., Zelko, I., Sueyoshi, T., and Negishi, M. (1998) Mol. Cell. Biol., 18, 5652–5658.

    PubMed  CAS  Google Scholar 

  20. Wagner, M., Halilbasic, E., Marschall, H. U., Zollner, G., Fickert, P., Langner, C., Zatloukal, K., Denk, H., and Trauner, M. (2005) Hepatology, 42, 420–430.

    Article  PubMed  CAS  Google Scholar 

  21. Sueyoshi, T., Moore, R., Sugatani, J., Matsumura, Y., and Negishi, M. (2008) Mol. Pharmacol., 73, 1113–1121.

    Article  PubMed  CAS  Google Scholar 

  22. Auerbach, S. S., Ramsden, R., Stoner, M. A., Verlinde, C., Hassett, C., and Omiecinski, C. J. (2003) Nucleic Acids Res., 31, 3194–3207.

    Article  PubMed  CAS  Google Scholar 

  23. Zelko, I., and Negishi, M. (2000) Biochem. Biophys. Res. Commun., 277, 1–6.

    Article  PubMed  CAS  Google Scholar 

  24. Wang, H., Faucette, S., Sueyoshi, T., Moore, R., Ferguson, S., Negishi, M., and LeCluyse, E. (2003) J. Biol. Chem., 278, 14146–14152.

    Article  PubMed  CAS  Google Scholar 

  25. Yamada, H., Ishii, Y., Yamamoto, M., and Oguri, K. (2006) Curr. Drug Metab., 7, 397–409.

    Article  PubMed  CAS  Google Scholar 

  26. Wang, H., Faucette, S., Moore, R., Sueyoshi, T., Negishi, M., and LeCluyse, E. (2004) J. Biol. Chem., 279, 29295–29301.

    Article  PubMed  CAS  Google Scholar 

  27. Muangmoonchai, R., Smirlis, D., Wong, S. C., Edwards, M., Phillips, I. R., and Shephard, E. A. (2001) Biochem. J., 355, 71–78.

    Article  PubMed  CAS  Google Scholar 

  28. Min, G., Kemper, J. K., and Kemper, B. (2002) J. Biol. Chem., 277, 26356–26363.

    Article  PubMed  CAS  Google Scholar 

  29. Shiraki, T., Sakai, N., Kanaya, E., and Jingami, H. (2003) J. Biol. Chem., 278, 11344–11350.

    Article  PubMed  CAS  Google Scholar 

  30. Xie, Y. B., Nedumaran, B., and Choi, H. S. (2009) Nucleic Acids Res., 37, 4100–4115.

    Article  PubMed  CAS  Google Scholar 

  31. Kanno, Y., Suzuki, M., Nakahama, T., and Inouye, Y. (2005) Biochim. Biophys. Acta, 1745, 215–222.

    Article  PubMed  CAS  Google Scholar 

  32. Kakizaki, S., Yamamoto, M., and Ueda, A. (2003) Biochim. Biophys. Acta, 1619, 239–242.

    PubMed  CAS  Google Scholar 

  33. Tzameli, I., Pissios, P., Schuetz, E. G., and Moore, D. D. (2000) Mol. Cell Biol., 20, 2951–2958.

    Article  PubMed  CAS  Google Scholar 

  34. Maglich, J. M., Parks, D. J., Moore, L. B., Collins, J. L., Goodwin, B., Billin, A. N., Stoltz, C. A., Kliewer, S. A., Lambert, M. H., Willson, T. M., and Moore, J. T. (2003) J. Biol. Chem., 278, 17277–17283.

    Article  PubMed  CAS  Google Scholar 

  35. Pustylnyak, V., Pivovarova, E., Slynko, N., Gulyaeva, L., and Lyakhovich, V. (2009) Life Sci., 85, 815–821.

    Article  PubMed  CAS  Google Scholar 

  36. Pustylnyak, V. O., Lebedev, A. N., Gulyaeva, L. F., Lyakhovich, V. V., and Slynko, N. M. (2007) Life Sci., 80, 324–328.

    Article  PubMed  CAS  Google Scholar 

  37. Mishin, V. M., Gutkina, N. I., Lyakhovich, V. V., Pospelova, L. N., and Chistyakov, V. V. (1990) Biokhimiya, 55, 29–36.

    CAS  Google Scholar 

  38. Jyrkkarinne, J., Windshugel, B., Makinen, J., Ylisirnio, M., Perakyla, M., Poso, A., Sippl, W., and Honkakoski, P. (2005) J. Biol. Chem., 280, 5960–5971.

    Article  PubMed  Google Scholar 

  39. Moore, L. B., Parks, D. J., Jones, S. A., Bledsoe, R. K., Consler, T. G., Stimmel, J. B., Goodwin, B., Liddle, C., Blanchard, S. G., Willson, T. M., Collins, J. L., and Kliewer, S. A. (2000) J. Biol. Chem., 275, 15122–15127.

    Article  PubMed  CAS  Google Scholar 

  40. Yoshinari, K., Kobayashi, K., Moore, R., Kawamoto, T., and Negishi, M. (2003) FEBS Lett., 548, 17–20.

    Article  PubMed  CAS  Google Scholar 

  41. Hosseinpour, F., Moore, R., Negishi, M., and Sueyoshi, T. (2006) Mol. Pharmacol., 69, 1095–1102.

    Article  PubMed  CAS  Google Scholar 

  42. Mutoh, S., Osabe, M., Inoue, K., Moore, R., Pedersen, L., Perera, L., Rebolloso, Y., Sueyoshi, T., and Negishi, M. (2009) J. Biol. Chem., 284, 34785–34792.

    Article  PubMed  CAS  Google Scholar 

  43. Saini, S. P., Sonoda, J., Xu, L., Toma, D., Uppal, H., Mu, Y., Ren, S., Moore, D. D., Evans, R. M., and Xie, W. (2004) Mol. Pharmacol., 65, 292–300.

    Article  PubMed  CAS  Google Scholar 

  44. Kullak-Ublick, G. A., and Becker, M. B. (2003) Drug Metab. Rev., 35, 305–317.

    Article  PubMed  CAS  Google Scholar 

  45. Olinga, P., Elferink, M. G., Draaisma, A. L., Merema, M. T., Castell, J. V., Perez, G., and Groothuis, G. M. (2008) Eur. J. Pharm. Sci., 33, 380–389.

    Article  PubMed  CAS  Google Scholar 

  46. Harris, R. Z., Jang, G. R., and Tsunoda, S. (2003) Clin. Pharmacokinet., 42, 1071–1088.

    Article  PubMed  CAS  Google Scholar 

  47. Gill, R. Q., and Sterling, R. K. (2001) J. Clin. Gastroenterol., 33, 191–198.

    Article  PubMed  CAS  Google Scholar 

  48. Schaffner, F. (1975) Vet. Pathol., 12, 145–156.

    PubMed  CAS  Google Scholar 

  49. Rogers, L. K., Moorthy, B., and Smith, C. V. (1997) Chem. Res. Toxicol., 10, 470–476.

    Article  PubMed  CAS  Google Scholar 

  50. Zhang, J., Huang, W., Chua, S. S., Wei, P., and Moore, D. D. (2002) Science, 298, 422–424.

    Article  PubMed  CAS  Google Scholar 

  51. Tien, E. S., and Negishi, M. (2006) Xenobiotica, 36, 1152–1163.

    Article  PubMed  CAS  Google Scholar 

  52. Kakizaki, S., Yamazaki, Y., Takizawa, D., and Negishi, M. (2008) Curr. Drug Metab., 9, 614–621.

    Article  PubMed  CAS  Google Scholar 

  53. Sutija, M., and Joss, J. M. (2006) J. Comp. Physiol., 176, 87–92.

    CAS  Google Scholar 

  54. Tien, E. S., Matsui, K., Moore, R., and Negishi, M. (2007) J. Pharmacol. Exp. Ther., 320, 307–313.

    Article  PubMed  CAS  Google Scholar 

  55. Jeyakumar, M., Webb, P., Baxter, J. D., Scanlan, T. S., and Katzenellenbogen, J. A. (2008) Biochemistry, 47, 7465–7476.

    Article  PubMed  CAS  Google Scholar 

  56. Qatanani, M., Zhang, J., and Moore, D. D. (2005) Endocrinology, 146, 995–1002.

    Article  PubMed  CAS  Google Scholar 

  57. Min, G., Kim, H., Bae, Y., Petz, L., and Kemper, J. K. (2002) J. Biol. Chem., 277, 34626–34633.

    Article  PubMed  CAS  Google Scholar 

  58. Shan, L., Vincent, J., Brunzelle, J. S., Dussault, I., Lin, M., Ianculescu, I., Sherman, M. A., Forman, B. M., and Fernandez, E. J. (2004) Mol. Cell, 16, 907–917.

    PubMed  CAS  Google Scholar 

  59. Rosenbrock, H., Hagemeyer, C. E., Singec, I., Knoth, R., and Volk, B. (1999) J. Neuroendocrinol., 11, 597–604.

    Article  PubMed  CAS  Google Scholar 

  60. Huang, W., Zhang, J., Washington, M., Liu, J., Parant, J. M., Lozano, G., and Moore, D. D. (2005) Mol. Endocrinol., 19, 1646–1653.

    Article  PubMed  CAS  Google Scholar 

  61. Yamamoto, Y., Moore, R., Goldsworthy, T. L., Negishi, M., and Maronpot, R. R. (2004) Cancer Res., 64, 7197–7200.

    Article  PubMed  CAS  Google Scholar 

  62. Ledda-Columbano, G. M., Pibiri, M., Cossu, C., Molotzu, F., Locker, J., and Columbano, A. (2004) Hepatology, 40, 981–988.

    PubMed  CAS  Google Scholar 

  63. Columbano, A., Ledda-Columbano, G. M., Pibiri, M., Cossu, C., Menegazzi, M., Moore, D. D., Huang, W., Tian, J., and Locker, J. (2005) Hepatology, 42, 1118–1126.

    Article  PubMed  CAS  Google Scholar 

  64. Bilger, A., Bennett, L. M., Carabeo, R. A., Chiaverotti, T. A., Dvorak, C., Liss, K. M., Schadewald, S. A., Pitot, H. C., and Drinkwater, N. R. (2004) Genetics, 167, 859–866.

    Article  PubMed  CAS  Google Scholar 

  65. Hundal, R. S., Krssak, M., Dufour, S., Laurent, D., Lebon, V., Chandramouli, V., Inzucchi, S. E., Schumann, W. C., et al. (2000) Diabetes, 49, 2063–2069.

    Article  PubMed  CAS  Google Scholar 

  66. Manenti, G., Dragani, T. A., and Porta, G. D. (1987) Chem. Biol. Interact., 64, 83–92.

    Article  PubMed  CAS  Google Scholar 

  67. Argaud, D., Halimi, S., Catelloni, F., and Leverve, X. M. (1991) Biochem. J., 280, 663–669.

    PubMed  CAS  Google Scholar 

  68. Nakae, J., Kitamura, T., Silver, D. L., and Accili, D. (2001) J. Clin. Invest., 108, 1359–1367.

    PubMed  CAS  Google Scholar 

  69. Kodama, S., Koike, C., Negishi, M., and Yamamoto, Y. (2004) Mol. Cell. Biol., 24, 7931–7940.

    Article  PubMed  CAS  Google Scholar 

  70. Gao, J., He, J., Zhai, Y., Wada, T., and Xie, W. (2009) J. Biol. Chem., 284, 25984–25992.

    Article  PubMed  CAS  Google Scholar 

  71. Dong, B., Saha, P. K., Huang, W., Chen, W., Abu-Elheiga, L. A., Wakil, S. J., Stevens, R. D., Ilkayeva, O., Newgard, C. B., Chan, L., and Moore, D. D. (2009) Proc. Natl. Acad. Sci. USA, 106, 18831–18836.

    Article  PubMed  CAS  Google Scholar 

  72. Miao, J., Fang, S., Bae, Y., and Kemper, J. K. (2006) J. Biol. Chem., 281, 14537–14546.

    Article  PubMed  CAS  Google Scholar 

  73. Konno, Y., Negishi, M., and Kodama, S. (2008) Drug Metab. Pharmacokinet., 23, 8–13.

    Article  PubMed  CAS  Google Scholar 

  74. Gao, J., and Xie, W. (2010) Drug Metab. Dispos., 38, 2091–2095.

    Article  PubMed  CAS  Google Scholar 

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Correspondence to V. O. Pustylnyak.

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Original Russian Text © E. M. Kachaylo, V. O. Pustylnyak, V. V. Lyakhovich, L. F. Gulyaeva, 2011, published in Biokhimiya, 2011, Vol. 76, No. 10, pp. 1335–1347.

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Kachaylo, E.M., Pustylnyak, V.O., Lyakhovich, V.V. et al. Constitutive androstane receptor (CAR) is a xenosensor and target for therapy. Biochemistry Moscow 76, 1087–1097 (2011). https://doi.org/10.1134/S0006297911100026

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