The nuclear receptor CAR mediates specific xenobiotic induction of drug metabolism (original) (raw)

Nature volume 407, pages 920–923 (2000)Cite this article

Abstract

Organisms encounter a wide range of foreign compounds—or ‘xenobiotics’—with potentially harmful consequences. The cytochrome P450 (CYP) enzymes metabolize xenobiotics and thus are a primary defence against these compounds. Increased expression of specific CYP genes in response to particular xenobiotics is a central component of this defence1, although such induction can also increase production of toxic metabolites. Here we show that the nuclear receptor CAR mediates the response evoked by a class of xenobiotics known as the ‘phenobarbital-like inducers’. The strong activation of Cyp2b10 gene expression by phenobarbital, or by the more potent TCPOBOP, is absent in mice lacking the CAR gene. These animals also show decreased metabolism of the classic CYP substrate zoxazolamine and a complete loss of the liver hypertrophic and hyperplastic responses to these inducers. Cocaine causes acute hepatotoxicity in wild-type mice previously exposed to phenobarbital-like inducers and this toxicity is also absent in the CAR-deficient animals. Thus, loss of CAR function alters sensitivity to toxins, increasing or decreasing it depending on the compound. Modulation of CAR activity in humans may significantly affect metabolism of drugs and other xenobiotics.

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References

  1. Waxman, D. J. P450 gene induction by structurally diverse xenochemicals: central role of nuclear receptors CAR, PXR, and PPAR. Arch. Biochem. Biophys. 369, 11–23 (1999).
    Article CAS Google Scholar
  2. Poland, A. et al. 1,4-Bis[2-(3,5-dichloropyridyloxy)]benzene, a potent phenobarbital-like inducer of microsomal monooxygenase activity. Mol. Pharmacol. 18, 571–580 (1980).
    CAS PubMed Google Scholar
  3. Honkakoski, P., Zelko, I., Sueyoshi, T. & Negishi, M. 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).
    Article CAS Google Scholar
  4. Sueyoshi, T., Kawamoto, T., Zelko, I., Honkakoski, P. & Negishi, M. The repressed nuclear receptor CAR responds to phenobarbital in activating the human CYP2B6 gene. J. Biol. Chem. 274, 6043–6046 (1999).
    Article CAS Google Scholar
  5. Tzameli, I., Pissios, P., Schuetz, E. G. & D, Moore, D. D. The xenobiotic compound 1,4-bis[2-(3,5-dichloropyridyloxy)]benzene is an agonist ligand for the nuclear receptor CAR. Mol. Cell. Biol. 20, 2951–2958 (2000).
    Article CAS Google Scholar
  6. Jones, S. A. et al. The pregnane X receptor: a promiscuous xenobiotic receptor that has diverged during evolution. Mol. Endocrinol. 14, 27–39 (2000).
    Article CAS Google Scholar
  7. Moore, L. B. et al. Orphan nuclear receptors, constitutive androstane receptor and pregnane X receptor share xenobiotic and steroid ligands. J. Biol. Chem. 275, 15122–15127 (2000).
    Article CAS Google Scholar
  8. Baes, M. et al. A new orphan member of the nuclear receptor superfamily that interacts with a subset of retinoic acid response elements. Mol. Cell. Biol. 14, 1544–1552 ( 1994).
    Article CAS Google Scholar
  9. Choi, H. S. et al. Differential transactivation by two isoforms of the orphan nuclear hormone receptor CAR. J. Biol. Chem. 272, 23565–23571 (1997).
    Article CAS Google Scholar
  10. Heubel, F., Reuter, T. & Gerstner, E. Differences between induction effects of 1,4-bis[2-(3,5-dichloropyridyloxy)]benzene and phenobarbitone. Biochem. Pharmacol. 38, 1293–1300 (1989).
    Article CAS Google Scholar
  11. Carthew, P., Edwards, R. E. & Nolan, B. M. The quantitative distinction of hyperplasia from hypertrophy in hepatomegaly induced in the rat liver by phenobarbital. Toxicol. Sci. 44, 46–51 (1998).
    Article CAS Google Scholar
  12. Cunningham, M. L. Role of increased DNA replication in the carcinogenic risk of nonmutagenic chemical carcinogens. Mutat. Res. 365, 59 –69 (1996).
    Article Google Scholar
  13. Robinson, J. R. & Nebert, D. W. Genetic expression of aryl hydrocarbon hydroxylase induction. Presence or absence of association with zoxazolamine, diphenylhydantoin, and hexobarbital metabolism. Mol. Pharmacol. 10, 484–493 (1974).
    CAS PubMed Google Scholar
  14. Bornheim, L. M. Effect of cytochrome P450 inducers on cocaine-mediated hepatotoxicity. Toxicol. Appl. Pharmacol. 150, 158– 165 (1998).
    Article CAS Google Scholar
  15. Kliewer, S. A. et al. An orphan nuclear receptor activated by pregnanes defines a novel steroid signaling pathway. Cell 92, 73–82 (1998).
    Article CAS Google Scholar
  16. Blumberg, B. et al. SXR, a novel steroid and xenobiotic-sensing nuclear receptor. Genes Dev. 12, 3195–3205 (1998).
    Article CAS Google Scholar
  17. Lehmann, J. M. et al. 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).
    Article CAS Google Scholar
  18. Xie, W. et al. Humanized xenobiotic response in mice expressing nuclear receptor SXR. Nature 406, 435–439 (2000).
    Article ADS CAS Google Scholar
  19. Shimada, T., Yamazaki, H., Mimura, M., Inui, Y. & Guengerich, F. P. Interindividual variations in human liver cytochrome P-450 enzymes involved in the oxidation of drugs, carcinogens and toxic chemicals: studies with liver microsomes of 30 Japanese and 30 Caucasians. J. Pharmacol. Exp. Ther. 270, 414– 423 (1994).
    CAS PubMed Google Scholar
  20. Code, E. L. et al. Human cytochrome P4502B6: interindividual hepatic expression, substrate specificity, and role in procarcinogen activation. Drug Metab. Dispos. 25, 985–993 (1997).
    CAS PubMed Google Scholar
  21. Selim, K. & Kaplowitz, N. Hepatotoxicity of psychotropic drugs. Hepatology 29, 1347– 1351 (1999).
    Article CAS Google Scholar
  22. Liang, H. C. et al. Cyp1a2(-/-) null mutant mice develop normally but show deficient drug metabolism. Proc. Natl Acad. Sci. USA 93, 1671–1676 (1996).
    Article ADS CAS Google Scholar

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Acknowledgements

This work was supported by a grant from NIH to D.D.M. We thank F. DeMayo for help with generating the knockout animals.

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Authors and Affiliations

  1. Department of Molecular and Cellular Biology, Baylor College of Medicine, 1 Baylor Plaza, Houston, 77030, Texas, USA
    Ping Wei, Jun Zhang, Margarete Egan-Hafley, Shuguang Liang & David D. Moore

Authors

  1. Ping Wei
  2. Jun Zhang
  3. Margarete Egan-Hafley
  4. Shuguang Liang
  5. David D. Moore

Corresponding author

Correspondence toDavid D. Moore.

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Wei, P., Zhang, J., Egan-Hafley, M. et al. The nuclear receptor CAR mediates specific xenobiotic induction of drug metabolism.Nature 407, 920–923 (2000). https://doi.org/10.1038/35038112

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