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  • Original Article
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Specific and overlapping functions of the nuclear hormone receptors CAR and PXR in xenobiotic response

Abstract

The products of the cytochrome P450 (CYP) genes play an important role in the detoxification of xenobiotics and environmental contaminants, and many foreign chemicals or xenobiotics can induce their expression. We have previously shown that the nuclear hormone receptor CAR (Constitutive Androstane Receptor, NR113) mediates the well studied induction of CYP2B10 gene expression by phenobarbital (PB) and 1, 4-bis-[2-(3, 5,-dichloropyridyloxy)] benzene (TCPOBOP). We have used the CAR knockout mouse model to explore the broader functions of this xenobiotic receptor. In addition to the liver, CAR is expressed in the epithelial cells of the villi in the small intestine, and this expression is required for CYP2B10 induction in response to PB and TCPOBOP in those cells. In agreement with previous observations that CAR can bind to regulatory elements in CYP3A genes, CAR is also required for induction of expression of CYP3A11 in response to both PB and TCPOBOP in liver. In males, CAR is also required for induction of liver CYP2A4 expression. In wild type animals, pretreatment with the CAR inverse agonist androstenol blocks the response of both the CYP2B10 and CYP3A11 genes to PB and TCPOBOP, and decreases basal CYP3A11 expression. CAR is also required for the response of CYP2B10 to several additional xenobiotic inducers, including chlorpromazine, clotrimazole and dieldrin, but not dexamethasone, an agonist for both the xenobiotic receptor PXR (Pregnane X Receptor NR112) and the glucocorticoid receptor. Chlorpromazine induction of CYP3A11 is also absent in CAR-deficient animals, but the responses to clotrimazole and dieldrin are retained, indicating that both of these inducers can also activate PXR (Pregnane X Receptor NR112). We conclude that CAR has broad functions in xenobiotic responses. Some are specific to CAR but others, including induction of the important drug metabolizing enzyme CYP3A, overlap with those of PXR.

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References

  1. Waxman DJ, Azaroff L . Phenobarbital induction of cytochrome P-450 gene expression Biochem J 1992 281 (Pt 3): 577–592

    Article  Google Scholar 

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

    Article  CAS  Google Scholar 

  3. Honkakoski P, Negishi M . Regulation of cytochrome P450 (CYP) genes by nuclear receptors Biochem J 2000 347(Pt 2): 321–337

    Article  Google Scholar 

  4. Smith DA . Induction and drug development Eur J Pharm Sci 2000 11: 185–189

    Article  CAS  Google Scholar 

  5. Thummel KE, Wilkinson GR . In vitro and in vivo drug interactions involving human CYP3A Annu Rev Pharmacol Toxicol 1998 38: 389–430

    Article  CAS  Google Scholar 

  6. Honkakoski P, Moore R, Gynther J, Negishi M . Characterization of phenobarbital-inducible mouse Cyp2b10 gene transcription in primary hepatocytes J Biol Chem 1996 271: 9746–9753

    Article  CAS  Google Scholar 

  7. Honkakoski P, Negishi M . Characterization of a phenobarbital-responsive enhancer module in mouse P450 Cyp2b10 gene J Biol Chem 1997 272: 14943–14949

    Article  CAS  Google Scholar 

  8. 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 1998 18: 5652–5658

    Article  CAS  Google Scholar 

  9. 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 1999 274: 6043–6046

    Article  CAS  Google Scholar 

  10. Tzameli I, Pissios P, Schuetz EG, Moore DD . The xenobiotic compound 1,4-Bis[2-(3,5-Dichloropyridyloxy)] Benzene is an agonist ligand for the nuclear receptor CAR Mol Cell Biol 2000 20: 2951–2958

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  12. Kliewer SA, Moore JT, Wade L, Staudinger JL, Watson MA, Jones SA et al . An orphan nuclear receptor activated by pregnanes defines a novel steroid signaling pathway Cell 1998 92: 73–82

    Article  CAS  Google Scholar 

  13. Blumberg B, Sabbagh W Jr, Juguilon H, Bolado J Jr, van Meter CM, Ong ES et al . SXR, a novel steroid and xenobiotic-sensing nuclear receptor Genes Dev 1998 12: 3195–3205

    Article  CAS  Google Scholar 

  14. Lehmann JM, McKee DD, Watson MA, Willson TM, Moore JT, Kliewer SA . The human orphan nuclear receptor PXR is activated by compounds that regulate CYP3A4 gene expression and cause drug interactions J Clin Invest 1998 102: 1016–1023

    Article  CAS  Google Scholar 

  15. Xie W, Barwick JL, Downes M, Blumberg B, Simon CM, Nelson MC et al . Humanized xenobiotic response in mice expressing nuclear receptor SXR Nature 2000 406: 435–439

    Article  CAS  Google Scholar 

  16. Moore LB, Parks DJ, Jones SA, Bloe RK eds Consler TG, Stimmel JB et al . Orphan nuclear receptors constitutive androstane receptor and pregnane X receptor share xenobiotic and steroid ligands J Biol Chem 2000 275: 15122–15127

    Article  CAS  Google Scholar 

  17. Xie W, Barwick JL, Simon CM, Pierce AM, Safe S, Blumberg B et al . Reciprocal activation of xenobiotic response genes by nuclear receptors SXR/PXR and CAR Genes Dev 2000 14: 3014–3023

    Article  CAS  Google Scholar 

  18. Asoh M, Tateishi T, Kumai T, Kobayashi S . Induction of hepatic CYP2B in foetal and neonatal rats after maternal administration of phenobarbital Pharmacol Toxicol 1999 84: 18–23

    Article  CAS  Google Scholar 

  19. Kolars JC, Lown KS, Schmiedlin-Ren P, Ghosh M, Fang C, Wrighton SA et al . CYP3A gene expression in human gut epithelium Pharmacogenetics 1994 4: 247–259

    Article  CAS  Google Scholar 

  20. Smith G, Henderson CJ, Parker MG, White R, Bars RG, Wolf CR . 1,4-Bis[2-(3,5-dichloropyridyloxy)] benzene, an extremely potent modulator of mouse hepatic cytochrome P-450 gene expression Biochem J 1993 289: 807–813

    Article  CAS  Google Scholar 

  21. Noshiro M, Negishi M . Pretranslational regulation of sex-dependent testosterone hydroxylases by growth hormone in mouse liver J Biol Chem 1986 261: 15923–15927

    CAS  PubMed  Google Scholar 

  22. Forman BM, Tzameli I, Choi HS, Chen J, Simha D, Seol W et al . Androstane metabolites bind to and deactivate the nuclear receptor CAR-beta Nature 1998 395: 612–615

    Article  CAS  Google Scholar 

  23. Honkakoski P, Moore R, Washburn KA, Negishi M . Activation by diverse xenochemicals of the 51-base pair phenobarbital-responsive enhancer module in the CYP2B10 gene Mol Pharmacol 1998 53: 597–601

    Article  CAS  Google Scholar 

  24. Schuetz EG, Schmid W, Schutz G, Brimer C, Yasuda K, Kamataki T et al . The glucocorticoid receptor is essential for induction of cytochrome P-4502B by steroids but not for drug or steroid induction of CYP3A or P-450 reductase in mouse liver Drug Metab Dispos 2000 28: 268–278

    CAS  PubMed  Google Scholar 

  25. Kawamoto T, Sueyoshi T, Zelko I, Moore R, Washburn K, Negishi M . Phenobarbital-responsive nuclear translocation of the receptor CAR in induction of the CYP2B gene Mol Cell Biol 1999 19: 6318–6322

    Article  CAS  Google Scholar 

  26. Zelko I, Sueyoshi T, Kawamoto T, Moore R, Negishi M . The peptide near the C terminus regulates receptor CAR nuclear translocation induced by xenochemicals in mouse liver Mol Cell Biol 2001 21: 2838–2846

    Article  CAS  Google Scholar 

  27. Pascussi JM, Gerbal-Chaloin S, Fabre JM, Maurel P, Vilarem MJ . Dexamethasone enhances constitutive androstane receptor expression in human hepatocytes: consequences on cytochrome P450 gene regulation Mol Pharmacol 2000 58: 1441–1450

    Article  CAS  Google Scholar 

  28. Goodwin B, Moore LB, Stoltz CM, McKee DD, Kliewer SA . Regulation of the human cyp2b6 gene by the nuclear pregnane x receptor Mol Pharmacol 2001 60: 427–431

    CAS  PubMed  Google Scholar 

  29. Paige LA, Christensen DJ, Gron H, Norris JD, Gottlin EB, Padilla KM et al . Estrogen receptor (ER) modulators each induce distinct conformational changes in ER alpha and ER beta Proc Natl Acad Sci U S A 1999 96: 3999–4004

    Article  CAS  Google Scholar 

  30. Cholerton S, Daly AK, Idle JR . The role of individual human cytochromes P450 in drug metabolism and clinical response Trends Pharmacol Sci 1992 13: 434–439

    Article  CAS  Google Scholar 

  31. Guengerich FP . Cytochrome P-450 3A4: regulation and role in drug metabolism Annu Rev Pharmacol Toxicol 1999 39: 1–17

    Article  CAS  Google Scholar 

  32. Lee YK, Dell H, Dowhan DH, Hadzopoulou-Cladaras M, Moore DD . The orphan nuclear receptor SHP inhibits hepatocyte nuclear factor 4 and retinoid X receptor transactivation: two mechanisms for repression Mol Cell Biol 2000 20: 187–195

    Article  CAS  Google Scholar 

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Acknowledgements

We thank Drs Erin G Schuetz (St Jude Children's Research Hospital) for providing antibodies to CYP2B1 and CYP3A1 and Steven Safe for TCPOBOP. We also thank Dr Fred A Pereira for help with mouse histology. This work was supported by a grant (R01 DK46546) from the National Institutes of Health to DDM.

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Correspondence to D D Moore.

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Wei, P., Zhang, J., Dowhan, D. et al. Specific and overlapping functions of the nuclear hormone receptors CAR and PXR in xenobiotic response. Pharmacogenomics J 2, 117–126 (2002). https://doi.org/10.1038/sj.tpj.6500087

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