Skip to content
Licensed Unlicensed Requires Authentication Published by De Gruyter July 19, 2005

A role for constitutive androstane receptor in the regulation of human intestinal MDR1 expression

  • Oliver Burk , Katja A. Arnold , Anke Geick , Heike Tegude and Michel Eichelbaum
From the journal Biological Chemistry

Abstract

MDR1/P-glycoprotein is an efflux transporter determining the absorption and presystemic elimination of many xenobiotics in the gut. Thus, interindividual differences in MDR1 expression may affect the efficacy of drug treatment. The expression of MDR1 is partially controlled by the pregnane X receptor (PXR), which mediates induction by many xenobiotics. Since it has been described that the nuclear receptors PXR and constitutive androstane receptor (CAR) can bind to the same binding sites, we investigated the role of CAR in the regulation of MDR1 gene expression. We demonstrate here by gel shift and transfection experiments that CAR binds to distinct nuclear receptor response elements in the -7.8 kbp enhancer of MDR1 and transactivates MDR1 expression through DR4 motifs to which the receptor binds as a heterodimer with RXR or as a monomer, respectively. Expression of the endogenous MDR1 gene is elevated in cells stably expressing CAR, thus arguing for the functional relevance of CAR-dependent activation of MDR1. The physiological relevance of the regulation of MDR1 by CAR is further suggested by correlation of the expression of CAR and MDR1 in the human small intestine. In summary, our data suggest that CAR plays a role in the regulation of intestinal MDR1 expression.

:

Corresponding author

References

Arnold, K.A., Eichelbaum, M., and Burk, O. (2004). Alternative splicing affects the function and tissue-specific expression of the human constitutive androstane receptor. Nucl. Recept.2, 1.10.1186/1478-1336-2-1Search in Google Scholar PubMed PubMed Central

Baes, M., Gulick, T., Choi, H.S., Martinoli, M.G., Simha, D., and 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, 1544–1552.Search in Google Scholar

Burk, O., Tegude, H., Koch, I., Hustert, E., Wolbold, R., Glaeser, H., Klein, K., Fromm, M.F., Nuessler, A.K., Neuhaus, P., et al. (2002). Molecular mechanisms of polymorphic CYP3A7 expression in adult human liver and intestine. J. Biol. Chem.277, 24280–24288.10.1074/jbc.M202345200Search in Google Scholar PubMed

Burk, O., Koch, I., Raucy, J., Hustert, E., Eichelbaum, M., Brockmöller, J., Zanger, U.M., and Wojnowski, L. (2004). The induction of cytochrome P450 3A5 (CYP3A5) in the human liver and intestine is mediated by the xenobiotic sensors pregnane X receptor (PXR) and constitutively activated receptor (CAR). J. Biol. Chem.279, 38379–38385.10.1074/jbc.M404949200Search in Google Scholar PubMed

Burk, O., Arnold, K.A., Nussler, A.K., Schaeffeler, E., Efimova, E., Avery, B.A., Avery, M.A., Fromm, M.F., and Eichelbaum, M. (2005). Anti-malarial artemisinin drugs induce CYP and MDR1 expression by activation of xenosensors pregnane X receptor and constitutive androstane receptor. Mol. Pharmacol. (2005 March 10, online publication ahead of print; DOI 10.1124/mol.104.009019).Search in Google Scholar

Chen, Y., Ferguson, S.S., Negishi, M., and Goldstein, J.A. (2003). Identification of constitutive androstane receptor and glucocorticoid receptor binding sites in the CYP2C19 promoter. Mol. Pharmacol.64, 316–324.10.1124/mol.64.2.316Search in Google Scholar PubMed

Dürr, D., Stieger, B., Kullak-Ublick, G.A., Rentsch, K.M., Steinert, H.C., Meier, P.J., and Fattinger, K. (2000). St. John's wort induces intestinal P-glycoprotein/MDR1 and intestinal and hepatic CYP3A4. Clin. Pharmacol. Ther.68, 598–604.Search in Google Scholar

Frank, C., Gonzalez, M.M., Oinonen, C., Dunlop, T.W., and Carlberg, C. (2003). Characterization of DNA complexes formed by the nuclear receptor constitutive androstane receptor. J. Biol. Chem.278, 43299–43310.10.1074/jbc.M305186200Search in Google Scholar PubMed

Fromm, M.F. (2004). Importance of P-glycoprotein at blood-tissue barriers. Trends Pharmacol. Sci.25, 423–429.10.1016/j.tips.2004.06.002Search in Google Scholar PubMed

Geick, A., Eichelbaum, M., and Burk, O. (2001). Nuclear receptor response elements mediate induction of intestinal MDR1 by rifampin. J. Biol. Chem.276, 14581–14587.10.1074/jbc.M010173200Search in Google Scholar PubMed

Gerbal-Chaloin, S., Daujat, M., Pascussi, J.M., Pichard-Garcia, L., Vilarem, M.J., and Maurel, P. (2002). Transcriptional regulation of CYP2C9 gene. J. Biol. Chem.277, 209–217.10.1074/jbc.M107228200Search in Google Scholar PubMed

Glaeser, H., Drescher, S., van der Kuip, H., Behrens C., Geick, A., Burk, O., Dent, J., Somogyi, A., von Richter, O., Griese, E.U., Eichelbaum, M., and Fromm, M.F. (2002). Shed human enterocytes as a tool for the study of expression and function of intestinal drug-metabolizing enzymes and transporters. Clin. Pharmacol. Ther.71, 131–140.10.1067/mcp.2002.121370Search in Google Scholar PubMed

Goodwin, B., Hodgson, E., D'Costa, D.J., Robertson, G.R., and Liddle, C. (2002a). Transcriptional regulation of the human CYP3A4 gene by the constitutive androstane receptor. Mol. Pharmacol.62, 359–365.10.1124/mol.62.2.359Search in Google Scholar PubMed

Goodwin, B., Redinbo, M., and Kliewer, S.A. (2002b). Regulation of CYP3A gene transcription by the pregnane X receptor. Annu. Rev. Pharmacol. Toxicol.42, 1–23.10.1146/annurev.pharmtox.42.111901.111051Search in Google Scholar

Greiner, B., Eichelbaum, M., Fritz, P., Kreichgauer, H.P., von Richter, O., Zundler, J., and Kroemer, H.K. (1999). The role of intestinal P-glycoprotein in the interaction of digoxin and rifampin. J. Clin. Invest.104, 147–153.10.1172/JCI6663Search in Google Scholar

Hoffmeyer, S., Burk, O., von Richter, O., Arnold, H.P., Brockmöller, J., Johne, A., Cascorbi, I., Gerloff, T., Roots, I., Eichelbaum, M., and Brinkmann, U. (2000). Functional polymorphisms of the human multi-drug resistance gene: multiple sequence variations and correlation of one allele with P-glycoprotein expression and activity in vivo. Proc. Natl. Acad. Sci. USA97, 3473–3478.10.1073/pnas.97.7.3473Search in Google Scholar

Honkakoski, P., Zelko, I., Sueyoshi, T., and Negishi, M. (1998). The nuclear orphan receptor CAR-retinoid X receptor heterodimer activates the phenobarbital-responsive enhancer module of the CYP2B gene. Mol. Cell. Biol.18, 5652–5658.10.1128/MCB.18.10.5652Search in Google Scholar

Hsing, S., Gatmaitan, Z., and Arias, I.M. (1992). The function of Gp170, the multidrug-resistance gene product, in the brush border of rat intestinal mucosa. Gastroenterology102, 879–885.10.1016/0016-5085(92)90173-VSearch in Google Scholar

Huang, L., Wring, S.A., Woolley, J.L., Brouwer, K.R., Serabjit-Singh, C., and Polli, J.W. (2001). Induction of P-glycoprotein and cytochrome P450 3a by HIV protease inhibitors. Drug Metab. Dispos.29, 754–760.Search in Google Scholar

Huang, W., Zhang, J., Wei, P., Schrader, W.T., and Moore, D.D. (2004). Meclizine is an agonist ligand for mouse constitutive androstane receptor (CAR) and an inverse agonist for human CAR. Mol. Endocrinol.18, 2402–2408.10.1210/me.2004-0046Search in Google Scholar

Johne, A., Brockmöller, J., Bauer, S., Maurer, A., Langheinrich, M., and Roots, I. (1999). Pharmacokinetic interaction of digoxin with an herbal extract from St. John's wort (Hypericum perforatum). Clin. Pharmacol. Ther.66, 338–345.Search in Google Scholar

Kast, H.R., Goodwin, B., Tarr, P.T., Jones, S.A., Anisfeld, A.M., Stoltz, C.M., Tontonoz, P., Kliewer, S., Willson, T.M., and Edwards, P.A. (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, 2908–2915.10.1074/jbc.M109326200Search in Google Scholar

Kim, W.Y. and Benet, L.Z. (2004). P-glycoprotein (P-gp/MDR1)-mediated efflux of sex-steroid hormones and modulation of P-gp expression in vitro. Pharm. Res.21, 1284–1293.10.1023/B:PHAM.0000033017.52484.81Search in Google Scholar

Lehmann, J.M., McKee, D.D., Watson, M.A., Willson, T.M., Moore, J.T., and 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, 1016–1023.10.1172/JCI3703Search in Google Scholar

Lown, K.S., Kolars, J.C., Thummel, K.E., Barnett, J.L., Kunze, K.L., Wrighton, S.A., and Watkins, P.B. (1994). Interpatient heterogeneity in expression of CYP3A4 and CYP3A5 in small bowel. Lack of prediction by the erythromycin breath test. Drug Metab. Dispos.22, 947–955.Search in Google Scholar

Lown, K.S., Mayo, R.R., Leichtman, A.B., Hsiao, H.L., Turgeon, D.K., Schmiedlin-Ren, P., Brown, M.B., Guo, W., Rossi, S.J., Benet, L.Z., and Watkins, P.B. (1997). Role of intestinal P-glycoprotein (mdr1) in interpatient variation in the oral bio-availability of cyclosporine. Clin. Pharmacol. Ther.62, 248–260.10.1016/S0009-9236(97)90027-8Search in Google Scholar

Mäkinen, J., Frank, C., Jyrkkärinne J., Gynther, J., Carlberg, C., and Honkakoski, P. (2002). Modulation of mouse and human phenobarbital-responsive enhancer module by nuclear receptors. Mol. Pharmacol.62, 366–378.10.1124/mol.62.2.366Search in Google Scholar

Maglich, J.M., Stoltz, C.M., Goodwin, B., Hawkins-Brown, D., Moore, J.T., and 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, 638–646.10.1124/mol.62.3.638Search in Google Scholar

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). Identification of a novel human constitutive androstane receptor (CAR) agonist and its use in the identification of CAR target genes. J. Biol. Chem.278, 17277–17283.10.1074/jbc.M300138200Search in Google Scholar

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). Orphan nuclear receptors constitutive androstane receptor and pregnane X receptor share xenobiotic and steroid ligands. J. Biol. Chem.275, 15122–15127.10.1074/jbc.M001215200Search in Google Scholar

Runge, D., Köhler, C., Kostrubsky, V.E., Jäger, D., Lehmann, T., Runge, D.M., May, U., Stolz, D.B., Strom, S.C., Fleig, W.E., and Michalopoulos, G.K. (2000). Induction of cytochrome P450 (CYP)1A1, CYP1A2, and CYP3A4 but not of CYP2C9, CYP2C19, multidrug resistance (MDR-1) and multidrug resistance associated protein (MRP-1) by prototypical inducers in human hepatocytes. Biochem. Biophys. Res. Commun.273, 333–341.10.1006/bbrc.2000.2902Search in Google Scholar

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

Sueyoshi, T. and Negishi, M. (2001). Phenobarbital response elements of cytochrome P450 genes and nuclear receptors. Annu. Rev. Pharmacol. Toxicol.41, 123–143.10.1146/annurev.pharmtox.41.1.123Search in Google Scholar

Sueyoshi, T., Kawamoto, T., Zelko, I., Honkakoski, P., and Negishi, M. (1999). The repressed nuclear receptor CAR responds to phenobarbital in activating the human CYP2B6 gene. J. Biol. Chem.274, 6043–6046.10.1074/jbc.274.10.6043Search in Google Scholar

Tzameli, I. and Moore, D.D. (2001). Role reversal: new insights from new ligands for the xenobiotic receptor CAR. Trends Endocrinol. Metab.12, 7–10.10.1016/S1043-2760(00)00332-5Search in Google Scholar

Ueda, A., Hamadeh, H.K., Webb, H.K., Yamamoto, Y., Sueyoshi, T., Afshari, C.A., Lehmann, J.M., and Negishi, M. (2002). Diverse roles of the nuclear orphan receptor CAR in regulating hepatic genes in response to phenobarbital. Mol. Pharmacol.61, 1–6.10.1124/mol.61.1.1Search in Google Scholar PubMed

Wei, P., Zhang, J., Dowhan, D.H., Han, Y., and Moore, D.D. (2002). Specific and overlapping functions of the nuclear hormone receptors CAR and PXR in xenobiotic response. Pharmacogenom. J.2, 117–126.10.1038/sj.tpj.6500087Search in Google Scholar PubMed

Westphal, K., Weinbrenner, A., Zschiesche, M., Franke, G., Knoke, M., Oertel, R., Fritz, P., von Richter, O., Warzok, R., Hachenberg, T., et al. (2000). Induction of P-glycoprotein by rifampin increases intestinal secretion of talinolol in human beings: a new type of drug/drug interaction. Clin. Pharmacol. Ther.68, 345–355.10.1067/mcp.2000.109797Search in Google Scholar PubMed

Wolbold, R., Klein, K., Burk, O., Nüssler, A.K., Neuhaus, P., Eichelbaum, M., Schwab, M., and Zanger, U.M. (2003). Sex is a major determinant of CYP3A4 expression in human liver. Hepatology38, 978–988.10.1002/hep.1840380424Search in Google Scholar

Xie, W., Barwick, J.L., Simon, C.M., Pierce, A.M., Safe, S., Blumberg, B., Guzelian, P.S., and Evans, R.M. (2000). Reciprocal activation of xenobiotic response genes by nuclear receptors SXR/PXR and CAR. Genes Dev.14, 3014–3023.10.1101/gad.846800Search in Google Scholar PubMed PubMed Central

Published Online: 2005-07-19
Published in Print: 2005-06-01

© Walter de Gruyter Berlin New York

Downloaded on 5.3.2024 from https://www.degruyter.com/document/doi/10.1515/BC.2005.060/html
Scroll to top button