Abstract
Cytochrome P450 3A4 is an important mediator of drug catabolism that can be regulated by the steroid and xenobiotic receptor (SXR). We show here that SXR also regulates drug efflux by activating expression of the gene MDR1, which encodes the protein P-glycoprotein (ABCB1). Paclitaxel (Taxol), a commonly used chemotherapeutic agent, activated SXR and enhanced P-glycoprotein–mediated drug clearance. In contrast, docetaxel (Taxotere), a closely related antineoplastic agent, did not activate SXR and displayed superior pharmacokinetic properties. Docetaxel's silent properties reflect its inability to displace transcriptional corepressors from SXR. We also found that ET-743, a potent antineoplastic agent, suppressed MDR1 transcription by acting as an inhibitor of SXR. These findings demonstrate how the molecular activities of SXR can be manipulated to control drug clearance.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Crown, J. & O'Leary, M. The taxanes: an update. Lancet 355, 1176–1178 (2000).
Monsarrat, B., Royer, I., Wright, M. & Cresteil, T. Biotransformation of taxoids by human cytochromes P450: structure-activity relationship. Bull. Cancer 84, 125–133 (1997).
Ambudkar, S.V. et al. Biochemical, cellular, and pharmacological aspects of the multidrug transporter. Annu. Rev. Pharmacol. Toxicol. 39, 361–398 (1999).
Savas, U., Griffin, K.J. & Johnson, E.F. Molecular mechanisms of cytochrome P-450 induction by xenobiotics: An expanded role for nuclear hormone receptors. Mol. Pharmacol. 56, 851–857 (1999).
Xie, W. et al. Humanized xenobiotic response in mice expressing nuclear receptor SXR. Nature 406, 435–439 (2000).
Staudinger, J.L. et al. The nuclear receptor PXR is a lithocholic acid sensor that protects against liver toxicity. Proc. Natl. Acad. Sci. USA 98, 3369–3374. (2001).
Jones, S.A. et al. The pregnane X receptor: a promiscuous xenobiotic receptor that has diverged during evolution. Mol. Endocrinol. 14, 27–39 (2000).
Moore, L.B. et al. St. John's wort induces hepatic drug metabolism through activation of the pregnane X receptor. Proc. Natl. Acad. Sci. USA 97, 7500–7502 (2000).
Wentworth, J.M. et al. St John's wort, a herbal antidepressant, activates the steroid X receptor. J. Endocrinol. 166, R11–6 (2000).
Blumberg, B. et al. SXR, a novel steroid and xenobiotic-sensing nuclear receptor. Genes Dev. 12, 3195–3205 (1998).
Kostrubsky, V.E. et al. Induction of cytochrome P4503A by taxol in primary cultures of human hepatocytes. Arch. Biochem. Biophys. 355, 131–136 (1998).
Kliewer, S.A. et al. An orphan nuclear receptor activated by pregnanes defines a novel steroid signaling pathway. Cell 92, 73–82 (1998).
Kearns, C.M. Pharmacokinetics of the taxanes. Pharmacotherapy 17, 105S–109S (1997).
Forman, B.M. et al. Androstane metabolites bind to and deactivate the nuclear receptor CAR- beta. Nature 395, 612–615 (1998).
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).
McKinnon, R.A. et al. Characterisation of CYP3A gene subfamily expression in human gastrointestinal tissues. Gut 36, 259–267 (1995).
Sparreboom, A. et al. Limited oral bioavailability and active epithelial excretion of paclitaxel (Taxol) caused by P-glycoprotein in the intestine. Proc. Natl. Acad. Sci USA 94, 2031–5 (1997).
Eckardt, J.R. Antitumor activity of docetaxel. Am. J. Health Syst. Pharm. 54, S2–6 (1997).
Glass, C.K. & Rosenfeld, M.G. The coregulator exchange in transcriptional functions of nuclear receptors. Genes Dev. 14, 121–141 (2000).
Wang, H. et al. Endogenous bile acids are ligands for the nuclear receptor FXR/BAR. Mol Cell 3, 543–553 (1999).
Jepsen, K. et al. Combinatorial roles of the nuclear receptor corepresor in transcription and development. Cell 102, 753–763 (2000).
Lavinsky, R.M. et al. Diverse signaling pathways modulate nuclear receptor recruitment of N-CoR and SMRT complexes. Proc Natl. Acad. Sci. USA 95, 2920–5 (1998).
Jackson, T.A. et al. The partial agonist activity of antagonist-occupied steroid receptors is controlled by a novel hinge domain-binding coactivator L7/SPA and the corepressors N-CoR or SMRT. Mol. Endocrinol. 11, 693–705 (1997).
Smith, C.L., Nawaz, Z. & O'Malley, B.W. Coactivator and corepressor regulation of the agonist/antagonist activity of the mixed antiestrogen, 4-hydroxytamoxifen. Mol Endocrinol. 11, 657–666 (1997).
Izbicka, E. et al. In vitro antitumor activity of the novel marine agent, ecteinascidin-743 (ET-743, NSC-648766) against human tumors explanted from patients. Ann. Oncol. 9, 981–987 (1998).
Martinez, E.J., Owa, T., Schreiber, S.L. & Corey, E.J. Phthalascidin, a synthetic antitumor agent with potency and mode of action comparable to ecteinascidin 743. Proc. Natl. Acad. Sci. USA 96, 3496–3501 (1999).
Minuzzo, M. et al. Interference of transcriptional activation by the antineoplastic drug ecteinascidin-743. Proc. Natl. Acad. Sci. USA 97, 6780–6784 (2000).
Jin, S., Gorfajn, B., Faircloth, G. & Scotto, K.W. Ecteinascidin 743, a transcription-targeted chemotherapeutic that inhibits MDR1 activation. Proc. Natl. Acad. Sci. USA 97, 6775–6779 (2000).
Pascussi, J.M. et al. Interleukin-6 negatively regulates the expression of pregnane X receptor and constitutively activated receptor in primary human hepatocytes. Biochem. Biophys. Res. Commun. 274, 707–713 (2000).
Sakuma, T., Yokoi, T. & Kamataki, T. Isolation and characterization of a new cDNA clone belonging to the cytochrome P450 2C gene subfamily in hamsters. Arch. Biochem. Biophys. 319, 267–273 (1995).
Smith, D.A., Abel, S.M., Hyland, R. & Jones, B.C. Human cytochrome P450s: selectivity and measurement in vivo. Xenobiotica 28, 1095–1128 (1998).
Goldstein, J.A. & de Morais, S.M. Biochemistry and molecular biology of the human CYP2C subfamily. Pharmacogenetics 4, 285–299 (1994).
Masuyama, H. et al. The expression of pregnane X receptor and its target gene, cytochrome P450 3A1, in perinatal mouse. Mol. Cell. Endocrinol. 172, 47–56. (2001).
Sparreboom, A., van Tellingen, O., Nooijen, W.J. & Beijnen, J.H. Preclinical pharmacokinetics of paclitaxel and docetaxel. Anticancer Drugs 9, 1–17 (1998).
Dotzlaw, H., Leygue, E., Watson, P. & Murphy, L.C. The human orphan receptor PXR messenger RNA is expressed in both normal and neoplastic breast tissue. Clin. Cancer Res. 5, 2103–2107 (1999).
Clarke, S.J. & Rivory, L.P. Clinical pharmacokinetics of docetaxel. Clin. Pharmacokinet. 36, 99–114 (1999).
Dorr, R.T. Pharmacology of the taxanes. Pharmacotherapy 17, 96S–104S (1997).
Royer, I. et al. Metabolism of docetaxel by human cytochromes P450: interactions with paclitaxel and other antineoplastic drugs. Cancer Res. 56, 58–65 (1996).
Pallis, M. & Russell, N. P-glycoprotein plays a drug-efflux-independent role in augmenting cell survival in acute myeloblastic leukemia and is associated with modulation of a sphingomyelin-ceramide apoptotic pathway. Blood 95, 2897–2904 (2000).
Ruth, A.C. & Roninson, I.B. Effects of the multidrug transporter P-glycoprotein on cellular responses to ionizing radiation. Cancer Res. 60, 2576–2578 (2000).
Forman, B.M., Chen, J. & Evans, R.M. Hypolipidemic drugs, polyunsaturated fatty acids and eicosanoids are ligands for peroxisome proliferator-activated receptors α and δ. Proc. Natl. Acad. Sci. USA 94, 4312–4317 (1997).
Forman, B.M. et al. 15-Deoxy-Δ12, 14-prostaglandin J2 is a ligand for the adipocyte determination factor PPARγ. Cell 83, 803–812 (1995).
Forman, B.M., Umesono, K., Chen, J. & Evans, R.M. Unique response pathways are established by allosteric interactions among nuclear hormone receptors. Cell 81, 541–550 (1995).
Acknowledgements
We thank E. Wang, M.A. Kirigin, K. Hollister, B. Xi and M. Lin for technical assistance; R. Beard and R. Chandraratna for synthesis of SR12813; L. Brown for assistance with cell sorting; B. Blumberg and R. Evans for SXR and the CYP3A4x3-TK-luc reporter; L. Freedman for PBP (DRIP205); H. Chen and R. Evans for ACTR; M. Stallcup for GRIP; I. Schulman for SRC1; S. Kane for an MDR1 probe; and D. Chakravarti, S. Kane and L. Lai for critical review of the manuscript. This work was supported by The Gonda Research Center at Beckman Research Institute of the City of Hope National Medical Center and by P01 CA 33572 (Cancer Center Support Grant).
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Synold, T., Dussault, I. & Forman, B. The orphan nuclear receptor SXR coordinately regulates drug metabolism and efflux. Nat Med 7, 584–590 (2001). https://doi.org/10.1038/87912
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1038/87912
This article is cited by
-
Natural product-based screening led to the discovery of a novel PXR agonist with anti-cholestasis activity
Acta Pharmacologica Sinica (2022)
-
Dexamethasone enhances the efficacy of atorvastatin in inhibiting excessively inflammation-induced abnormal angiogenesis by regulating macrophages
Journal of Neuroinflammation (2021)
-
Application of modified Michaelis – Menten equations for determination of enzyme inducing and inhibiting drugs
BMC Pharmacology and Toxicology (2021)
-
Megestrol acetate is a specific inducer of CYP3A4 mediated by human pregnane X receptor
Cancer Chemotherapy and Pharmacology (2021)
-
Mutation of a single amino acid of pregnane X receptor switches an antagonist to agonist by altering AF-2 helix positioning
Cellular and Molecular Life Sciences (2021)