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The orphan nuclear receptor SXR coordinately regulates drug metabolism and efflux

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.

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Figure 1: Paclitaxel is a specific activator of SXR.
Figure 2: SXR activates expression of CYP2C8 and MDR1.
Figure 3: Docetaxel does not activate SXR or induce drug clearance.
Figure 4: Paclitaxel and docetaxel recruit co-activators but only paclitaxel displaces corepressors.
Figure 5: Ecteinascidin 743 (ET-743) inhibits transcriptional activation by SXR.
Figure 6: SXR coordinately regulates drug metabolism and efflux.

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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).

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Correspondence to Barry Marc Forman.

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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

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