The orphan nuclear receptor SXR coordinately regulates drug metabolism and efflux

Nat Med. 2001 May;7(5):584-90. doi: 10.1038/87912.


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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / genetics
  • Animals
  • Antineoplastic Agents, Phytogenic / pharmacokinetics*
  • Aryl Hydrocarbon Hydroxylases*
  • Cell Line
  • Cytochrome P-450 Enzyme System / genetics
  • Dioxoles / pharmacology
  • Docetaxel
  • Gene Expression Regulation / physiology
  • Humans
  • Isoquinolines / pharmacology
  • Paclitaxel / analogs & derivatives*
  • Paclitaxel / pharmacokinetics*
  • Pregnane X Receptor
  • Receptors, Steroid / antagonists & inhibitors
  • Receptors, Steroid / physiology*
  • Steroid 16-alpha-Hydroxylase*
  • Steroid Hydroxylases / genetics
  • Taxoids*
  • Tetrahydroisoquinolines
  • Trabectedin


  • ATP Binding Cassette Transporter, Subfamily B, Member 1
  • Antineoplastic Agents, Phytogenic
  • Dioxoles
  • Isoquinolines
  • Pregnane X Receptor
  • Receptors, Steroid
  • Taxoids
  • Tetrahydroisoquinolines
  • Docetaxel
  • Cytochrome P-450 Enzyme System
  • Steroid Hydroxylases
  • Aryl Hydrocarbon Hydroxylases
  • Steroid 16-alpha-Hydroxylase
  • Trabectedin
  • Paclitaxel