Modulation of P-glycoprotein efflux pump: induction and activation as a therapeutic strategy

Pharmacol Ther. 2015 May:149:1-123. doi: 10.1016/j.pharmthera.2014.11.013. Epub 2014 Nov 27.


P-glycoprotein (P-gp) is an ATP-dependent efflux pump encoded by the MDR1 gene in humans, known to mediate multidrug resistance of neoplastic cells to cancer therapy. For several decades, P-gp inhibition has drawn many significant research efforts in an attempt to overcome this phenomenon. However, P-gp is also constitutively expressed in normal human epithelial tissues and, due to its broad substrate specificity, to its cellular polarized expression in many excretory and barrier tissues, and to its great efflux capacity, it can play a crucial role in limiting the absorption and distribution of harmful xenobiotics, by decreasing their intracellular accumulation. Such a defense mechanism can be of particular relevance at the intestinal level, by significantly reducing the intestinal absorption of the xenobiotic and, consequently, avoiding its access to the target organs. In this review, the current knowledge on this important efflux pump is summarized, and a new focus is brought on the therapeutic interest of inducing and/or activating P-gp for limiting the toxicity caused by its substrates. Several in vivo and in vitro studies validating the use of such a therapeutic strategy are discussed. An extensive literature search for reported P-gp inducers/activators and for the experimental models used in their characterization was conducted. Those studies demonstrate that effective antidotal pathways can be achieved by efficiently promoting the P-gp-mediated efflux of deleterious xenobiotics, resulting in a significant reduction in their intracellular levels and, consequently, in a significant reduction of their toxicity.

Keywords: Activation; Induction; P-glycoprotein; Paraquat; Toxicity.

Publication types

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

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / antagonists & inhibitors
  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / biosynthesis
  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / metabolism*
  • ATP-Binding Cassette Transporters / biosynthesis
  • Animals
  • Antidotes / pharmacology*
  • Antidotes / therapeutic use*
  • Gene Expression Regulation / drug effects*
  • Humans
  • Models, Biological
  • Molecular Targeted Therapy / methods*
  • Signal Transduction
  • Stress, Physiological
  • Xenobiotics / pharmacokinetics*
  • Xenobiotics / toxicity


  • ATP Binding Cassette Transporter, Subfamily B, Member 1
  • ATP-Binding Cassette Transporters
  • Antidotes
  • Xenobiotics