Regulation of P-glycoprotein by orphan nuclear receptors in human brain microvessel endothelial cells

J Neurochem. 2011 Jul;118(2):163-75. doi: 10.1111/j.1471-4159.2011.07288.x. Epub 2011 May 25.


In mammalian systems, pregnane X receptor (PXR) and constitutive androstane receptor (CAR) have been recognized as xenobiotic-sensors which can up-regulate the functional expression of drug transporters, such as P-glycoprotein (P-gp). In the brain, an increase in P-gp expression can further limit drug permeability across the blood-brain barrier (BBB) and potentially reduce CNS pharmacotherapy efficacy. At present, the involvement of human PXR (hPXR) and CAR (hCAR) in the regulation of P-gp expression at the human BBB is unknown. In this study, we investigate the role of hPXR and hCAR in the regulation of P-gp expression using a human cerebral microvessel endothelial cell culture system. We demonstrate that activation of hPXR and hCAR by their respective ligands leads to P-gp induction at both mRNA and protein levels, while pharmacological inhibitors of hPXR and hCAR prevent ligand-mediated P-gp induction. Ligand-induced nuclear translocation of hPXR is observed, although such effect could not be demonstrated for hCAR. Furthermore, down-regulation of hPXR and hCAR proteins using small-interfering RNA decreased P-gp expression. Our findings provide first evidence for P-gp regulation by hPXR and hCAR at the human BBB and suggest insights on how to achieve selective P-gp regulation at this site.

Publication types

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

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / antagonists & inhibitors
  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / metabolism*
  • Animals
  • Blood-Brain Barrier / cytology
  • Blood-Brain Barrier / physiology
  • Brain / blood supply
  • Brain / cytology
  • Brain / metabolism*
  • Cell Line, Transformed
  • Cells, Cultured
  • Endothelial Cells / cytology
  • Endothelial Cells / metabolism
  • Endothelial Cells / physiology*
  • Hep G2 Cells
  • Humans
  • Ligands
  • Microvessels / cytology
  • Microvessels / metabolism
  • Microvessels / physiology*
  • Orphan Nuclear Receptors / physiology*
  • Pregnane X Receptor
  • RNA, Messenger / physiology
  • Rats
  • Receptors, Cytoplasmic and Nuclear / antagonists & inhibitors
  • Receptors, Cytoplasmic and Nuclear / physiology*
  • Receptors, Steroid / antagonists & inhibitors
  • Receptors, Steroid / physiology*


  • ATP Binding Cassette Transporter, Subfamily B, Member 1
  • Ligands
  • Orphan Nuclear Receptors
  • Pregnane X Receptor
  • RNA, Messenger
  • Receptors, Cytoplasmic and Nuclear
  • Receptors, Steroid
  • constitutive androstane receptor