Pregnane X receptor up-regulation of P-glycoprotein expression and transport function at the blood-brain barrier

Björn Bauer, Anika M.S. Hartz, Gert Fricker, David S. Miller

Research output: Contribution to journalArticlepeer-review

275 Scopus citations

Abstract

P-glycoprotein, an ATP-driven drug export pump, is a critical, selective component of the blood-brain barrier responsible for the poor penetration of many therapeutic drugs. In liver, ligand-activated, nuclear receptors are transcriptional regulators of drug metabolizing enzymes and drug export pumps, but only one, the pregnane X receptor (PXR in rodents, SXR in humans), regulates p-glycoprotein expression. We report for the first time that PXR is expressed in rat brain capillaries. Moreover, exposing isolated capillaries to the PXR ligands pregnenolone-16α-carbonitrile (PCN) and dexamethasone increased p-glycoprotein expression and p-glycoprotein-specific transport of a fluorescent cyclosporine A derivative into capillary lumens. Dosing rats with PCN and dexamethasone increased p-glycoprotein expression in liver plasma membranes and in brain capillaries and up-regulated specific transport in capillaries. This is the first evidence for PXR expression in brain and for regulation by nuclear receptors of a xenobiotic export pump at the blood-brain barrier. These results imply selective tightening of the barrier in patients exposed to the wide range of xenobiotics that are PXR/SXR ligands, including drugs, dietary constituents, and toxicants.

Original languageEnglish
Pages (from-to)413-419
Number of pages7
JournalMolecular Pharmacology
Volume66
Issue number3
StatePublished - Sep 2004

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology

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