Coordinated nuclear receptor regulation of the efflux transporter, Mrp2, and the phase-II metabolizing enzyme, GSTπ, at the blood-brain barrier

Björn Bauer, Anika M.S. Hartz, Jonathan R. Lucking, Xiaodong Yang, Gary M. Pollack, David S. Miller

Research output: Contribution to journalArticlepeer-review

116 Scopus citations

Abstract

Xenobiotic efflux pumps at the blood-brain barrier are critical modulators of central nervous system pharmacotherapy. We previously found expression of the ligand-activated nuclear receptor, pregnane X receptor (PXR), in rat brain capillaries, and showed increased expression and transport activity of the drug efflux transporter, P-glycoprotein, in capillaries exposed to PXR ligands (pregnenolone-16α-carbonitrile (PCN) and dexamethasone) in vitro and in vivo. Here, we show increased protein expression and transport activity of another efflux pump, multidrug resistance-associated protein isoform 2 (Mrp2), in rat brain capillaries after in vitro and in vivo exposure to PCN and dexamethasone. The phase-II drug-metabolizing enzyme, glutathione S-transferase-π (GSTπ), was found to be expressed in brain capillaries, where it colocalized to a large extent with Mrp2 at the endothelial cell luminal plasma membrane. Like Mrp2, GSTπ protein expression increased with PXR activation. Colocalization and coordinated upregulation suggest functional coupling of the metabolizing enzyme and efflux transporter. These findings indicate that, as in hepatocytes, brain capillaries possess a regulatory network consisting of nuclear receptors, metabolizing enzymes, and efflux transporters, which modulate blood-brain barrier function.

Original languageEnglish
Pages (from-to)1222-1234
Number of pages13
JournalJournal of Cerebral Blood Flow and Metabolism
Volume28
Issue number6
DOIs
StatePublished - Jun 30 2008

Keywords

  • Blood-brain barrier
  • GSTπ
  • Mrp2
  • PXR
  • Regulation

ASJC Scopus subject areas

  • Neurology
  • Clinical Neurology
  • Cardiology and Cardiovascular Medicine

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