1. ¹Laboratory of Pharmacology and Chemistry, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina, USA
2. ²Department of Pharmaceutical Sciences, College of Pharmacy, University of Minnesota, Duluth, Minnesota, USA
3. ³Department of Biochemistry and Molecular Biology, Medical School, University of Minnesota, Duluth, Minnesota, USA
4. ⁴Division of Pharmacotherapy and Experimental Therapeutics, School of Pharmacy, University of North Carolina, Chapel Hill, North Carolina, USA

Correspondence: Dr DS Miller, Laboratory of Pharmacology and Chemistry, National Institute of Environmental Health Science, National Institutes of Health, Research Triangle Park, NC 27709, USA. E-mail: miller@niehs.nih.gov

Received 31 August 2007; Revised 21 December 2007; Accepted 16 February 2008; Published online 19 March 2008.

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-16-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- (GST), 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, GST 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.