Coordinated Nuclear Receptor Regulation of the Efflux Transporter, Mrp2, and the Phase-Ii Metabolizing Enzyme, GSTπ, at the Blood—Brain Barrier

• Published in: Journal of cerebral blood flow and metabolism Vol. 28; no. 6; pp. 1222 - 1234
• Main Authors: Bauer, Björn, Hartz, Anika M S, Lucking, Jonathan R, Yang, Xiaodong, Pollack, Gary M, Miller, David S
• Format: Journal Article
• Language: English
• Published: London, England SAGE Publications 01.06.2008; Lippincott Williams & Wilkins
• Subjects: Biological and medical sciences; Medical sciences; Neurology; Neuropharmacology; Neuroprotective agent; Pharmacology. Drug treatments; Vascular diseases and vascular malformations of the nervous system; GSTπ; Mrp2; PXR; regulation; blood—brain barrier; blood-brain barrier; Nervous system diseases; Enzyme; Central nervous system disease; Phase II trial; Blood brain barrier; Cerebrovascular disease; Cerebral disorder
• ISSN: 0271-678X; 1559-7016
• DOI: 10.1038/jcbfm.2008.16

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.