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Laboratory of Pharmacology and Chemistry, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina (B.B., A.M.S.H., D.S.M.); and Institute for Pharmacy and Molecular Biotechnology, University of Heidelberg, Heidelberg, Germany (A.M.S.H., G.F.)
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-16
-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.
Address correspondence to: Dr. David S. Miller, Laboratory of Pharmacology and Chemistry, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC 27709. E-mail: miller{at}niehs.nih.gov
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