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Vol. 294, Issue 1, 73-79, July 2000

Organic Anion-Transporting Polypeptides Mediate Transport of Opioid Peptides across Blood-Brain Barrier1

Bo Gao, Bruno Hagenbuch, Gerd A. Kullak-Ublick, Dietmar Benke, Adriano Aguzzi and Peter J. Meier

Clinical Pharmacology and Toxicology, Department of Medicine, University Hospital Zurich (B.G., B.H., G.A.K.-U., P.J.M.); Institute of Pharmacology and Toxicology, University of Zurich (D.B.); and Institute of Neuropathology, University Hospital Zurich (A.A.), Zurich, Switzerland

Organic anion-transporting polypeptides (Oatps) are a rapidly growing gene family of polyspecific membrane transporters. In rat brain, Oatp1 (gene symbol Slc21a1) and Oatp2 (Slc21a5) are localized at the apical and basolateral domains, respectively, of the choroid plexus epithelium. Furthermore, Oatp2 is strongly expressed at the rat blood-brain barrier (BBB). This study localizes the human OATP (now called OATP-A; SLC21A3) at the BBB in humans. Furthermore, with the Xenopus laevis oocyte system the delta -opioid receptor agonists [D-penicillamine2,5]enkephalin (DPDPE) and deltorphin II were identified as new transport substrates of OATP-A. This OATP-A-mediated DPDPE and deltorphin II transport exhibited apparent Km values of ~202 and 330 µM, respectively, and OATP-A-mediated deltorphin II transport was inhibited by the µ-opioid receptor agonist Tyr-D-Ala-Gly-N-methyl-Phe-glycinol, the endogenous peptide Leu-enkephalin, and the opiate antagonists naloxone and naltrindole. DPDPE also was transported by rat Oatp1 (Km ~48 µM) and Oatp2 (Km ~19 µM), whereas deltorphin II was only transported by Oatp1 (Km ~137 µM). These results demonstrate that OATP-A can mediate transport of the analgesic opioid peptides DPDPE and deltorphin II across the human BBB. Furthermore, because rat Oatp1 and Oatp2 exhibit similar but not identical transport activities as OATP-A, the results generally indicate that members of the Oatp/OATP gene family of membrane transporters play an important role in carrier-mediated transport of opioid peptides across the BBB and blood-cerebrospinal fluid barrier of the mammalian brain.

1 This study was supported by the Swiss National Science Foundation (Grant 31-045536.95); the Olga Mayenfisch Foundation, Zurich; and the Hartmann-Muller Foundation, Zurich, Switzerland.

0022-3565/00/2941-0073$03.00/0
THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
Copyright © 2000 by The American Society for Pharmacology and Experimental Therapeutics


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