Abstract

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 theXenopus laevis oocyte system the δ-opioid receptor agonists [d-penicillamine^2,5]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 K_m 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 (K_m ∼48 μM) and Oatp2 (K_m ∼19 μM), whereas deltorphin II was only transported by Oatp1 (K_m ∼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.