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