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Research ArticleABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

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

Bo Gao, Bruno Hagenbuch, Gerd A. Kullak-Ublick, Dietmar Benke, Adriano Aguzzi and Peter J. Meier
Journal of Pharmacology and Experimental Therapeutics July 2000, 294 (1) 73-79;
Bo Gao
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Bruno Hagenbuch
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Gerd A. Kullak-Ublick
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Dietmar Benke
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Adriano Aguzzi
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Peter J. Meier
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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-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.

Footnotes

  • Send reprint requests to: Prof. Dr. Peter J. Meier-Abt, Clinical Pharmacology and Toxicology, Department of Medicine, University Hospital Zurich, CH-8091 Zurich, Switzerland. E-mail:meierabt{at}kpt.unizh.ch

  • ↵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.

  • ↵2 OATP (=OATP-A), first cloned human organic anion-transporting polypeptide (Kullak-Ublick et al., 1995), which is now called OATP-A (accession no. U21943) because additional human OATPs (e.g., OATP-B and OATP-C/LST-1/OATP2) have recently been reported in the gene data bank (accession nos. OATP-B, AB026256; NM_007256; OATP-C/LST-1/OATP2, AB026257; AF205071; AF060500; and AJ132573). Because various names have been given to individual Oatps/OATPs on the protein level, we also indicate for clearcut identification the accepted gene symbols in parenthesis for OATP-A (SLC21A3), Oatp1 (Slc21a1), and Oatp2 (Slc21a5) at their first mention in the Abstract and in the text.

  • Abbreviations:
    Oatp
    organic anion-transporting polypeptide
    BBB
    blood-brain barrier
    DPDPE
    [d-penicillamine2,5]enkephalin
    deltrophin II
    Tyr-Ala-Phe-Glu-Val-Val-Gly-NH2
    Leu-enkephalin
    Tyr-Gly-Gly-Phe-Leu-OH
    DAMGO
    Tyr-d-Ala-Gly-N-methyl-Phe-glycinol
    • Received January 6, 2000.
    • Accepted March 17, 2000.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 294 (1)
Journal of Pharmacology and Experimental Therapeutics
Vol. 294, Issue 1
1 Jul 2000
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Research ArticleABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

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

Bo Gao, Bruno Hagenbuch, Gerd A. Kullak-Ublick, Dietmar Benke, Adriano Aguzzi and Peter J. Meier
Journal of Pharmacology and Experimental Therapeutics July 1, 2000, 294 (1) 73-79;

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Research ArticleABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

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

Bo Gao, Bruno Hagenbuch, Gerd A. Kullak-Ublick, Dietmar Benke, Adriano Aguzzi and Peter J. Meier
Journal of Pharmacology and Experimental Therapeutics July 1, 2000, 294 (1) 73-79;
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