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Research ArticleArticle

Organic Anion Transporter 3 Mediates the Efflux Transport of an Amphipathic Organic Anion, Dehydroepiandrosterone Sulfate, across the Blood-Brain Barrier in Mice

Mari Miyajima, Hiroyuki Kusuhara, Miki Fujishima, Yasuhisa Adachi and Yuichi Sugiyama
Drug Metabolism and Disposition May 2011, 39 (5) 814-819; DOI: https://doi.org/10.1124/dmd.110.036863
Mari Miyajima
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Hiroyuki Kusuhara
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Miki Fujishima
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Yasuhisa Adachi
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Yuichi Sugiyama
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Abstract

The present study investigated the efflux transport systems of organic anions across the blood-brain barrier (BBB) using dehydroepiandrosterone sulfate (DHEAS) as a probe. The elimination of DHEAS from the brain after microinjection into the cerebral cortex was characterized in wild-type mice and mice with deficiency of well characterized organic anion transporters, organic anion-transporting polypeptide 1a4 (Oatp1a4)/Slco1a4 and organic anion transporter 3 (Oat3)/Slc22a8, at the BBB. The saturable efflux of DHEAS from the brain was completely inhibited by probenecid, benzylpenicillin, and estrone-3-sulfate and moderately inhibited by taurocholate and p-aminohippurate (50–57%). Uptake of DHEAS and estrone-3-sulfate was greater in murine Oat3 cRNA-injected oocytes than that in water-injected oocytes. Efflux of these compounds from the brain was significantly delayed in Oat3(−/−) mice compared with that in wild-type mice, indicating that indeed Oat3 is functionally important in vivo. Furthermore, probenecid and taurocholate inhibited DHEAS efflux completely in Oat3(−/−) mice. Contrary to the past report in rats that suggested involvement of Oatp1a4, specific uptake of DHEAS and estrone-3-sulfate by murine Oatp1a4 was not detected in vitro, and efflux of both compounds from the brain was not altered in Oatp1a4(−/−) mice. There was no significant difference in the uptake of DHEAS by brain slices prepared from wild-type, Oatp1a4(−/−), and Oat3(−/−) mice. Taken together, these results suggest that Oat3 plays a significant role in the efflux of steroid conjugates across the BBB in mice and that the BBB also expresses other unknown organic anion transporters for the efflux of DHEAS. Transport mechanisms of organic anions at the BBB are far more diverse than they were assumed to be.

Footnotes

  • This study was supported by the Ministry of Education, Culture, Sports, Science and Technology, Japan [Grant-in-Aid for Scientific Research (A) 20249008, Grant-in-Aid for Scientific Research (B) 20390046] (to Y.S. and H.K., respectively); and Research on Publicly Essential Drugs and Medical Devices of The Japan Health Sciences Foundation [Grant KHB1005] (to H.K.).

  • Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.

    doi:10.1124/dmd.110.036863.

  • ABBREVIATIONS:

    BBB
    blood-brain barrier
    BQ-123
    cyclo-d-Trp-d-Asp-Pro-d-Val-Leu
    Oatp/OATP
    organic anion transporting polypeptide
    Oat/OAT
    organic anion transporter
    Ro 64-0902
    [3R,4R,5S]-4-acetamido-5-amino-3-(1-ethylpropoxy)-1-cyclohexene-1-carboxylate
    DHEAS
    dehydroepiandrosterone sulfate
    PAH
    p-aminohippuric acid
    HEK
    human embryonic kidney
    BEI
    brain efflux index
    Gadph
    glyceraldehyde 3-phosphate dehydrogenase
    RT
    real time
    PCR
    polymerase chain reaction
    m
    mouse
    r
    rat.

  • Received October 20, 2010.
  • Accepted February 15, 2011.
  • Copyright © 2011 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 39 (5)
Drug Metabolism and Disposition
Vol. 39, Issue 5
1 May 2011
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Research ArticleArticle

Organic Anion Transporter 3 Mediates the Efflux Transport of an Amphipathic Organic Anion, Dehydroepiandrosterone Sulfate, across the Blood-Brain Barrier in Mice

Mari Miyajima, Hiroyuki Kusuhara, Miki Fujishima, Yasuhisa Adachi and Yuichi Sugiyama
Drug Metabolism and Disposition May 1, 2011, 39 (5) 814-819; DOI: https://doi.org/10.1124/dmd.110.036863

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Research ArticleArticle

Organic Anion Transporter 3 Mediates the Efflux Transport of an Amphipathic Organic Anion, Dehydroepiandrosterone Sulfate, across the Blood-Brain Barrier in Mice

Mari Miyajima, Hiroyuki Kusuhara, Miki Fujishima, Yasuhisa Adachi and Yuichi Sugiyama
Drug Metabolism and Disposition May 1, 2011, 39 (5) 814-819; DOI: https://doi.org/10.1124/dmd.110.036863
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