Role of blood–brain barrier organic anion transporter 3 (OAT3) in the efflux of indoxyl sulfate, a uremic toxin: its involvement in neurotransmitter metabolite clearance from the brain

Authors

  • Sumio Ohtsuki,

    1. Department of Molecular Biopharmacy and Genetics, Graduate School of Pharmaceutical Sciences, and
    2. New Industry Creation Hatchery Center, Tohoku University, Sendai, Japan
    3. CREST of the Japan Science and Technology Corporation (JST), Japan
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  • Hiroshi Asaba,

    1. Department of Molecular Biopharmacy and Genetics, Graduate School of Pharmaceutical Sciences, and
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  • Hitomi Takanaga,

    1. Department of Molecular Biopharmacy and Genetics, Graduate School of Pharmaceutical Sciences, and
    2. New Industry Creation Hatchery Center, Tohoku University, Sendai, Japan
    3. CREST of the Japan Science and Technology Corporation (JST), Japan
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  • Tsuneo Deguchi,

    1. Department of Molecular Biopharmacy and Genetics, Graduate School of Pharmaceutical Sciences, and
    2. Faculty of Pharmaceutical Sciences, Kumamoto University, Kumamoto, Japan
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  • Ken-ichi Hosoya,

    1. CREST of the Japan Science and Technology Corporation (JST), Japan
    2. Faculty of Pharmaceutical Sciences, Toyama Medical and Pharmaceutical University, Toyama, Japan
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  • Masaki Otagiri,

    1. Faculty of Pharmaceutical Sciences, Kumamoto University, Kumamoto, Japan
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  • Tetsuya Terasaki

    1. Department of Molecular Biopharmacy and Genetics, Graduate School of Pharmaceutical Sciences, and
    2. New Industry Creation Hatchery Center, Tohoku University, Sendai, Japan
    3. CREST of the Japan Science and Technology Corporation (JST), Japan
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Address correspondence and reprint requests to Tetsuya Terasaki, Department of Molecular Biopharmacy and Genetics, Graduate Schoolof Pharmaceutical Sciences, Tohoku University, Aoba,Aramaki,Aoba-ku, Sendai 980–8578, Japan. E-mail: terasaki@mail.pharm.tohoku.ac.jp

Abstract

Renal impairment is associated with CNS dysfunctions and the accumulation of uremic toxins, such as indoxyl sulfate, in blood. To evaluate the relevance of indoxyl sulfate to CNS dysfunctions, we investigated the brain-to-blood transport of indoxyl sulfate at the blood–brain barrier (BBB) using the Brain Efflux Index method. [3H]Indoxyl sulfate undergoes efflux transport with an efflux transport rate of 1.08 × 10−2/min, and the process is saturable with a Km of 298 µm. This process is inhibited by para-aminohippuric acid, probenecid, benzylpenicillin, cimetidine and uremic toxinins, such as hippuric acidand 3-carboxy-4-methyl-5-propyl-2-furanpropanoic acid. RT–PCR revealed that an OAT3 mRNA is expressed in conditionally immortalized rat brain capillary endothelial cell lines and rat brain capillary fraction. Xenopus oocytes expressing OAT3 were found to exhibit [3H]indoxyl sulfate uptake, which was significantly inhibited by neurotransmitter metabolites, such as homovanillic acid and 3-methoxy-4-hydroxymandelic acid, and by acyclovir, cefazolin, baclofen, 6-mercaptopurine, benzoic acid, and ketoprofen. These results suggest that OAT3 mediates the brain-to-blood transport of indoxyl sulfate, and is also involved in the efflux transport of neurotransmitter metabolites and drugs. Therefore, inhibition of the brain-to-blood transport involving OAT3 would occur in uremia and lead to the accumulation of neurotransmitter metabolites and drugs in the brain.

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