Brain-to-blood elimination of 24S-hydroxycholesterol from rat brain is mediated by organic anion transporting polypeptide 2 (oatp2) at the blood–brain barrier

Authors

  • Sumio Ohtsuki,

    1. Department of Molecular Biopharmacy and Genetics, Graduate School of Pharmaceutical Sciences, Tohoku University, Aoba, Aramaki, Aoba-ku, Sendai, Japan
    2. New Industry Creation Hatchery Center, Tohoku University, Aoba, Aramaki, Aoba-ku, Sendai, Japan
    3. SORST and CREST of Japan Science and Technology Agency, Japan
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  • Shingo Ito,

    1. Department of Molecular Biopharmacy and Genetics, Graduate School of Pharmaceutical Sciences, Tohoku University, Aoba, Aramaki, Aoba-ku, Sendai, Japan
    2. SORST and CREST of Japan Science and Technology Agency, Japan
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  • Akihiro Matsuda,

    1. Department of Molecular Biopharmacy and Genetics, Graduate School of Pharmaceutical Sciences, Tohoku University, Aoba, Aramaki, Aoba-ku, Sendai, Japan
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  • Satoko Hori,

    1. Department of Molecular Biopharmacy and Genetics, Graduate School of Pharmaceutical Sciences, Tohoku University, Aoba, Aramaki, Aoba-ku, Sendai, Japan
    2. New Industry Creation Hatchery Center, Tohoku University, Aoba, Aramaki, Aoba-ku, Sendai, Japan
    3. SORST and CREST of Japan Science and Technology Agency, Japan
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  • Takaaki Abe,

    1. Division of Nephrology, Endocrinology, and Vascular Medicine, Department of Medicine, Tohoku University School of Medicine, Aoba-ku, Sendai, Japan
    2. PRESTO of Japan Science and Technology Agency, Japan
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  • Tetsuya Terasaki

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

Abstract

24S-Hydroxycholesterol (24S-OH-chol), a major cerebral cholesterol metabolite, is an endogenous ligand for the liver X receptor and is a potential stimulant of cholesterol release from glial cells. The elimination mechanism of 24S-OH-chol from the brain is one of the key issues for understanding cerebral cholesterol homeostasis. The purpose of the present study was to clarify the molecular mechanism of the elimination process of 24S-OH-chol across the blood–brain barrier (BBB). After an intracerebral injection in rats, [3H]24S-OH-chol was eliminated from the brain and the radioactivity derived from [3H]24S-OH-chol was detected in the plasma, while [3H]cholesterol was not significantly eliminated from the brain. Co-administration of unlabeled 24S-OH-chol significantly inhibited the [3H]24S-OH-chol elimination, while no inhibitory effect was seen at the same concentration of cholesterol. The [3H]24S-OH-chol elimination was inhibited by co-administration of probenecid, but not by benzylpenicillin. Pre-administration of digoxin completely inhibited the elimination. Xenopus laevis oocytes expressing rat oatp2 exhibited significant transport of [3H]24S-OH-chol, and this was inhibited by unlabeled 24S-OH-chol and digoxin, indicating that rat oatp2 transports 24S-OH-chol. These results are the first direct demonstration that 24S-OH-chol undergoes elimination from the brain to blood across the BBB via a carrier-mediated process, which involves oatp2 expressed at the BBB in rats.

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