Brain-to-blood elimination of 24S-hydroxycholesterol from rat brain is mediated by organic anion transporting polypeptide 2 (oatp2) at the blood-brain barrier
Brain-to-blood elimination of 24S-hydroxycholesterol from rat brain is mediated by organic anion transporting polypeptide 2 (oatp2) at the blood-brain barrier
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DOI：
10.1111/j.1471-4159.2007.04901.x
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发表时间：
2007-11-01
影响因子：
4.7
通讯作者：
Terasaki, Tetsuya
中科院分区：
文献类型：
--
作者：
Ohtsuki, Sumio;Ito, Shingo;Terasaki, Tetsuya
24s -羟基胆固醇（24S-OH-chol）是一种主要的脑胆固醇代谢物，是肝脏X受体的内源性配体，是神经胶质细胞释放胆固醇的潜在刺激物。24S-OH-chol在脑内的消除机制是了解脑内胆固醇稳态的关键问题之一。本研究的目的是阐明24S-OH-chol通过血脑屏障（BBB）消除过程的分子机制。大鼠经脑内注射后，[H-3]24S-OH-chol从脑内消除，血浆中检测到[H-3]24S-OH-chol的放射性，而[H-3]胆固醇在脑内未明显消除。同时给予未标记的24S-OH-chol显著抑制[H-3]24S-OH-chol的消除，而相同浓度的胆固醇没有抑制作用。同时给药可抑制[H-3]24S-OH-chol的消除，而青霉素则无此作用。预先给药地高辛完全抑制消除。表达大鼠oatp2的非洲爪蟾卵母细胞明显转运[H-3]24S-OH-chol，未标记的24S-OH-chol和地高辛抑制了这种转运，表明大鼠oatp2转运24S-OH-chol。这些结果是第一次直接证明24S-OH-chol通过载体介导的过程从大脑通过血脑屏障进入血液，这一过程涉及大鼠血脑屏障表达的oatp2。
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, [H-3]24S-OH-chol was eliminated from the brain and the radioactivity derived from [H-3]24S-OH-chol was detected in the plasma, while [H-3]cholesterol was not significantly eliminated from the brain. Co-administration of unlabeled 24S-OH-chol significantly inhibited the [H-3]24S-OH-chol elimination, while no inhibitory effect was seen at the same concentration of cholesterol. The [H-3]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 [H-3]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.