Ohtsuki Sumio, Asaba Hiroshi, Takanaga Hitomi, Deguchi Tsuneo, Hosoya Ken-ichi, Otagiri Masaki, Terasaki Tetsuya
Department of Molecular Biopharmacy and Genetics, Graduate School of Pharmaceutical Sciences, Tohoku University, Aoba, Aramaki, Aoba-ku, Sendai 980-8578, Japan.
J Neurochem. 2002 Oct;83(1):57-66. doi: 10.1046/j.1471-4159.2002.01108.x.
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. [(3)H]Indoxyl sulfate undergoes efflux transport with an efflux transport rate of 1.08 x 10(-2)/min, and the process is saturable with a Km of 298 microm. This process is inhibited by para-aminohippuric acid, probenecid, benzylpenicillin, cimetidine and uremic toxinins, such as hippuric acid and 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 [(3)H]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.
肾功能损害与中枢神经系统功能障碍以及血液中尿毒症毒素（如硫酸吲哚酚）的蓄积有关。为了评估硫酸吲哚酚与中枢神经系统功能障碍的相关性，我们使用脑外排指数法研究了硫酸吲哚酚在血脑屏障（BBB）处的脑-血转运。[（3）H]硫酸吲哚酚以1.08×10（-2）/分钟的外排转运速率进行外排转运，该过程具有饱和性，Km为298微摩尔。此过程受到对氨基马尿酸、丙磺舒、苄青霉素、西咪替丁以及尿毒症毒素（如马尿酸和3-羧基-4-甲基-5-丙基-2-呋喃丙酸）的抑制。逆转录-聚合酶链反应显示，OAT3 mRNA在条件性永生化大鼠脑毛细血管内皮细胞系和大鼠脑毛细血管组分中表达。发现表达OAT3的非洲爪蟾卵母细胞表现出[（3）H]硫酸吲哚酚摄取，该摄取受到神经递质代谢产物（如高香草酸和3-甲氧基-4-羟基扁桃酸）以及阿昔洛韦、头孢唑林、巴氯芬、6-巯基嘌呤、苯甲酸和酮洛芬的显著抑制。这些结果表明，OAT3介导硫酸吲哚酚的脑-血转运，并且还参与神经递质代谢产物和药物的外排转运。因此，尿毒症时会发生涉及OAT3的脑-血转运抑制，并导致神经递质代谢产物和药物在脑中蓄积。
