Organic Anion Transporting Polypeptide 1a4 (Oatp1a4/Slco1a4) at the Blood-Arachnoid Barrier is the Major Pathway of Sulforhodamine-101 Clearance from Cerebrospinal Fluid of Rats
Organic Anion Transporting Polypeptide 1a4 (Oatp1a4/Slco1a4) at the Blood-Arachnoid Barrier is the Major Pathway of Sulforhodamine-101 Clearance from Cerebrospinal Fluid of Rats
复制标题
血蛛网膜屏障处的有机阴离子转运多肽 1a4 (Oatp1a4/Slco1a4) 是大鼠脑脊液中 Sulforhodamine-101 清除的主要途径
DOI：
10.1021/acs.molpharmaceut.9b00005
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发表时间：
2019
期刊：
影响因子：
--
通讯作者：
Terasaki T.
中科院分区：
文献类型：
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作者：
Yaguchi Y;Tachikawa M;Zhang Z;Terasaki T.
血蛛网膜屏障（BAB）由通过紧密连接连接的蛛网膜上皮细胞形成，通常被认为对水溶性物质是不可渗透的。然而，我们最近证明有机阴离子转运蛋白 1 和 3（Oat1 和 Oat3）在 BAB 的药物清除中发挥作用。在这里，我们使用荧光有机阴离子磺基罗丹明-101 (SR-101) 作为模型底物，检查了有机阴离子转运多肽 (Oatp) 是否也发挥了作用。将 SR-101 注射到大鼠小脑延髓池中，以尽量减少脉络丛运输的影响。脑池内给药后，SR-101 的体内脑脊液 (CSF) 消除清除率比荧光素标记的菊粉（一种大流量标记物）高九倍。在预先施用牛磺胆酸盐（Oatps 的广谱抑制剂）或地高辛（Oatp1a4 的强底物/抑制剂，但不包括 Oatp1a1、Oat1 和 Oat3）的情况下，SR-101 的 CSF 消除显着减少，变得与菊粉相似，因此表明完全抑制了 SR-101 从 CSF 的清除。在没有抑制剂的情况下，SR-101荧光的分布仅限于蛛网膜，而在共注射牛磺胆酸盐或地高辛后，荧光在脊髓实质中增加。免疫染色证实了 Oatp1a4 在蛛网膜中的定位。这些结果表明 BAB 处的 Oatp1a4 充当 CSF 中 SR-101 到血液的快速清除途径。因此，Oatp1a4 通过限制有机阴离子向大脑和脊髓的分布，似乎在脑脊液解毒中发挥着重要作用。
The blood–arachnoid barrier (BAB), which is formed by arachnoid epithelial cells linked by tight junctions, has generally been considered impermeable to water-soluble substances. However, we recently demonstrated that organic anion transporters 1 and 3 (Oat1 and Oat3) play roles in drug clearance at the BAB. Here, we examined whether an organic anion-transporting polypeptide (Oatp) also plays a role, using the fluorescent organic anion sulforhodamine-101 (SR-101) as a model substrate. SR-101 was injected into the cisterna magna of rats in order to minimize the contribution of choroid plexus transport. The in vivo cerebrospinal fluid (CSF) elimination clearance of SR-101 after intracisternal administration was ninefold greater than that of fluorescein-labeled inulin, a bulk flow marker. In the case of pre-administration of taurocholate, a broad-spectrum inhibitor of Oatps, or digoxin, a strong substrate/inhibitor for Oatp1a4 but not for Oatp1a1, Oat1, and Oat3, the CSF elimination of SR-101 was significantly reduced, becoming similar to that of inulin, and thus indicating complete inhibition of SR-101 clearance from the CSF. The distribution of SR-101 fluorescence was restricted to the arachnoid mater in the absence of inhibitor, whereas the fluorescence was increased in the parenchyma of the spinal cord after co-injection of taurocholate or digoxin. Immunostaining confirmed the localization of Oatp1a4 in the arachnoid mater. These results indicate that Oatp1a4 at the BAB acts as an avid clearance pathway of SR-101 in the CSF to the blood. Thus, Oatp1a4 appears to play a major role in CSF detoxification by limiting the distribution of organic anions to the brain and spinal cord.