Mechanisms of glutathione-conjugate efflux from the brain into blood: Involvement of multiple transporters in the course
Mechanisms of glutathione-conjugate efflux from the brain into blood: Involvement of multiple transporters in the course
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DOI：
10.1177/0271678x18808399
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发表时间：
2020-01-01
影响因子：
6.3
通讯作者：
Zhang, Ming-Rong
中科院分区：
文献类型：
--
作者：
Okamura, Toshimitsu;Okada, Maki;Zhang, Ming-Rong
有害的谷胱甘肽结合代谢物在大脑中的积累可能会导致神经系统疾病，因此必须从大脑中输出。然而，谷胱甘肽结合物从大脑流出的体内机制仍然未知。我们使用6-溴-7-[C-11]甲基嘌呤（[C-11]1）研究了谷胱甘肽结合物外排中转运蛋白的参与，6-溴-7-[C-11]甲基嘌呤（[C-11]1）进入大脑并转化为谷胱甘肽结合物S-（7-[C-11]甲基嘌呤-6-基）谷胱甘肽（[C-11]2）。在对照和敲除P-糖蛋白/乳腺癌耐药蛋白和多药耐药相关蛋白2（[Mrp 2]（-/-））的小鼠中，脑中形成的[C-11]2被迅速清除，外排率无显著差异。相反，在Mrp 1（-/-）小鼠脑中形成的[C-11]2被缓慢清除，而显微注射到对照组和Mrp 1（-/-）小鼠脑中的[C-11] 2在60 min内被清除75%，外排率无显著差异。这些表明Mrp 1有助于[C-11]2跨细胞膜流出，但不是BBB。与对照小鼠相比，Mrp 4（-/-）和有机阴离子转运蛋白3（Oat 3）（-/-）小鼠脑中形成的[C-11]2的外排率显著降低。总之，Mrp 1，Oat 3和Mrp 4介导[C-11]2从脑中流出。Mrp 1可能有助于[C-11]2从脑实质细胞流出，而细胞外[C-11]2可能通过BBB清除，部分由Oat 3和Mrp 4清除。
Accumulation of detrimental glutathione-conjugated metabolites in the brain potentially causes neurological disorders, and must therefore be exported from the brain. However, in vivo mechanisms of glutathione-conjugates efflux from the brain remain unknown. We investigated the involvement of transporters in glutathione-conjugates efflux using 6-bromo-7-[C-11]methylpurine ([C-11]1), which enters the brain and is converted into its glutathione conjugate, S-(7-[C-11]methylpurin-6-yl)glutathione ([C-11]2). In mice of control and knockout of P-glycoprotein/breast cancer resistance protein and multidrug resistance-associated protein 2 ([Mrp2](-/-)), [C-11]2 formed in the brain was rapidly cleared, with no significant difference in efflux rate. In contrast, [C-11]2 formed in the brain of Mrp1(-/-) mice was slowly cleared, whereas [C-11]2 microinjected into the brain of control and Mrp1(-/-) mice was 75% cleared within 60 min, with no significant difference in efflux rate. These suggest that Mrp1 contributes to [C-11]2 efflux across cell membranes, but not BBB. Efflux rate of [C-11]2 formed in the brain was significantly lower in Mrp4(-/-) and organic anion transporter 3 (Oat3)(-/-) mice compared with control mice. In conclusion, Mrp1, Oat3, and Mrp4 mediate [C-11]2 efflux from the brain. Mrp1 may contribute to [C-11]2 efflux from brain parenchymal cells, while extracellular [C-11]2 is likely cleared across the BBB, partly by Oat3 and Mrp4.