Department of Pediatrics, UCSD, La Jolla, CA 92093, United States.
Neurosci Lett. 2013 Feb 8;534:133-8. doi: 10.1016/j.neulet.2012.11.027. Epub 2012 Nov 27.
Transporters in the choroid plexus (CP) regulate transport of numerous compounds of physiological and therapeutic interest between blood and CSF and thus likely play a key role in determining CNS levels of drugs, toxins and metabolites. Here, high CP expression was noted for the organic anion transporters, Oat1 (SLC22A6 or NKT) and Oat3 (SLC22A8) which are also the principal Oats in the renal proximal tubule, as well as SLC22A17, hypothesized to be involved in iron transport. Because Oat1 and Oat3 have overlapping substrate specificity, ex vivo preparations of CP from Oat1((-/-)) and Oat3((-/-)) mice were used to isolate the individual transport function of each, respectively. Tissue from either knockout mouse mediated the probenecid-inhibitable transport of the Oat substrate, 6-carboxyfluorescein (6CF), confirming the presence of Oat1 and Oat3 function. Because many antiviral medications are Oat substrates, including those crucial in the treatment of HIV infections, the interaction of the antivirals zidovudine, acyclovir, tenofovir, lamivudine, and stavudine, with Oat1 and Oat3 in CP, was investigated by determining the inhibition of 6CF uptake. All the antivirals tested manifested significant interaction with both Oat1 and Oat3, with the exception of stavudine which did not significantly affect Oat1 function. These results could have important implications for antiretroviral (and other drugs) penetration into or retention within the CNS, a major reservoir for virus during HIV infection. Apart from any effect at the blood brain barrier (BBB), designing specific inhibitors of Oat1 and Oat3 may be helpful in altering CNS drug levels by blocking organic anion transporters in the CP. The role of SLC22A17 in the CP deserves further exploration. The ability of Oats to regulate the movement of small molecules across the BBB, CP, proximal tubule and other tissues may also be important for their role in remote sensing and signaling [1,21]).
脉络丛中的转运体调节着许多具有生理和治疗意义的化合物在血液和 CSF 之间的转运，因此很可能在决定药物、毒素和代谢物在中枢神经系统中的水平方面发挥关键作用。在这里，有机阴离子转运体 Oat1（SLC22A6 或 NKT）和 Oat3（SLC22A8）在脉络丛中的表达水平较高，它们也是肾脏近端小管中的主要 Oat，同时还发现 SLC22A17 可能参与铁转运。由于 Oat1 和 Oat3 具有重叠的底物特异性，因此使用 Oat1((-/-))和 Oat3((-/-))小鼠的脉络丛体外制备物分别分离每种转运体的功能。来自敲除小鼠的组织介导了 Oat 底物 6-羧基荧光素（6CF）的丙磺舒抑制性转运，证实了 Oat1 和 Oat3 功能的存在。由于许多抗病毒药物是 Oat 的底物，包括在 HIV 感染治疗中至关重要的那些药物，因此研究了抗病毒药物齐多夫定、阿昔洛韦、替诺福韦、拉米夫定和司他夫定与脉络丛中的 Oat1 和 Oat3 的相互作用，通过确定 6CF 摄取的抑制作用来确定。所有测试的抗病毒药物都与 Oat1 和 Oat3 表现出显著的相互作用，除了司他夫定，它没有显著影响 Oat1 功能。这些结果可能对逆转录病毒（和其他药物）进入或保留在中枢神经系统（HIV 感染期间病毒的主要储存库）中具有重要意义。除了对血脑屏障（BBB）的任何影响外，设计 Oat1 和 Oat3 的特异性抑制剂可能有助于通过阻断脉络丛中的有机阴离子转运体来改变中枢神经系统中的药物水平。SLC22A17 在脉络丛中的作用值得进一步探索。Oat 调节小分子穿过 BBB、脉络丛、近端小管和其他组织的运动的能力，对于它们在远程传感和信号传递中的作用也可能很重要[1,21]）。
