Multidrug resistance protein MRP2 contributes to blood-brain barrier function and restricts antiepileptic drug activity
Multidrug resistance protein MRP2 contributes to blood-brain barrier function and restricts antiepileptic drug activity
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DOI：
10.1124/jpet.103.049858
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发表时间：
2003-07-01
影响因子：
3.5
通讯作者：
Löscher, W
中科院分区：
文献类型：
--
作者：
Potschka, H;Fedrowitz, M;Löscher, W
血脑屏障（BBB）是大脑和体循环之间的物理和代谢屏障，其功能是保护大脑免受循环药物，毒素和异种生物的影响。atp依赖的多药物转运体，如p -糖蛋白（Pgp; ABCB1），存在于脑毛细血管内皮细胞的顶（管腔）膜中，被认为通过限制药物渗透到大脑中，在血脑屏障功能中发挥重要作用。最近，在包括人类在内的不同物种的脑毛细血管内皮管腔表面发现了多药耐药蛋白MRP2 （ABCC2）。在耐药癫痫患者的内皮细胞中，MRP2被证明过表达，表明它可能在这类患者的多药耐药中起关键作用。然而，MRP2在药物进入大脑中的作用尚未明确。在此，我们采用不同的策略来研究MRP2对血脑屏障功能的贡献。首先，MRP抑制剂probenecid可增加大鼠主要抗癫痫药物苯妥英的细胞外脑水平，表明苯妥英是血脑屏障中MRP2的底物。用mrp2缺陷的TR-大鼠证实了这一点，其中细胞外脑苯妥英水平明显高于正常背景菌株。在癫痫点燃模型中，同时给药丙苯尼可显著提高苯妥英的抗惊厥活性。在点燃的mrp2缺陷大鼠中，苯妥英的抗惊厥活性明显高于正常大鼠。这些数据表明MRP2对血脑屏障功能有重要作用。
The blood-brain barrier (BBB) is a physical and metabolic barrier between the brain and the systemic circulation, which functions to protect the brain from circulating drugs, toxins, and xenobiotics. ATP-dependent multidrug transporters such as P-glycoprotein (Pgp; ABCB1), which are found in the apical (luminal) membranes of brain capillary endothelial cells, are thought to play an important role in BBB function by limiting drug penetration into the brain. More recently, the multidrug resistance protein MRP2 (ABCC2) has been found in the luminal surface of brain capillary endothelium of different species, including humans. In endothelial cells from patients with drug-resistant epilepsy, MRP2 was shown to be overexpressed, indicating that it may be critically involved in multidrug resistance of such patients. However, the role of MRP2 in drug disposition into the brain is defined poorly. Herein, we used different strategies to study the contribution of MRP2 to BBB function. First, the MRP inhibitor probenecid was shown to increase extracellular brain levels of the major antiepileptic drug phenytoin in rats, indicating that phenytoin is a substrate of MRP2 in the BBB. This was substantiated by using MRP2-deficient TR- rats, in which extracellular brain levels of phenytoin were significantly higher compared with the normal background strain. In the kindling model of epilepsy, coadministration of probenecid significantly increased the anticonvulsant activity of phenytoin. In kindled MRP2-deficient rats, phenytoin exerted a markedly higher anticonvulsant activity than in normal rats. These data indicate that MRP2 substantially contributes to BBB function.