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首页> 外文期刊>BMC Neuroscience >RLIP76, a non-ABC transporter, and drug resistance in epilepsy
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RLIP76, a non-ABC transporter, and drug resistance in epilepsy

机译：RLIP76，一种非ABC转运蛋白，在癫痫病中具有耐药性

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Background Permeability of the blood-brain barrier is one of the factors determining the bioavailability of therapeutic drugs and resistance to chemically different antiepileptic drugs is a consequence of decreased intracerebral accumulation. The ABC transporters, particularly P-glycoprotein, are known to play a role in antiepileptic drug extrusion, but are not by themselves sufficient to fully explain the phenomenon of drug-resistant epilepsy. Proteomic analyses of membrane protein differentially expressed in epileptic foci brain tissue revealed the frequently increased expression of RLIP76/RALBP1, a recently described non-ABC multi-specific transporter. Because of a significant overlap in substrates between P-glycoprotein and RLIP76, present studies were carried out to determine the potential role of RLIP76 in AED transport in the brain. Results RLIP76 was expressed in brain tissue, preferentially in the lumenal surface of endothelial cell membranes. The expression was most prominent in blood brain barrier tissue from excised epileptic foci. Saturable, energy-dependent, anti-gradient transport of both phenytoin and carbamazepine were demonstrated using recombinant RLIP76 reconstituted into artificial membrane liposomes. Immunotitration studies of transport activity in crude membrane vesicles prepared from whole-brain tissue endothelium showed that RLIP76 represented the dominant transport mechanism for both drugs. RLIP76-/- knockout mice exhibited dramatic toxicity upon phenytoin administration due to decreased drug extrusion mechanisms at the blood-brain barrier. Conclusion We conclude that RLIP76 is the predominant transporter of AED in the blood brain barrier, and that it may be a transporter involved in mechanisms of drug-resistant epilepsy.
机译：背景技术血脑屏障的通透性是决定治疗药物生物利用度的因素之一，而化学上不同的抗癫痫药的耐药性是脑内积聚减少的结果。已知ABC转运蛋白，特别是P-糖蛋白在抗癫痫药的挤出中起着作用，但其本身不足以充分解释耐药性癫痫现象。在癫痫灶脑组织中差异表达的膜蛋白的蛋白质组学分析表明，RLIP76 / RALBP1是最近描述的非ABC多特异性转运蛋白，其表达经常增加。由于P-糖蛋白和RLIP76之间的底物存在显着重叠，因此进行了当前研究以确定RLIP76在大脑AED转运中的潜在作用。结果RLIP76在脑组织中表达，优先在内皮细胞膜腔表面表达。该表达在切除的癫痫灶的血脑屏障组织中最突出。使用重组到人工膜脂质体中的重组RLIP76证明了苯妥英钠和卡马西平的饱和，能量依赖性，抗梯度转运。从全脑组织内皮制备的粗膜囊泡中的转运活性的免疫分析研究表明，RLIP76代表了这两种药物的主要转运机制。 RLIP76 -/-敲除小鼠在苯妥英钠给药后表现出显着的毒性，这是由于在血脑屏障处的药物挤出机制降低。结论我们得出结论，RLIP76是AED在血脑屏障中的主要转运蛋白，它可能是耐药性癫痫机制的转运蛋白。

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