RLIP76, a non-ABC transporter, and drug resistance in epilepsy.
RLIP76, a non-ABC transporter, and drug resistance in epilepsy.
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RLIP76，一种非ABC转运蛋白和癫痫中的耐药性。
DOI：
10.1186/1471-2202-6-61
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发表时间：
2005-09-27
期刊：
影响因子：
2.4
通讯作者：
Janigro, D
中科院分区：
文献类型：
--
作者：
Awasthi, S;Hallene, KL;Fazio, V;Singhal, SS;Cucullo, L;Awasthi, YC;Dini, G;Janigro, D
血脑屏障的渗透性是决定治疗药物生物利用度的因素之一，而对化学上不同的抗癫痫药物的耐药性是脑内蓄积减少的结果。已知 ABC 转运蛋白，特别是 P-糖蛋白在抗癫痫药物的排出中发挥作用，但其本身不足以完全解释耐药性癫痫的现象。对癫痫病灶脑组织中差异表达的膜蛋白的蛋白质组学分析显示，RLIP76/RALBP1（一种最近描述的非 ABC 多特异性转运蛋白）的表达频繁增加。由于 P-糖蛋白和 RLIP76 之间的底物显着重叠，目前的研究旨在确定 RLIP76 在大脑中 AED 转运中的潜在作用。 RLIP76 在脑组织中表达，优先在内皮细胞膜的管腔表面中表达。该表达在切除的癫痫病灶的血脑屏障组织中最为突出。使用重组到人工膜脂质体中的重组 RLIP76 证明了苯妥英和卡马西平的饱和、能量依赖性、反梯度转运。对全脑组织内皮制备的粗膜囊泡转运活性的免疫滴定研究表明，RLIP76 代表了两种药物的主要转运机制。 RLIP76-/- 基因敲除小鼠在服用苯妥英后表现出剧烈的毒性，因为血脑屏障的药物挤出机制减少。我们得出结论，RLIP76 是血脑屏障中 AED 的主要转运蛋白，并且它可能是参与耐药性癫痫机制的转运蛋白。
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. 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. 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.
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影响因子：
2.9
作者：
Awasthi, S;Cheng, JZ;Awasthi, YC
通讯作者：
Awasthi, YC
影响因子：
5.6
作者：
Boonyapisit, K;Najm, I;Lüders, H
通讯作者：
Lüders, H
影响因子：
4.8
作者：
JULLIENFLORES, V;DORSEUIL, O;CAMONIS, JH
通讯作者：
CAMONIS, JH
DOI：
10.1124/jpet.103.049858
发表时间：
2003-07-01
影响因子：
3.5
作者：
Potschka, H;Fedrowitz, M;Löscher, W
通讯作者：
Löscher, W
影响因子：
4.8
作者：
Rossé, C;L'Hoste, B;Camonis, J
通讯作者：
Camonis, J