[Functional involvement of P-glycoprotein in blood-brain barrier].
[Functional involvement of P-glycoprotein in blood-brain barrier].
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发表时间：
1992-10
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通讯作者：
T. Tatsuta;M. Naito;T. Oh‐hara;I. Sugawara;T. Tsuruo
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作者：
T. Tatsuta;M. Naito;T. Oh‐hara;I. Sugawara;T. Tsuruo
p -糖蛋白是多药耐药肿瘤细胞抗肿瘤药物的主动外排泵，存在于包括脑毛细血管在内的多种正常组织中。为了研究p -糖蛋白在脑毛细血管内皮表达的生理功能，我们建立了9个小鼠脑毛细血管内皮细胞（MBEC）系，观察了抗肿瘤药物在MBEC单层上皮中的转运情况。在MBECs中，脑毛细血管内皮细胞特异性标志物碱性磷酸酶和γ -谷氨酰转肽酶的活性比包括人脐静脉内皮细胞在内的其他细胞的活性高约3倍。通过免疫印迹分析，9个MBEC克隆均检测到p -糖蛋白。MBECs中表达的p -糖蛋白与多药耐药细胞中表达的p -糖蛋白特异性结合[125I]碘芳基偶氮唑啉，并且在MBECs中观察到新碱的外排。当MBECs在多孔过滤膜上生长时，它们形成单层上皮。免疫电镜分析显示，p -糖蛋白在MBEC上皮中定位于细胞的顶端表面。此外，体外实验还证实了长春新碱从基侧到根尖侧的单向经上皮转运。这些观察结果表明，脑毛细血管内皮中的p糖蛋白可以阻止长春新碱进入中枢神经系统，因此可能是血脑屏障的功能成分之一。
Abstract P-glycoprotein, an active efflux pump of antitumor agents in multidrug-resistant tumor cells, exists in various normal tissues, including brain capillaries. To study the physiological function of P-glycoprotein expressed in brain capillary endothelium, we established nine mouse brain capillary endothelial cell (MBEC) lines and examined the transport of antitumor agents across the monolayer of MBEC epithelia. In the MBECs, the activities of alkaline phosphatase and gamma-glutamyl transpeptidase, specific markers for brain capillary endothelial cells, were about three times higher than those in other cells including human umbilical vein endothelial cells. By immunoblot analysis, P-glycoprotein was detected in all of the nine MBEC clones. The P-glycoprotein expressed in MBECs specifically bound [125I]iodoaryl azidoprazosin as that in multidrug-resistant cells, and efflux of vincristine was observed in the MBECs. When MBECs were grown on a porous filter membrane, they formed a monolayer of epithelium. By immunoelectron microscopic analysis, P-glycoprotein in MBEC epithelia was shown to be localized to the apical surface of the cells. Moreover, the unidirectional transepithelial transport of vincristine from basal side to apical side was demonstrated in vitro. These observations indicate that P-glycoprotein in brain capillary endothelium prevents vincristine from entering the central nervous system and thus may be one of the functional components of the blood-brain barrier.