17-β-Estradiol: a powerful modulator of blood-brain barrier BCRP activity
17-β-Estradiol: a powerful modulator of blood-brain barrier BCRP activity
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DOI：
10.1038/jcbfm.2010.36
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发表时间：
2010-10-01
影响因子：
6.3
通讯作者：
Bauer, Bjoern
中科院分区：
文献类型：
--
作者：
Hartz, Anika M. S.;Mahringer, Anne;Bauer, Bjoern
atp驱动的外排转运体，乳腺癌抵抗蛋白（BCRP），处理许多治疗药物，包括化疗药物，限制了它们穿过血脑屏障的能力。这项研究为血脑屏障中BCRP转运活性的快速、非基因组调控提供了新的见解。利用大鼠和小鼠分离的脑毛细血管作为离体血脑屏障模型，我们发现BCRP蛋白在脑毛细血管膜中高表达，在完整的毛细血管中具有功能活性。我们发现，纳米摩尔浓度的17- β -雌二醇（E2）迅速降低了BCRP在脑毛细血管中的运输活性。这种e2介导的效应发生在几分钟内，不涉及转录、翻译或蛋白酶体降解，表明非基因组机制。1 h后去除E2完全逆转BCRP活性的丧失。使用雌激素受体(ER) α和ER β以及ER α和ER β敲除小鼠的脑毛细血管的激动剂和拮抗剂进行的实验表明，E2可以通过任一受体发出信号，降低BCRP的转运功能。我们推测这种非基因组e2信号通路可能潜在地用于靶向血脑屏障、脑肿瘤和脑肿瘤干细胞的BCRP，以改善中枢神经系统的化疗。脑血流与代谢杂志（2010）30,1742-1755；doi: 10.1038 / jcbfm.2010.36;2010年3月10日在线发布
The ATP-driven efflux transporter, breast cancer resistance protein (BCRP), handles many therapeutic drugs, including chemotherapeutics, limiting their ability to cross the blood-brain barrier. This study provides new insight into rapid, nongenomic regulation of BCRP transport activity at the blood-brain barrier. Using isolated brain capillaries from rats and mice as an ex vivo blood-brain barrier model, we show that BCRP protein is highly expressed in brain capillary membranes and functionally active in intact capillaries. We show that nanomolar concentrations of 17-beta-estradiol (E2) rapidly reduced BCRP transport activity in the brain capillaries. This E2-mediated effect occurred within minutes and did not involve transcription, translation, or proteasomal degradation, indicating a nongenomic mechanism. Removing E2 after 1 h fully reversed the loss of BCRP activity. Experiments using agonists and antagonists for estrogen receptor (ER)alpha and ER beta and brain capillaries from ER alpha and ER beta knockout mice demonstrated that E2 could signal through either receptor to reduce BCRP transport function. We speculate that this nongenomic E2-signaling pathway could potentially be used for targeting BCRP at the blood-brain barrier, in brain tumors, and in brain tumor stem cells to improve chemotherapy of the central nervous system. Journal of Cerebral Blood Flow & Metabolism (2010) 30, 1742-1755; doi:10.1038/jcbfm.2010.36; published online 10 March 2010