Multidrug resistance P-glycoprotein hampers the access of cortisol but not of corticosterone to mouse and human brain
Multidrug resistance P-glycoprotein hampers the access of cortisol but not of corticosterone to mouse and human brain
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DOI：
10.1210/en.142.6.2686
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发表时间：
2001-06-01
期刊：
影响因子：
4.8
通讯作者：
de Kloet, ER
中科院分区：
文献类型：
--
作者：
Karssen, AM;Meijer, OC;de Kloet, ER
在本研究中，我们调查的作用，多药耐药（mdr）的P-糖蛋白（Pgp）在血脑屏障的皮质醇和皮质酮进入小鼠和人脑的控制。[H-3]肾上腺切除的野生型小鼠皮质醇渗透性较差，但在mdr 1a（-/-）小鼠中Pgp表达中断后，皮质醇的吸收增强了3.5倍。与此形成鲜明对比的是，用[H-3]皮质酮处理显示脑组织的高标记，而两种基因型之间没有差异。有趣的是，人MDR1 Pgp也差异运输皮质醇和皮质酮。用MDR 1互补DNA稳定转染的LLC-PK 1单层细胞显示[H-3]皮质醇的极性转运，其可被特异性Pgp阻断剂阻断，而[H-3]用液相色谱-质谱法测定人死后脑组织提取物中两种类固醇的浓度，发现脑中皮质酮与皮质醇的比例总之，数据表明，在小鼠和人脑中，皮质醇的渗透小于皮质酮的渗透。这一发现表明，皮质酮在控制人脑功能中的作用比迄今为止认识到的更为突出。
In the present study, we investigated the role of the multidrug resistance (mdr) P-glycoprotein (Pgp) at the blood-brain barrier in the control of access of cortisol and corticosterone to the mouse and human brain.[H-3] Cortisol poorly penetrated the brain of adrenalectomized wildtype mice, but the uptake was 3.5-fold enhanced after disruption of Pgp expression in mdr 1a(-/-) mice. In sharp contrast, treatment with [H-3]corticosterone revealed high labeling of brain tissue without difference between both genotypes.Interestingly, human MDR1 Pgp also differentially transported cortisol and corticosterone. LLC-PK1 monolayers stably transfected with MDR1 complementary DNA showed polar transport of [H-3]cortisol that could be blocked by a specific Pgp blocker, whereas [H-3]corticosterone transport did not differ between transfected and host cells.Determination of the concentration of both steroids in extracts of human postmortem brain tissue using liquid chromatography mass spectrometry revealed that the ratio of corticosterone over cortisol in the brain was significantly increased relative to plasma.In conclusion, the data demonstrate that in both mouse and human brain the penetration of cortisol is less than that of corticosterone. This finding suggests a more prominent role for corticosterone in control of human brain function than hitherto recognized.