Brain-to-blood efflux transport of estrone-3-sulfate at the blood-brain barrier in rats
Brain-to-blood efflux transport of estrone-3-sulfate at the blood-brain barrier in rats
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DOI：
10.1016/s0024-3205(00)00861-4
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发表时间：
2000-10-20
期刊：
影响因子：
6.1
通讯作者：
Terasaki, T
中科院分区：
文献类型：
--
作者：
Hosoya, K;Asaba, H;Terasaki, T
用脑流出指数(BEI)法评价雌激素如雌酮-3-硫酸酯(E1S)和雌酮(E-1)跨血脑屏障(BBB)的外流转运。[H-3]E-1和[H-3]E-1的表观血脑屏障外流速率常数分别为6.63×10(-2)+/-0.77×10(-2)min(-1)和6.91×10(-2)+/-1.23×10(-2)min(-1)。[H-3]E1s从脑通过血脑屏障的转运是一个饱和过程，用两种方法估算的米氏常数(K-m)分别为96.0+/-34.4微米和93.4+/-22.0微米。脑内注射后用高效液相色谱法测定[H-3]E1s代谢物，在颈静脉血浆中发现了大量的[H-3]E1s，这直接证明了[H-3]E1s是以完整的形式从大脑通过血脑屏障转运的。用脑片摄取法测定E1s和E1b的脑分布体积，比较E1s和E1b的表观外流清除量。[H-3]E1s的表观外排清除量为74.9+/-3.8mul/(Min)。G脑)，其分布体积为1.13+/-0.06ml/g脑。相比之下，E-1的表观外排清除量大于227±3mul/(min.[H-3]E-1在60min的分布体积为3.28+/-0.13ml/g，胆汁酸(牛磺胆酸盐、胆酸盐)和有机阴离子(磺基溴邻苯二甲酸、丙磺舒)对E1s的外流转运过程有40%以上的抑制作用，而其他有机阴离子不影响E1s的外流转运。预先给予5 mM脱氢表雄酮后，[H-3]E1S外流显著减少48.6%。这些结果表明，E1s是通过载体介导的外流系统从大脑通过血脑屏障转运到循环血液中的。(C)2000 Elsevier Science Inc.保留所有权利。
Efflux transport of estrogens such as estrone-3-sulfate (E1S), and estrone (E-1) across the blood-brain barrier (BBB) was evaluated using the Brain Efflux Index (BEI) method. The apparent BBB efflux rate constant (K-eff) of [H-3]E1S, and [H-3]E-1 was 6.63 x 10(-2) +/- 0.77 x 10(-2) min(-1), and 6.91 x 10(-2) +/- 1.23 x 10(-2) min(-1), respectively. The efflux transport of [H-3]E1S from brain across the BBB was a saturable process with Michaelis constant (K-m) of 96.0 +/- 34.4 muM and 93.4 +/- 22.0 muM estimated by two different methods. By determining [H-3]E1S metabolites using high performance liquid chromatography (HPLC) after intracerebral injection, significant amounts of [H-3]E1S were found in the jugular venous plasma, providing direct evidence that most of [H-3]E1S is transported from brain across the BBB in intact form. To compare the apparent efflux clearance across the BBB of E1S with that of E-1, the brain distribution volume of E1S and E-1 was estimated using the brain slice uptake method. The apparent efflux clearance of [H-3]E1S was determined to be 74.9 +/- 3.8 mul/(min . g brain) due to the distribution volume of 1.13 +/- 0.06 ml/g brain. By contrast, the apparent efflux clearance of E-1 was more than 227 +/- 3 mul/(min . g brain), since the distribution volume of [H-3]E-1 at 60 min was 3.28 +/- 0.13 ml/g. The E1S efflux transport process was inhibited by more than 40% by coadministration of bile acids (taurocholate, and cholate), and organic anions (sulfobromophthalein, and probenecid), whereas other organic anions did not affect the E1S efflux transport. The [H-3]E1S efflux was significantly reduced by 48.6% after preadministration of 5 mM dehydroepiandrosterone sulfate. These results suggest that E1S is transported from brain to the circulating blood across the BBB via a carrier-mediated efflux transport system. (C) 2000 Elsevier Science Inc. All rights reserved.