Brain-to-blood efflux transport of estrone-3-sulfate at the blood-brain barrier in rats

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• 作者：Hosoya ; Ken-ichi ; Asaba ; Hiroshi ; Terasaki ; Tetsuya
• 关键词：Efflux transport ; Estrone-3-sulfate ; Organic anion transporting polypeptide ; Blood-brain barrier
• 刊名：Life Sciences
• 出版年：2000
• 期刊代码：62_00243205
• 类别：imm
• 出版时间：October 20, 2000
• 卷：67
• 期：22
• 页码：2699-2711
• 文件大小：126 K

摘要

Efflux transport of estrogens such as estrone-3-sulfate (E₁S), and estrone (E₁) across the blood-brain barrier (BBB) was evaluated using the Brain Efflux Index (BEI) method. The apparent BBB efflux rate constant (K_eff) of [³H]E₁S, and [³H]E₁ was 6.63 × 10⁻² ± 0.77 × 10⁻² min⁻¹, and 6.91 × 10⁻² ± 1.23 × 10⁻² min⁻¹, respectively. The efflux transport of [³H]E₁S from brain across the BBB was a saturable process with Michaelis constant (K_m) of 96.0 ± 34.4 μM and 93.4 ± 22.0 μM estimated by two different methods. By determining [³H]E₁S metabolites using high performance liquid chromatography (HPLC) after intracerebral injection, significant amounts of [³H]E₁S were found in the jugular venous plasma, providing direct evidence that most of [³H]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 E₁, the brain distribution volume of E₁S and E₁ was estimated using the brain slice uptake method. The apparent efflux clearance of [³H]E₁S was determined to be 74.9 ± 3.8 μl/(min·g brain) due to the distribution volume of 1.13 ± 0.06 ml/g brain. By contrast, the apparent efflux clearance of E₁ was more than 227 ± 3 μl/(min·g brain), since the distribution volume of [³H]E₁ 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 [³H]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.