Functional multiplicity of blood-brain barrier transporters as a detoxifying system of the brain

本研究的目的是为主要研究者的假设提供证据，即血脑屏障（BBB）具有多种外排转运系统，这些系统在中枢神经系统（CNS）的解毒中起重要作用。采用脑外排指数（BEI）法测定几种底物的血脑屏障外排率。1.牛磺胆酸通过一种不同于对氨基马尿酸的载体介导系统从脑转运到循环血液中。该转运系统可能在保护CNS免受血浆中胆汁酸渗透到脑中方面发挥重要作用。2. L-天冬氨酸被显著地从脑转运到循环血液，但D-天冬氨酸没有。这些结果表明，血脑屏障在从脑中泵出酸性氨基酸（一种神经递质）到循环血液中作为这些神经递质的脑毒性的拯救系统中起重要作用。3.硫酸雌酮和硫酸脱氢表雄酮选择性地从脑转运到血液。有机阴离子转运蛋白（oatp 2）负责这些有机阴离子在脑内的外排转运。4. BQ 123是一种环肽模拟物药物，通过载体介导的系统从脑转运到血液中，该系统不同于牛磺胆酸、对氨基马尿酸的外排系统。虽然有必要阐明转运系统的详细机制，但它将负责外源性物质从血液非特异性渗透到大脑中。基于这几个发现，可以得出结论，BBB通过泵出胆汁酸、酸性氨基酸、类固醇激素的磺基缀合物和疏水性外源性物质而作为解毒系统发挥重要作用。

The purpose of the present study is to provide evidences for the principle investigator's hypothesis that blood-brain barrier (BBB) has several efflux transport systems which play an important role for the detoxification of central nervous system (CNS). Employing brain efflux index (BEI) method, the BBB efflux rate of several substrates was determined. 1. Taurocholic acid was transported form the brain to the circulating blood via a carrier-mediated system which is different from that of para-aminohippuric acid. This transport system may play an important role to protect the CNS from the penetration of bile acids in the plasma to the brain. 2. L-Aspartic acid was significantly transported from the brain to the circulating blood, but D-aspartic acid was not. These results suggest that the BBB play an important role to pump out acidic amino acid, a neurotransmitter, from the brain to the circulating blood as a rescue system for the cerebral toxicity of these neurotransmitters. 3. Estrone sulfate and dehydroepiandrosterone sulfate were selectively transported from the brain to the blood. Organic anion transport protein (oatp 2) would be responsible for the efflux transport of these organic anions in the brain. 4. BQ123, a cyclic peptidomimetic drug was transported from the brain to the blood via a carrier-mediated system which is different from efflux systems for taurocholic acid, para-aminohippuric acid. Although it is necessary to clarify the detailed mechanisms for transport systems, it would be responsible for the non-specific penetration of the xenobiotics into the brain from the blood. Based on these several findings, it would be possible to conclude that the BBB play an important role as a detoxifying system by pumping out of bile acids, acidic amino acids, sulfo-conjugates of steroid hormone and hydrophobic xenobiotics.