Functional properties of multispecific amino acid transporters and their implications to transporter-mediated toxicity.
Functional properties of multispecific amino acid transporters and their implications to transporter-mediated toxicity.
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DOI：
10.2131/jts.28.1
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发表时间：
2003-02-01
期刊：
影响因子：
--
通讯作者：
Endou, Hitoshi
中科院分区：
文献类型：
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作者：
Kanai, Yoshikatsu;Endou, Hitoshi
大多数外源性物质、药物、环境毒素及其代谢产物的吸收、分布和排泄都是由膜转运蛋白介导的。近年来，转运蛋白分子生物学的发展使人们能够在分子水平上研究这些外源性化合物的转运机制及其转运蛋白介导的毒性。环境中存在的外源性化合物包括药物和有毒物质通过具有广泛底物选择性的转运蛋白，即“多特异性”转运蛋白，利用其多特异性发挥毒性作用。这种转运蛋白介导的毒性的显著实例是多巴胺转运蛋白介导的1-甲基-4-苯基-2，3-二氢吡啶（MPP+）-神经毒性、有机阴离子转运蛋白介导的头孢定-肾毒性和系统L氨基酸转运蛋白介导的甲基汞-毒性。L型氨基酸转运蛋白1（L-type amino acid transporter 1，LAT 1）的分子鉴定使人们了解了其多特异性底物识别的机制，并揭示了其在血脑屏障和胎盘屏障的定位。LAT 1依赖于底物氨基酸侧链和底物结合位点之间的疏水相互作用，因此底物氨基酸侧链可能存在许多变化，这是广泛底物选择性的基础。因此，系统L转运蛋白作为在具有氨基酸相关结构的环境中发生的药物和毒性化合物的膜渗透的途径。除了甲基汞-半胱氨酸缀合物之外，氨基酸相关的神经毒素如β-N-甲基氨基-L-丙氨酸、S-（1，2-二氯乙烯基）-L-半胱氨酸和3-羟基犬尿氨酸被提出通过系统L转运蛋白发挥其毒性。由于此类转运蛋白的存在对于器官毒性的表现至关重要，因此预期转运蛋白的抑制将有益于预防由转运蛋白介导的毒性引起的病症。
The absorption, distribution and excretion of most of xenobiotics, drugs, environmental toxins and their metabolites are mediated by membrane transporters. Recent advances in the transporter molecular biology have made it possible to investigate the mechanisms of transport of those exogenous compounds and their transporter-mediated toxicity at the molecular level. Exogenous compounds including drugs and toxic substances occurring in the environment pass through the transporters with broad substrate selectivity, namely "multispecific" transporters, taking advantage of the multispecific nature to exert their toxic effects. The remarkable examples of such transporter-mediated toxicity are 1-methyl-4-phenyl-2,3-dihydropyridinium (MPP+)-neurotoxicity mediated by dopamine transporters, cephaloridine-nephrotoxicity mediated by organic anion transporters and methylmercury-toxicity mediated by system L amino acid transporters. The molecular identification of system L transporter LAT1 (L-type amino acid transporter 1) has lead to the understanding of the mechanisms of their multispecific substrate recognition and revealed their localization at the blood-brain barrier and placental barrier. LAT1 relies on the hydrophobic interaction between substrate amino acid side chains and the substrate binding site, so that many variations are possible for the substrate amino acid side chains, which is the basis of the broad substrate selectivity. System L transporters, thus, function as a path for the membrane permeation of drugs and toxic compounds occurring in the environment with amino acid-related structures. Beside methylmercury-cysteine conjugate, amino acid-related neurotoxins such as beta-N-methylamino-L-alanine, S-(1,2-dichlorovinyl)-L-cysteine and 3-hydroxykynurenine are proposed to pass through system L transporters to exert their toxicity. Because the presence of such transporters is crucial for the manifestation of the organ toxicity, the inhibition of the transporters would be expected to be beneficial to prevent the disorders caused by the transporter-mediated toxicity.