Mechanisms of 5-aminolevulinic acid uptake at the choroid plexus
Mechanisms of 5-aminolevulinic acid uptake at the choroid plexus
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DOI：
10.1046/j.1471-4159.2000.0750321.x
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发表时间：
2000-07-01
影响因子：
4.7
通讯作者：
Keep, RF
中科院分区：
文献类型：
--
作者：
Novotny, A;Xiang, J;Keep, RF
5-氨基乙酰丙酸 (5-ALA) 是卟啉和血红素的前体，与卟啉症相关的神经精神症状有关。它也在临床上用于描绘恶性神经胶质瘤。血脑脊液屏障可能是血液和大脑之间 5-ALA 转运的重要界面，因为体内研究表明 5-ALA 被脉络丛吸收，而正常的母脑屏障似乎相对不可渗透。本研究检查了离体大鼠侧脑室脉络丛摄取 5-[H-3]ALA 的机制，结果表明有两种摄取机制。第一个是不依赖于 Na+ 的、依赖于 pH 值的吸收系统（在低 pH 值下受到刺激）。二肽 Gly-Gly 和头孢羟氨苄（一种含 α-氨基的头孢菌素）抑制摄取。这些特性与质子依赖性肽转运蛋白 PEPT1 和 PEPT2 相同，最近在青蛙卵母细胞表达实验中显示它们可以转运 5-ALA。卡托普利（一种 PEPT1 抑制剂）不会抑制脉络丛的摄取，表明 PEPT2 介导的摄取。通过蛋白质印迹证实脉络丛中存在 PEPT2 且不存在 PEPT1。第二个潜在机制是 Na+ 和 HCO3- 依赖性的，并且似乎是有机阴离子转运蛋白，尽管 Na+ 和 HCO3- 的去除可能通过影响细胞内 pH 值来间接影响 PEPT2。 PEPT2 和假定的 Na+/HCO3 依赖性有机阴离子转运蛋白的存在不仅对于理解血液和大脑之间的 5-ALA 运动很重要，而且还因为这些转运蛋白可能影响许多药物在血液和脑脊液之间的分布。
5-Aminolevulinic acid (5-ALA) is a precursor of porphyrins and heme that has been implicated in the neuropsychiatric symptoms associated with porphyrias. it is also being used clinically to delineate malignant gliomas. The blood-CSF barrier may be an important interface for 5-ALA transport between blood and brain as in vivo studies have indicated 5-ALA is taken up by the choroid plexuses whereas the normal brood-brain barrier appears to be relatively impermeable, This study examines the mechanisms of 5-[H-3]ALA uptake into isolated rat lateral ventricle choroid plexuses, Results suggest that there are two uptake mechanisms. The first was a Na+-independent uptake system that was pH dependent (being stimulated at low pH). Uptake was inhibited by the dipeptide Gly-Gly and by cefadroxil, an alpha-amino-containing cephalosporin. These properties are the same as the proton-dependent peptide transporters PEPT1 and PEPT2, which have recently been shown to transport 5-ALA in frog oocyte expression experiments. Choroid plexus uptake was not inhibited by captopril, a PEPT1 inhibitor, suggesting PEPT2-mediated uptake. The presence of PEPT2 and absence of PEPT1 in the choroid plexus were confirmed by western blotting. The second potential mechanism was both Na+ and HCO3- dependent and appears to be an organic anion transporter, although it is possible that removal of Na+ and HCO3- may indirectly affect PEPT2 by affecting intracellular pH. The presence of PEPT2 and a putative Na+/HCO3--dependent organic anion transporter is important not only for an understanding of 5-ALA movement between blood and brain but also because these transporters may affect the distribution of a number of drugs between blood and CSF.