Peptide transporter 2 (PEPT2) expression in brain protects against 5-aminolevulinic acid neurotoxicity
Peptide transporter 2 (PEPT2) expression in brain protects against 5-aminolevulinic acid neurotoxicity
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DOI：
10.1111/j.1471-4159.2007.04905.x
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发表时间：
2007-12-01
影响因子：
4.7
通讯作者：
Smith, David E.
中科院分区：
文献类型：
--
作者：
Hu, Yongjun;Shen, Hong;Smith, David E.
质子偶联寡肽转运蛋白PEPT 2（或SLC 15 A2）是参与肾脏回收肽结合氨基酸和肽类药物的主要蛋白。PEPT 2在脉络丛处从CSF流出肽和肽模拟物中也是重要的，从而限制它们在脑中的暴露。在这项研究中，我们报告了PEPT 2在调节血红素前体5-氨基酮戊酸（5-ALA）毒性方面的神经保护作用。我们的研究结果表明，在PEPT 2缺陷小鼠中，5-ALA给药导致存活率降低，神经肌肉功能障碍恶化，CSF底物浓度比野生型对照动物高8-30倍。PEPT 2限制CSF中5-ALA暴露的能力表明，它也可能与5-ALA代谢改变和5-ALA毒性重要的疾病（如急性肝卟啉症和铅中毒）的继发遗传修饰剂有关。
The proton-coupled oligopeptide transporter PEPT2 (or SLC15A2) is the major protein involved in the reclamation of peptide-bound amino acids and peptide-like drugs in kidney. PEPT2 is also important in effluxing peptides and peptidomimetics from CSF at the choroid plexus, thereby limiting their exposure in brain. In this study, we report a neuroprotective role for PEPT2 in modulating the toxicity of a heme precursor, 5-aminolevulinic acid (5-ALA). Our findings demonstrate that in PEPT2-deficient mice, 5-ALA administration results in reduced survivability, a worsening of neuromuscular dysfunction, and CSF concentrations of substrate that are 8-30 times higher than that in wild-type control animals. The ability of PEPT2 to limit 5-ALA exposure in CSF suggests that it may also have relevance as a secondary genetic modifier of conditions (such as acute hepatic porphyrias and lead poisoning) in which 5-ALA metabolism is altered and in which 5-ALA toxicity is important.