Hu Yongjun, Shen Hong, Keep Richard F, Smith David E
Department of Pharmaceutical Sciences and Upjohn Center for Clinical Pharmacology, The University of Michigan, Ann Arbor, Michigan, USA.
J Neurochem. 2007 Dec;103(5):2058-65. doi: 10.1111/j.1471-4159.2007.04905.x. Epub 2007 Sep 13.
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.
质子偶联寡肽转运体PEPT2（或SLC15A2）是参与肾脏中肽结合氨基酸和类肽药物回收的主要蛋白质。PEPT2在脉络丛处将肽和拟肽从脑脊液中流出也很重要，从而限制它们在大脑中的暴露。在本研究中，我们报告了PEPT2在调节血红素前体5-氨基乙酰丙酸（5-ALA）毒性方面的神经保护作用。我们的研究结果表明，在PEPT2缺陷小鼠中，给予5-ALA会导致存活率降低、神经肌肉功能障碍恶化，并且脑脊液中底物浓度比野生型对照动物高8至30倍。PEPT2限制脑脊液中5-ALA暴露的能力表明，它可能也与5-ALA代谢改变且5-ALA毒性起重要作用的疾病（如急性肝卟啉症和铅中毒）的二级基因修饰有关。
