Peptide transporter 2 (PEPT2) expression in brain protects against 5-aminolevulinic acid neurotoxicity.
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.
Hu
Yongjun
Y
Department of Pharmaceutical Sciences and Upjohn Center for Clinical Pharmacology, The University of Michigan, Ann Arbor, Michigan, USA.
Shen
Hong
H
Keep
Richard F
RF
Smith
David E
DE
D000622:Aminolevulinic Acid / Q000493:pharmacokinetics / Q000633:toxicity*; D000818:Animals; D001921:Brain / Q000378:metabolism*; D004195:Disease Models, Animal; D051379:Mice; D018345:Mice, Knockout; D009469:Neuromuscular Junction / Q000503:physiopathology; D020258:Neurotoxicity Syndromes / Q000209:etiology* / Q000517:prevention & control*; D017319:Photosensitizing Agents / Q000493:pharmacokinetics / Q000633:toxicity*; D027981:Symporters / Q000172:deficiency / Q000502:physiology*; D014018:Tissue Distribution / Q000187:drug effects
D017319:Photosensitizing Agents; D027981:Symporters; C093694:hydrogen-coupled oligopeptide transporter PepT2; D000622:Aminolevulinic Acid