Mechanisms of 5-aminolevulinic acid uptake at the choroid plexus.
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 blood-brain barrier appears to be relatively impermeable. This study examines the mechanisms of 5-[(3)H]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 HCO(3)(-) dependent and appears to be an organic anion transporter, although it is possible that removal of Na(+) and HCO(3)(-) may indirectly affect PEPT2 by affecting intracellular pH. The presence of PEPT2 and a putative Na(+)/HCO(3)(-)-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.
Novotny
A
A
Department of Surgery (Neurosurgery) College of Pharmacy and Upjohn Center for Clinical Pharmacology, University of Michigan, Ann Arbor, Michigan, USA.
Xiang
J
J
Stummer
W
W
Teuscher
N S
NS
Smith
D E
DE
Keep
R F
RF
D000622:Aminolevulinic Acid / Q000378:metabolism*; D000818:Animals; D001639:Bicarbonates; D001692:Biological Transport / Q000187:drug effects; D001812:Blood-Brain Barrier; D015153:Blotting, Western; D002021:Buffers; D002216:Captopril / Q000494:pharmacology; D002352:Carrier Proteins / Q000032:analysis / Q000037:antagonists & inhibitors / Q000378:metabolism; D002555:Cerebrospinal Fluid; D002831:Choroid Plexus / Q000737:chemistry / Q000378:metabolism*; D006863:Hydrogen-Ion Concentration; D066298:In Vitro Techniques; D008297:Male; D000074011:Peptide Transporter 1; D051381:Rats; D017207:Rats, Sprague-Dawley; D012964:Sodium / Q000494:pharmacology; D027982:Sodium-Bicarbonate Symporters; D027981:Symporters; D014316:Tritium
D001639:Bicarbonates; D002021:Buffers; D002352:Carrier Proteins; D000074011:Peptide Transporter 1; C489940:Slc15a1 protein, rat; D027982:Sodium-Bicarbonate Symporters; D027981:Symporters; C093694:hydrogen-coupled oligopeptide transporter PepT2; D014316:Tritium; D000622:Aminolevulinic Acid; D002216:Captopril; D012964:Sodium