Large neutral amino acids auto exchange when infused by microdialysis into the rat brain: implication for maple syrup urine disease and phenylketonuria.
Maple syrup urine disease (MSUD) and phenylketonuria (PKU) are associated with accumulation of large neutral amino acids (LNAA) in blood and tissues and a decrease of other LNAA not directly related to the enzyme defects. One characteristic shared by both the elevated and decreased amino acids is that all are substrates for transport via the large neutral amino acid transporter. In this study, the blood brain barrier was effectively bypassed using microdialysis to determine the immediate effect of infused phenylalanine, tyrosine, 2-amino-2-norborane-carboxylic acid (BCH), and leucine and alpha-ketoisocaproate on extracellular levels of LNAA. The concentration of non-infused LNAA increased in the interstitial fluid, presumably due to trans-stimulated exchange of these LNAA from intracellular pools as the infused LNAA entered the cells. Such trans-stimulated exchange can potentially deplete cells of multiple essential LNAA. It is proposed that brain cells in disorders such as MSUD and PKU may be subject to two mechanisms that limit the availability of a full complement of these amino acids: competition for transport of LNAAs at the blood brain barrier and trans-stimulated exchange out of neuronal cells for subsequent metabolism or sequestration in the periphery.
Zielke
H Ronald
HR
Department of Pediatrics, University of Maryland, Pediatric Research, 10-035 BRB, 655 W Baltimore Street, Baltimore, MD 21201, USA. rzielke@umaryland.edu
Zielke
Carol L
CL
Baab
Peter J
PJ
Collins
Roger M
RM
D026921:Amino Acid Transport Systems, Neutral / Q000378:metabolism*; D000598:Amino Acids, Cyclic / Q000494:pharmacology; D021542:Amino Acids, Neutral / Q000008:administration & dosage / Q000378:metabolism / Q000493:pharmacokinetics*; D000818:Animals; D001667:Binding, Competitive; D001692:Biological Transport / Q000187:drug effects; D001812:Blood-Brain Barrier; D001921:Brain / Q000378:metabolism*; D005110:Extracellular Space / Q000378:metabolism; D006624:Hippocampus / Q000378:metabolism; D007651:Keto Acids / Q000494:pharmacology; D007930:Leucine / Q000494:pharmacology; D008375:Maple Syrup Urine Disease / Q000378:metabolism*; D017551:Microdialysis; D008954:Models, Biological; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism; D010649:Phenylalanine / Q000494:pharmacology; D010661:Phenylketonurias / Q000378:metabolism*; D051381:Rats; D014443:Tyrosine / Q000494:pharmacology
D026921:Amino Acid Transport Systems, Neutral; D000598:Amino Acids, Cyclic; D021542:Amino Acids, Neutral; D007651:Keto Acids; D009419:Nerve Tissue Proteins; C006504:2-aminobicyclo(2,2,1)heptane-2-carboxylic acid; D014443:Tyrosine; D010649:Phenylalanine; C013082:alpha-ketoisocaproic acid; D007930:Leucine