Abstract
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 α-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.
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