The Role of Blood-Brain Barrier Transport of Tryptophan and Other Neutral Amino Acids in the Regulation of Substrate-Lim
Many pathways of essential neutral amino acid metabolism in the CNS are influenced by precursor availability. Since the delivery of circulating amino acids to brain cells is primarily controlled by the rate of amino acid transport through the blood-brain
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The Role of Blood-Brain Barrier Transport of Tryptophan and Other Neutral Amino Acids in the Regulation of Substrate-Limited Pathways of Brain Amino Acid Metabolism * W. M. Pardridge Dcpartment of Medicine, Division of Endocrinology and Metabolism, UCLA School of Medicine, Los Angeles, California, U.S.A. With 1 Figure
Summary Many pathways of essential neutral amino acid metabolism in the CNS are influenced by precursor availability. Since the delivery of circulating amino acids to brain cells is primarily controlled by the rate of amino acid transport through the blood-brain barrier (BBB), pathways of brain amino acid metabolism are ultimately influenced by the activity (Km, Vmax) of the BBB neutral amino acid transport system. The Km of BBB transport is in the 0.1-0.6 mM range, which approximates the physiologic plasma levels and forms the basis of the unusual sensitivity of the brain to competition effects on neutral amino acid transport. Unlike the brain, the Km of amino acid transport into other organs is in the 1-10 mM range or greater, which frees these tissues from competition effects in the physiologic range of plasma amino acids. Tryptophan circulates 80-90 °/o bound to albumin; however, the capacity/affinity ratio of the BBB neutral amino acid transport system exceeds the capacity/affinity ratio of albumirr binding of tryptophan, which enables the carrier to strip tryptophan off albumirr as it traverses the brain capillary. The activity of the BBB neutral amino acid transport system is probably not modulated by insulin, but is influenced by changes in thyroid hormone status; the transport system is also induced in states of hepatic encephalopathy and this induction process is the primary cause of the increased brain tryptophan and serotonirr levels in cirrhosis. ,,. Supported by the National Science Foundation (BNS 78-05500).
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W. M. Pardridge:
Substrate-Limited Pathways of Brain Amino Acid Metabolism The transport of tryptophan or other metabolic substrates through the brain capillary wall, i.e., the blood-brain barrier (BBB), is an important regulatory unit in the control of brain function if the circulating substrate is precursor to a substrate-limited pathway of cerebral metabolism. There are two types of substrate-limited pathways (Table 1); their classification depends on whether the BBB transport step is rate-limiting or rate-affecting for the overall pathway of brain metabolism. Pathways limited by the transport step are ketone body utilization (Ruderman et al., 1974) or glycolysis under states of either decreased glucose supply (hypoglycemia) or increased glucose demand (seizures, anoxia, salicylism) (Pardridge and Oldendorf, 1977); pathways limited by the transport step are characterized by immeasureably low precursor substrate concentrations. Conversely, intracellular levels of the essential amino acids such as tryptophan are always measureable, which indicates their metabolism is never limited by the BBB transport step, but rather is limited by an intracellular enzymatic step. However, i
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