TRYPTOPHAN TRANSPORT ACROSS THE BLOOD-BRAIN BARRIER DURING ACUTE HEPATIC FAILURE

Authors

  • Anke M. Mans,

    Corresponding author
    1. Department of Anesthesia, The Pennsylvania State University College of Medicine, The Milton S. Hershey Medical Center, Hershey, PA 17033, USA.
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  • Julien F. Biebuyck,

    1. Department of Anesthesia, The Pennsylvania State University College of Medicine, The Milton S. Hershey Medical Center, Hershey, PA 17033, USA.
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  • Stuart J. Saunders,

    1. Liver Research Group, Department of Medicine, University of Cape Town Medical School, Observatory 7925, Cape Town, South Africa
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  • Ralph E. Kirsch,

    1. Liver Research Group, Department of Medicine, University of Cape Town Medical School, Observatory 7925, Cape Town, South Africa
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  • Richard A. Hawkins

    1. Department of Anesthesia, The Pennsylvania State University College of Medicine, The Milton S. Hershey Medical Center, Hershey, PA 17033, USA.
    2. Department of Physiology, The Pennsylvania State University College of Medicine, The Milton S. Hershey Medical Center, Hershey, PA 17033, USA.
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To whom correspondence should be addressed.

Abstract

Abstract— Tryptophan transport across the blood-brain barrier was studied using a single injection dual isotope label technique, in the following three conditions: normal rats, rats with portacaval shunts, and rats with portacaval shunts followed 65 h later by hepatic artery ligation. In both normal rats and those with acute hepatic failure the tryptophan transport system was found to be comprised of two kinetically distinct components. One component was saturable and obeyed Michaelis-Menten kinetics (normal: Vmax= 19.5 nmol.min−1.g−1. Km= 113 μM; hepatic failure: Vmax, = 33.8 nmol.min−1.g−1, Km= 108 μM), and the second was a high capacity system which transported tryptophan in direct proportion to concentration over the range tested (normal: K= 0.026 ml.min−1.g−1; hepatic failure: K= 0.067 ml.min−1.g−1). Since the saturable low capacity component transports several neutral amino acids, and their collective plasma concentration is high in relation to the individual Kms, tryptophan transport by this component is reduced by competitive inhibition under physiological conditions. Thus it was calculated that in normal rats approx 40% of tryptophan influx occurs via the high capacity system. During acute hepatic failure transport via both components was increased substantially, approximately doubling the rate of tryptophan penetration of the blood-brain barrier at all concentrations tested. The contribution by the high capacity component became even more significant than in normal rats, accounting for about 75% of all tryptophan passage from plasma to brain. Brain tryptophan content was 29.9 nmol/g in normal rats and rose to 45.2 nmol/g in rats with portacaval shunts and 50.5 nmol/g in those with acute hepatic failure, correlating with the increased rate of tryptophan transport. In a previous study we found that plasma competing amino acids were greatly increased during acute hepatic failure. Calculations predict that these increased concentrations would cause a reduction in tryptophan transport by the low capacity system. However, because of the increase in the rate of transport by the high capacity component, net tryptophan entry across the blood-brain barrier was actually increased. This increased rate of transport clearly contributes to the increased content of brain tryptophan found during hepatic failure.

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