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Evidence for inhibition of exodus of small neutral amino acids from non-brain tissues in hyperphenylalaninaemic rats

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Journal of Inherited Metabolic Disease

Summary

The mechanism of the depletion of several plasma amino acids in PKU has remained unexplained. In the present study, a statistically significant decrease in the plasma concentration of several amino acids was observed 2 h after the intraperitoneal injection of Phe to weanling rats. The pattern was very similar to the one observed in PKU patients. Statistically significant increases in the distribution ratios liver/plasma and, mainly, muscle/plasma ratios accompanied in most of the cases the corresponding decreases in plasma concentrations. Equimolar injection under the same conditions of the non-insulinogenic transport system L analogue, the a(±) isomer of the 2-amino-norbornane-2-carboxylic acid, produced, in a parallel effect to Phe, statistically significant increases in the distribution ratios of Ala and Gly, and probably of Pro in muscle, as well as of Ala in liver. These results seem to indicate that the high intracellular Phe attained inhibits the exodus of small neutral amino acids through system L, causing their depletion in plasma and ultimately in the brain. This effect may be additive to the inhibition by Phe of the entry of bulky neutral amino acids at the level of the blood-brain barrier. Further study is needed to assess the relevance of these effects to PKU.

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References

  • Antonozzi, I., Carducci, C., Vestri, L., Manzari, V. and Dominici, R. Plasma amino acid values and pancreatic β-cell function in phenylketonuria.J. Inher. Metab. Dis. 10 (1987) 66–72

    Google Scholar 

  • Betz, A. L. and Goldstein, G. W. Polarity of the blood brain barrier. Neutral amino acid transport into isolated brain capillaries.Science 202 (1978) 225–227

    Google Scholar 

  • Brunner, R. L., Vorhees, C. V., McLean, M. S., Butcher, R. E. and Berry, H. K. Beneficial effects of isoleucine on fetal brain development in induced phenylketonuria.Brain Res. 154 (1978) 191–195

    Google Scholar 

  • Choi, T. B. and Partridge, W. M. Phenylalanine transport at the human blood brain barrier. Studies with isolated brain capillaries.J. Biol. Chem. 261 (1986) 6536–6541

    Google Scholar 

  • Christensen, H. N. Metabolism of amino acids and proteins.Ann. Rev. Biochem. 22 (1953) 233–260

    Google Scholar 

  • Christensen, H. N. Interorgan amino acid nutrition.Physiol. Rev. 62 (1982) 1193–1233

    Google Scholar 

  • Christensen, H. N. Where do the depleted plasma amino acids go in phenylketonuria?Biochem. J. 233 (1986) 929–930

    Google Scholar 

  • Christensen, H. N. Hypothesis: Where the depleted plasma amino acids go in phenylketonuria, and why.Perspect. Biol. Med. 30 (1987a) 186–196

    Google Scholar 

  • Christensen, H. N. Role of membrane transport in interorgan amino acid flows: Where do the depleted amino acids go in phenylketonuria? In Kaufman, S. (ed.)Amino Acids in Health and Disease: New Perspectives, Alan R. Liss, Inc., New York, 1987b, Vol. 55, pp. 1–16

    Google Scholar 

  • Christensen, H. N. and Cullen, A. M. Effects of non-metabolizable analogs on the distribution of amino acids in the rat.Biochim. Biophys. Acta 150 (1968) 237–252

    Google Scholar 

  • Christensen, H. N. and Cullen, A. M. Intensified gradients for endogenous amino acid substrates for transport system L on injecting a specific competitor for that system.Life Sci. 29 (1981) 749–753

    Google Scholar 

  • Christensen, H. N. and Handlogten, M. E. Interaction between parallel transport systems examined with tryptophan and related amino acids.J. Neural. Transm. Suppl. 15 (1979) 1–13

    Google Scholar 

  • Christensen, H. N., Streicher, J. A. and Elbinger, R. L. Effects of feeding individual amino acids upon the distribution of other amino acids between cells and extracellular fluid.J. Biol. Chem. 172 (1948) 515–524

    Google Scholar 

  • Dolan, G. and Golin, C. Phenylketonuria in rats: a model for biochemical studies.Nature (London) 4 (1967) 916–917

    Google Scholar 

  • Efron, M. L., Song Kong, E., Visakorpi, J. and Feller, F. X. Effects of elevated plasma phenylalanine levels on other amino acids in phenylketonuric and normal subjects.J. Pediatr. 74 (1969) 399–405

    Google Scholar 

  • Erikson, S., Hagenfeldt, L. and Wahren, J. A comparison of the effects of intravenous infusion of individual branched chain amino acids on blood amino acid levels in man.Clin. Sci. 60 (1981) 95–100

    Google Scholar 

  • Fajans, S. S., Floyd, J. S. Jr., Knopf, R. F. and Conn, J. W. Effects of amino acids and proteins on insulin secretion in man.Recent Progr. Horm. Res. 23 (1967) 617–662

    Google Scholar 

  • Fukagawa, N. K., Minaker, K. L., Young, V. R. and Rowe, J. W. Insulin dose-dependent reductions in plasma amino acids in man.Am. J. Physiol. 250 (1986) E13-E17

    Google Scholar 

  • Huether, G., Schott, K., Sprotte, U., Thoemke, F. and Neuhoff, V. Regulation of the amino acid availability in the developing brain. No physiological significance of amino acid competition in experimental hyperphenylalaninemia.Int. J. Dev. Neurosci. 2 (1984) 43–54

    Google Scholar 

  • Huether, G. Regulation of the free amino acid pool in the brain: a lesson learned from experimental phenylketonuria. In Kaufman, S. (ed.)Amino Acids in Health and Disease: New Perspectives, Alan R. Liss, Inc., New York, 1987, Vol. 55, pp. 107–122

    Google Scholar 

  • Kaufman, S. Phenylketonuria: Biochemical mechanisms. In Agranoff, B. W. and Aprison, M. H. (eds.),Adv. Neurochem., Vol. 2, Plenum Press, New York, 1977, pp. 1–132

    Google Scholar 

  • Landgraff, R., Landgraf-Leurs, M. M. C. and Hörl, R.l-phenylalanine induced insulin release and the influence ofd-glucose. Kinetic studies with the perfused rat pancreas.Diabetologia 10 (1974) 415–420

    Google Scholar 

  • Linneweh, F. and Ehrlich, M. Zur pathogenese des schwachsinns bei phenylketonuria.Klin. Wochenschr. 40 (1962) 225–226

    Google Scholar 

  • Lowden, J. A. and LaRamee, M. A. Hyperphenylalaninemia: the effect on cerebral amino acid levels during development.Can. J. Biochem. 47 (1969) 883–888

    Google Scholar 

  • Lowry, O. H. and Hastings, A. B. Histochemical changes associated with aging. I. Methods and calculations.J. Biol. Chem. 143 (1942) 257–269

    Google Scholar 

  • McKean, C. M. The effect of high phenylalanine concentrations on serotonin and catecholamine metabolism in the human brain.Brain Res. 47 (1972) 469–476

    Google Scholar 

  • McKean, C. M., Boggs, D. E. and Peterson, N. A. The influence of high phenylalanine and tyrosine on the concentration of essential amino acids in brain.J. Neurochem. 15 (1968) 235–241

    Google Scholar 

  • Nyhan, W. L., Borden, M. and Childs, B. Idiopathic hyperglycinemia. A new disorder of amino acid metabolism. II. The concentration of other amino acids in plasma and their modification by the administration of leucine.Pediatrics 27 (1961) 539–545

    Google Scholar 

  • Oldendorf, W. H., Crane, P. D., Braun, L. D., Gosschalk, E. A. and Diamond, J. M. pH Dependence of histidine affinity for blood-brain barrier transport systems for neutral and cationic amino acids.J. Neurochem. 50 (1988) 857–862

    Google Scholar 

  • Partridge, W. M. and Oldendorf, W. H. Transport of metabolic substrates through the blood brain barrier.J. Neurochem. 28 (1977) 5–12

    Google Scholar 

  • Perry, T. L., Hansen, S., Tischler, B., Bunting, R. and Diamond, S. Glutamine depletion in phenylketonuria: possible cause of mental defect.N. Engl. J. Med. 282 (1970) 761–766

    Google Scholar 

  • Pratt, O. E. A new approach to the treatment of phenylketonuria.J. Ment. Def. Res. 24 (1980) 203–217

    Google Scholar 

  • Scriver, C. R. and Clow, C. L. Phenylketonuria: Epitome of human biochemical genetics.N. Engl. J. Med. 303 (1980) 1336–1342

    Google Scholar 

  • Sershen, H., Debler, E. A. and Lajtha, A. Alteration of cerebral amino acid transport processes. In Kaufman, S. (ed.)Amino Acids in Health and Disease: New Perspectives, Alan R. Liss, Inc., New York, Vol. 55, 1987, pp. 87–104

    Google Scholar 

  • Shotwell, M. A., Kilberg, M. S. and Oxender, D. L. The regulation of neutral amino acid transport in mammalian cells.Biochim. Biophys. Acta 737 (1983) 267–284

    Google Scholar 

  • Snyderman, S. E., Sansaricq, C., Norton, P. M. and Castro, J. V. Plasma and cerebrospinal fluid amino acid concentrations in phenylketonuria during the newborn period.J. Pediatr. 99 (1981) 63–67

    Google Scholar 

  • Tager, H. S. and Christensen, H. N. Hypoglycemic action of 2-aminonorbornane-2-carboxylic acid in the rat.Biochem. Biophys. Res. Commun. 44 (1971) 185–191

    Google Scholar 

  • Tager, H. S. and Christensen, H. N. 2-Aminonorbornane-2-carboxylic acid. Preparation, properties and identification of the four isomers.J. Am. Chem. Soc. 94 (1972) 968–972

    Google Scholar 

  • Tourian, A. and Sidbury, J. B. Phenylketonuria and hyperphenylalaninemia. In Stanbury, J. B., Wyngaarden, J. B., Fredrickson, D. S., Goldstein, J. L. and Brown, M. S. (eds.)The Metabolic Basis of Inherited Disease. 5th edn., McGraw Hill, New York, 1983, pp. 270–286

    Google Scholar 

  • Voorhees, C. V., Butcher, R. E. and Berry, H. K. Progress in experimental phenylketonuria: a critical review.Neurosci. Biobehav. Rev. 5 (1981) 117–190

    Google Scholar 

  • Wade, L. A. and Katzman, R. Synthetic amino acids and the nature ofl-dopa transport at the blood brain barrier.J. Neurochem. 25 (1975) 837–842

    Google Scholar 

  • Wilkinson, L. SYSTAT: The system for statistics. SYSTAT, inc., Evanston, IL, 1986

    Google Scholar 

  • Zanic-Grubisic, T. and Lipovac, K. Disturbances of amino acid transport in rats with experimental hyperphenylalaninemia.J. Inher. Metab. Dis. 4 (1981) 105–106

    Google Scholar 

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  1. Departments of Biological Chemistry and Pediatrics, University of Michigan Medical School, 48109, Ann Arbor, Michigan, USA

    C. de Cespedes, J. G. Thoene, K. Lowler & H. N. Christensen

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  1. C. de Cespedes
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  2. J. G. Thoene
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  3. K. Lowler
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  4. H. N. Christensen
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de Cespedes, C., Thoene, J.G., Lowler, K. et al. Evidence for inhibition of exodus of small neutral amino acids from non-brain tissues in hyperphenylalaninaemic rats. J Inherit Metab Dis 12, 166–180 (1989). https://doi.org/10.1007/BF01800722

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  • DOI: https://doi.org/10.1007/BF01800722

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