Journal of Inherited Metabolic Disease

, Volume 12, Issue 2, pp 166–180 | Cite as

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

  • C. de Cespedes
  • J. G. Thoene
  • K. Lowler
  • H. N. Christensen
Article

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.

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 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) 66–72Google Scholar
  2. Betz, A. L. and Goldstein, G. W. Polarity of the blood brain barrier. Neutral amino acid transport into isolated brain capillaries.Science 202 (1978) 225–227Google Scholar
  3. 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) 191–195Google Scholar
  4. 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) 6536–6541Google Scholar
  5. Christensen, H. N. Metabolism of amino acids and proteins.Ann. Rev. Biochem. 22 (1953) 233–260Google Scholar
  6. Christensen, H. N. Interorgan amino acid nutrition.Physiol. Rev. 62 (1982) 1193–1233Google Scholar
  7. Christensen, H. N. Where do the depleted plasma amino acids go in phenylketonuria?Biochem. J. 233 (1986) 929–930Google Scholar
  8. Christensen, H. N. Hypothesis: Where the depleted plasma amino acids go in phenylketonuria, and why.Perspect. Biol. Med. 30 (1987a) 186–196Google Scholar
  9. 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. 1–16Google Scholar
  10. 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) 237–252Google Scholar
  11. 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) 749–753Google Scholar
  12. 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) 1–13Google Scholar
  13. 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) 515–524Google Scholar
  14. Dolan, G. and Golin, C. Phenylketonuria in rats: a model for biochemical studies.Nature (London) 4 (1967) 916–917Google Scholar
  15. 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) 399–405Google Scholar
  16. 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) 95–100Google Scholar
  17. 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) 617–662Google Scholar
  18. 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-E17Google Scholar
  19. 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) 43–54Google Scholar
  20. 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. 107–122Google Scholar
  21. Kaufman, S. Phenylketonuria: Biochemical mechanisms. In Agranoff, B. W. and Aprison, M. H. (eds.),Adv. Neurochem., Vol. 2, Plenum Press, New York, 1977, pp. 1–132Google Scholar
  22. 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) 415–420Google Scholar
  23. Linneweh, F. and Ehrlich, M. Zur pathogenese des schwachsinns bei phenylketonuria.Klin. Wochenschr. 40 (1962) 225–226Google Scholar
  24. Lowden, J. A. and LaRamee, M. A. Hyperphenylalaninemia: the effect on cerebral amino acid levels during development.Can. J. Biochem. 47 (1969) 883–888Google Scholar
  25. Lowry, O. H. and Hastings, A. B. Histochemical changes associated with aging. I. Methods and calculations.J. Biol. Chem. 143 (1942) 257–269Google Scholar
  26. McKean, C. M. The effect of high phenylalanine concentrations on serotonin and catecholamine metabolism in the human brain.Brain Res. 47 (1972) 469–476Google Scholar
  27. 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) 235–241Google Scholar
  28. 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) 539–545Google Scholar
  29. 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) 857–862Google Scholar
  30. Partridge, W. M. and Oldendorf, W. H. Transport of metabolic substrates through the blood brain barrier.J. Neurochem. 28 (1977) 5–12Google Scholar
  31. 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) 761–766Google Scholar
  32. Pratt, O. E. A new approach to the treatment of phenylketonuria.J. Ment. Def. Res. 24 (1980) 203–217Google Scholar
  33. Scriver, C. R. and Clow, C. L. Phenylketonuria: Epitome of human biochemical genetics.N. Engl. J. Med. 303 (1980) 1336–1342Google Scholar
  34. 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. 87–104Google Scholar
  35. 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) 267–284Google Scholar
  36. 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) 63–67Google Scholar
  37. Tager, H. S. and Christensen, H. N. Hypoglycemic action of 2-aminonorbornane-2-carboxylic acid in the rat.Biochem. Biophys. Res. Commun. 44 (1971) 185–191Google Scholar
  38. 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) 968–972Google Scholar
  39. 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. 270–286Google Scholar
  40. Voorhees, C. V., Butcher, R. E. and Berry, H. K. Progress in experimental phenylketonuria: a critical review.Neurosci. Biobehav. Rev. 5 (1981) 117–190Google Scholar
  41. Wade, L. A. and Katzman, R. Synthetic amino acids and the nature ofl-dopa transport at the blood brain barrier.J. Neurochem. 25 (1975) 837–842Google Scholar
  42. Wilkinson, L. SYSTAT: The system for statistics. SYSTAT, inc., Evanston, IL, 1986Google Scholar
  43. Zanic-Grubisic, T. and Lipovac, K. Disturbances of amino acid transport in rats with experimental hyperphenylalaninemia.J. Inher. Metab. Dis. 4 (1981) 105–106Google Scholar

Copyright information

© SSIEM and Kluwer Academic Publishers 1989

Authors and Affiliations

  • C. de Cespedes
    • 1
  • J. G. Thoene
    • 1
  • K. Lowler
    • 1
  • H. N. Christensen
    • 1
  1. 1.Departments of Biological Chemistry and PediatricsUniversity of Michigan Medical SchoolAnn ArborUSA

Personalised recommendations