Neurochemical Research

, Volume 23, Issue 5, pp 635–644 | Cite as

Blood-Brain Barrier Carrier-Mediated Transport and Brain Metabolism of Amino Acids

  • William M. Pardridge
Article

Abstract

The transport of neutral amino acids through the brain capillary endothelial wall, which makes up the blood-brain barrier (BBB) in vivo, is an important control point for the overall regulation of cerebral metabolism, including protein synthesis and neurotransmitter production. The Michaelis-Menten kinetics of BBB amino acid transport have been investigated in vivo with the brain uptake index (BUI) technique, and in vitro with the isolated human brain capillary preparation. The only amino acid that is albumin-bound is tryptophan, and the majority of albumin-bound tryptophan in the plasma is available for transport through the BBB via an enhanced dissociation mechanism that operates at the surface of the brain capillary endothelium. The availability in brain of amino acids is predicted from the BBB Km values to be sharply influenced by supra-physiological concentrations of phenyalanine in the 200–500 μM range. Moreover, the measurement of cerebral protein synthesis with an internal carotid artery perfusion technique and HPLC-based measurements of aminoacyl-transfer RNA specific activities shows an inverse relationship between cerebral protein synthesis and plasma phenyalanine concentrations in the 200–500 μM range. These findings indicate the neurotoxicity of hyperphenylalninemia is not restricted to the phenylketonuria range of approximately 2000 μM, but is exerted in the supra-physiological range of 200–500 μM.

Tryptophan phenylalanine aspartame albumin cerebral microvasculature protein synthesis 

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REFERENCES

  1. 1.
    Oldendorf, W. H. 1971. Brain uptake of radiolabeled amino acids, amines, and hexoses after arterial injection. Am. J. Physiol. 221:1629–1639.Google Scholar
  2. 2.
    Brightman, M. W. 1977. Morphology of blood-brain interfaces. Exp. Eye Res. 25(Suppl.):1–25.Google Scholar
  3. 3.
    Pardridge, W. M. 1977. Regulation of amino acid availability to the brain. Pages 141–204, in Wurtman, R. J., and Wurtman, J. J., (eds.), Nutrition and the Brain, Raven Press, New York.Google Scholar
  4. 4.
    Pardridge, W. M., and Oldendorf, W. H. 1977. Transport of metabolic substrates through the blood-brain barrier. J. Neurochem. 28:5–12.Google Scholar
  5. 5.
    Pardridge, W. M. 1983. Brain metabolism: A perspective from the blood-brain barrier. Physiol. Rev. 63:1481–1535.Google Scholar
  6. 6.
    Smith, Q. R., and Stoll, J. 1998, in press. Blood-brain barrier amino acid transport. in Pardridge, W. M. (ed.), An Introduction to the Blood-Brain Barrier: Methodology and Biology, Cambridge University Press.Google Scholar
  7. 7.
    Oldendorf, W. H., Sisson, W. B., and Silverstein, A. 1971. Brain uptake of selenomethionine Se75. II. Reduced brain uptake of selenomethionine Se75 in phenylketonuria. Arch Neurol. 24:524.Google Scholar
  8. 8.
    Pardridge, W. M., and Oldendorf, W. H. 1975. Kinetic analysis of blood-brain barrier transport of amino acids. Biochim. Biophys. Acta. 401:128–136.Google Scholar
  9. 9.
    Drewes, L. R. 1998. Biology of the blood-brain glucose transporter. in Pardridge, W. M. (ed.), An Introduction to the Blood-Brain Barrier: Methodology and Biology, Cambridge University Press, in press.Google Scholar
  10. 10.
    Malandro, M. S., and Kilberg, M. S. 1996. Molecular biology of mammalian amino acid transporters. Annu. Rev. Biochem. 65:305–36.Google Scholar
  11. 11.
    Oldendorf, W. H. 1970. Measurement of brain uptake of radiolabeled substances using a tritiated water internal standard. Brain Res. 24:372.Google Scholar
  12. 12.
    Pardridge, W. M., and Oldendorf, W. H. 1975. Kinetics of blood-brain barrier transport of hexoses. Biochim. Biophys. Acta. 382:377–392.Google Scholar
  13. 13.
    Pardridge, W. M. 1977. Kinetics of competitive inhibition of neutral amino acid transport across the blood-brain barrier. J. Neurochem. 28:103–108.Google Scholar
  14. 14.
    Pardridge, W. M., and Mietus, L. J. 1982. Kinetics of neutral amino acid transport through the blood-brain barrier of the newborn rabbit. J. Neurochem. 38:955–962.Google Scholar
  15. 15.
    Miller, L. P., Pardridge, W. M., Braun, L. D., and Oldendorf, W. H. 1985. Kinetic constants for blood-brain barrier amino acid transport in conscious rats. J. Neurochem. 45:1427–1432.Google Scholar
  16. 16.
    Pardridge, W. M., and Fierer, G. 1985. Blood-brain barrier transport of butanol and water relative to N-isopropyl-p-[125I] iodoamphetamine (IMP) as the internal reference. J. Cereb. Blood Flow Metab. 5:275–281.Google Scholar
  17. 17.
    Pardridge, W. M., Landaw, E. M., Miller, L. P., Braun, L. D., and Oldendorf, W. H. 1985. Carotid artery injection technique: Bounds for bolus mixing by plasma and by brain. J. Cereb. Blood Flow Metab. 5:576–583.Google Scholar
  18. 18.
    Choi, T., and Pardridge, W. M. 1986. Phenylalanine transport at the human blood-brain barrier. Studies in isolated human brain capillaries. J. Biol. Chem. 261:6536–6541.Google Scholar
  19. 19.
    Hargreaves, K. M., and Pardridge, W. M. 1988. Neutral amino acid transport at the human blood-brain barrier. J. Biol. Chem. 263:19392–19397.Google Scholar
  20. 20.
    Smith, Q. R., Aoyagi, M., Robinson, P. J., and Rapoport, S. I. 1987. Kinetics of neutral amino acid transport across the blood-brain barrier. J. Neurochem. 49:1651–1658.Google Scholar
  21. 21.
    Christensen, H. N. 1969. Some special kinetic problems of transport. Adv. Enzymol. 32:1–20.Google Scholar
  22. 22.
    Fernstrom, J. D., and Wurtman, R. J. 1972. Brain serotonin content-physiological regulation by plasma neutral amino acids. Science. 178:414–416.Google Scholar
  23. 23.
    Munro, H. N., Fernstrom, J. D., and Wurtman, R. J. 1975. Insulin, plasma aminoaid imbalance, and hepatic coma. Lancet. 1:722–726.Google Scholar
  24. 24.
    Pardridge, W. M. 1975. Tryptophan and hepatic encephalopathy. The Lancet. 1:1035.Google Scholar
  25. 25.
    James, J. H., Escourrou, J., and Fischer, J. E. 1978. Blood-brain neutral amino acid transport activity is increased after portacaval anastomosis. Science. 200:1395–1397.Google Scholar
  26. 26.
    Carter, D. C., and He, J. X. 1994. Structure of serum albumin. Adv. Protein Chem. 45:153–203.Google Scholar
  27. 27.
    Brown, J. R. 1977. Serum albumin: Amino acid sequence. Pages 27–51, in Rosehoer, V. M., Oratz, M., and Rothschild, M. A. (eds.), Albumin Structure, Function, and Uses, Pergamon Press, New York.Google Scholar
  28. 28.
    Wilting, J., Kremer, J. M. H., Ijzerman, A. P., and Schulman, G. 1982. The kinetics of the binding of warfarin to human serum albumin as studied by stopped-flow spectrophotometry. Biochim. Biophys. Acta. 706:96–104.Google Scholar
  29. 29.
    Reed, R. G., and Burrington, C. M. 1989. The albumin receptor effect may be due to a surface-induced conformational change in albumin. J. Biol. Chem. 264:9867–9872.Google Scholar
  30. 30.
    Pardridge, W. M. 1998, in press. Targeted delivery of hormones to tissues by plasma proteins. In Conn, P. M. (ed.), Handbook of Physiology—Cellular Mechanisms, Oxford University Press, New York.Google Scholar
  31. 31.
    Pardridge, W. M., and Fierer, G. 1990. Transport of tryptophan into brain from the circulating albumin-bound pool in rats and in rabbits. J. Neurochem. 54:971–976.Google Scholar
  32. 32.
    Binek-Singer, P., and Johnson, T. C. 1982. The effects of chronic hyperphenylalaninemia on mouse brain protein synthesis can be prevented by other amino acids. Biochem. J. 206:407–414.Google Scholar
  33. 33.
    Hargreaves-Wall, K. M., Buciak, J. B., and Pardridge, W. M. 1990. Measurement of free-intracellular and transfer RNA amino acid specific activity and protein synthesis in rat brain in vivo. J. Cerebral Blood Flow Metabol. 10:162–169.Google Scholar
  34. 34.
    Wall, K. M., and Pardridge, W. M. 1990. Decreases in brain protein synthesis elicited by moderate increases in plasma phenylalanine. Biochem. Biophys. Res. Comm. 168:1177–1183.Google Scholar
  35. 35.
    Smith, C. B., Deibler, G. E., Eng, N., Schmidt, K., and Sokoloff, L. 1988. Measurement of local cerebral protein synthesis in vivo: Influence of recycling of amino acids derived from protein degradation. Proc. Natl. Acad. Sci. USA 85:9341–9345.Google Scholar
  36. 36.
    Hawkins, R. A., Mans, A. M., and Biebuyck, J. F. 1987. Changes in brain metabolism in hepatic encephalopathy. Neurochem. Pathol. 6:35–66.Google Scholar
  37. 37.
    Filer, L. J. Jr., and Stegink, L. D. 1987. Effect of aspartame on plasma phenylalanine concentration in humans. Pages 25–56, in Wurtman, R. J. and Ritter-Walker E. (eds.), Dietary Phenylalanine and Brain Function, Center for Brain Sciences and Metabolism Charitable Trust, Mass.Google Scholar
  38. 38.
    Levy, H. L., and Waisbren, S. E. 1983. Effects of untreated maternal phenylketonuria and hyperphenylalaninemia on the fetus. N. Engl. J. Med., 309:1269–1274.Google Scholar
  39. 39.
    Pardridge, W. M. 1986. Potential effects of the dipeptide sweetener aspartame on the brain. Pages 199–241, in Wurtman, R. J., and Wurtman, J. J. (eds.), Nutrition and the Brain, Vol. 7, Raven Press, New York.Google Scholar
  40. 40.
    Kirkman, H. N. Jr., and Hicks, R. E. 1984. More on untreated maternal hyperphenylalaninemia. N. Engl. J. Med. 311:1125.Google Scholar
  41. 41.
    Krause, W., Halminski, M., McDonald, L., Dembure, P., Salvo, R., Freides, D., and Elsas, L. 1985. Biochemical and neuropsychological effects of elevated plasma phenylalanine in patients with treated phenylketonuria. J. Clin. Invest. 75:40–48.Google Scholar
  42. 42.
    Pardridge, W. M. 1987. Phenylalanine transport at the human blood-brain barrier. Pages 43–64, in Kaufman, S. (ed.), Amino Acids in Health and Disease: New Perspectives, Alan R. Liss, Inc., New York.Google Scholar

Copyright information

© Plenum Publishing Corporation 1998

Authors and Affiliations

  • William M. Pardridge
    • 1
  1. 1.Department of Medicine, UCLA School of MedicineLos Angeles

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