Advertisement

Ammonia in Liver and Extrahepatic Tissues: An Overview of Metabolism and Toxicity in Mammals

  • Arthur J. L. Cooper
  • James C. K. Lai
  • Alan S. Gelbard
Chapter
Part of the Experimental Biology and Medicine book series (EBAM, volume 22)

Abstract

Ammonia is a major byproduct of systemic and cerebral nitrogen metabolism and is generated in at least 20 enzymatic reactions within the major organs of the body. Ammonia is thought to be generated in the gastrointestinal tract by the action of bacteria on nitrogenous substrates and by deamidation of glutamine in the large and small intestine. Substantial amounts of ammonia are generated in the liver from glutamate and in the kidney by deamidation of glutamine. The principal fate of systemic blood ammonia, in the brain and other organs, is incorporation into glutamine (amide). Portal vein ammonia (which is present at a much higher concentration (~0.5–1.0 mM) than in the peripheral arterial or venous (20–110 μM) blood), on the other hand, is largely detoxified as urea in the liver. The glutamine derived from brain, muscle and other tissues acts as an energy source for the gut and at the same time releases ammonia for urea synthesis. Thus, ultimately, most extrahepatic ammonia is incorporated into urea by temporary storage in glutamine (amide).

Keywords

Glutamine Synthetase Glutamate Dehydrogenase Urea Cycle Glutamine Synthetase Activity Urea Synthesis 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Benjamin, A.M. (1982) Ammonia. In: Handbook of Neurochemistry (2nd Ed) (A. Lajtha, ed); Plenum Press; New York; pp. 117–137.Google Scholar
  2. Benjamin, A.M., and Quastel, J.H. (1975) Metabolism of amino acids and ammonia in rat brain cortex slices in vitro: A possible role of ammonia in brain function. J. Neurochem. 25, 197–206.PubMedCrossRefGoogle Scholar
  3. Berl, S., Takagaki, G., Clarke, D.D., and Waelsch, H. (1962) Mebabolic compartments in vivo: Ammonia and glutamic acid metabolism in brain and liver. J. Biol. Chem. 237, 2562–2569.PubMedGoogle Scholar
  4. Bessman, S.P., and Bessman, A.N. (1955) The cerebral and peripheral uptake of ammonia in liver disease with an hypothesis for the mechanism of hepatic coma. J. Clin. Invest. 34, 622–628.PubMedCrossRefGoogle Scholar
  5. Bradford, H.F. and Ward, H.K. (1975) Glutamine as a metabolic substrate for isolated nerve endings: inhibition by ammonium ion. Biochem Soc. Trans. 3, 1223–1226.Google Scholar
  6. Braunstein, A.E. (1957) Les voies principales de l’assimilation et dissimilation de l’azote chez les animaux. Adv. Enzymol. Rel. Areas Mol. Biol. 19, 335–389.Google Scholar
  7. Butterworth, R.F., Girard G., and Giguere J.-F. (1988) Regional differences in the capacity for ammonia removal by brain following portocaval anastomosis. J. Neurochem. 51, 486–490.PubMedCrossRefGoogle Scholar
  8. Cooper, A.J.L. (1988) Glutamine synthetase. In: Glutamine and Glutamate in Mammals, Vol 1. (E. Kvarame, ed) CRC Press, Inc.; Boca Raton, Florida; pp 7–31.Google Scholar
  9. Cooper, A.J.L., and Plum, F. (1987) Biochemistry and Physiology of Brain Ammonia. Physiol. Rev. 67, 440–519.PubMedGoogle Scholar
  10. Cooper, A.J.L., McDonald, J.M., Gelbard, A.S., Gledhill, R.F., and Duffy, T.E. (1979) The metabolic fate of 13N-labeled ammonia in rat brain. J. Biol. Chem. 254, 4982–4992.PubMedGoogle Scholar
  11. Cooper, A.J.L., Mora, S.N., Cruz, N.F., and Gelbard, A.S. Cerebral ammonia metabolism in hyperammonemic rats (1985) J. Neurochem. 44, 1716–1723.PubMedCrossRefGoogle Scholar
  12. Cooper, A.J.L., Nieves, E., Coleman, A.E., Filc-DeRicco, S., and Gelbard, A.S. (1987) Short-term metabolic fate of [13N] ammonia in rat liver. J. Biol. Chem. 262, 1073–1080.PubMedGoogle Scholar
  13. Cooper, A.J.L., Nieves, E., Filc-DeRicco, S., and Gelbard, A.S. (1988a) Short-term metabolic fate of [13N]ammonia, L-[13N]al anine, L-[13N] glutamate and L- [amide-13N] glutamine in normal rat liver in vivo. In: Advances in Ammonia Metabolism and Hepatic Encephalopathy (P.B. Soeters, J.H.P. Wilson, A.J. Meijer and E. Holm, eds) Elsevier; Amsterdam; pp. 11–25.Google Scholar
  14. Cooper, A.J.L., Nieves, E., Rosenspire, K.C., Filc-DeRicco, S., Gelbard, A.S., and Brusilow, S.W. (1988b) Short-term metabolic fate of 13N-labeled glutamate, alanine and glutamine(amide) in rat liver. J. Biol. Chem. 263, 12268–12273.PubMedGoogle Scholar
  15. Cruz, N.F., and Duffy, T.E. (1983) Local cerebral glucose metabolism in rats with chronic portacaval shunts. J. Cereb. Blood Flow Metab. 3, 311–320.PubMedCrossRefGoogle Scholar
  16. Duffy, T.E., Plum, F., and Cooper, A.J.L. (1983) Cerebral ammonia metabolism in vivo. In: Glutamine, Glutamate and GABA in the Central Nervous System (L. Hertz, E. Kvamme, E.G. McGeer, and A. Schousboe, eds) Alan R. Liss; New York; pp. 371–388.Google Scholar
  17. Felig, P. (1973) The glucose-alanine cycle. Metabolism 22, 179–207.PubMedCrossRefGoogle Scholar
  18. Felig, P., Wahren, J., and Ahlborg, G. (1973) Uptake of individual amino acids by the human brain. Proc. Soc. Exp. Biol. Med. 142, 230–231.PubMedGoogle Scholar
  19. Ferraro, T.N., and Hare, T.A. (1984) Triple-column ion-exchange physiological amino acid analysis with fluorescent detection: Baseline characterization of human cerebrospinal fluid. Anal. Biochem. 143, 82–94.PubMedCrossRefGoogle Scholar
  20. Freed, B.R., and Gelbard, A.S. (1982) Distribution of 13N following intravenous injection of ammonia in the rat. Can J. Pharmacol. 60, 60–67.CrossRefGoogle Scholar
  21. Gjedde, A., Lockwood, A.H., Duffy, T.E., and Plum, F. (1978) Cerebral blood flow and metabolism in chronically hyperammonemic rats: Effect of an acute ammonia challenge. Ann. Neurol. 3, 325–330.PubMedCrossRefGoogle Scholar
  22. Harper, A.E., Miller, R.H., and Block, K.P. (1984) Branched-chain amino acid metabolism. Ann. Rev. Nutr. 4, 409–545.CrossRefGoogle Scholar
  23. Haussinger, D. and Gerok, W. (1984) Hepatocyte heterogeneity in ammonia metabolism: impairment of glutamine synthesis in CC14 induced liver cell necrosis with no effect on urea synthesis. Chem-Biol. Interactions 48, 191–194.CrossRefGoogle Scholar
  24. Haussinger, D., and Gerok, W. (1986) Metabolism of amino acids and ammonia. In: Regulation of Hepatic Metabolism: Intra- and Intercellular Compartmentation (R.G. Thurman, F.C. Kauffman, and K. Jungermann, eds) Plenum Press; New York; pp 253–291.Google Scholar
  25. Hems, R., Stubbs, M., and Krebs, H.A. (1968) Restricted permeability of rat liver for glutamate and succinate. Biochem J. 107, 807–815.PubMedGoogle Scholar
  26. Hindfelt, B. (1983) Ammonia intoxication and brain energy metabolism. In: New Aspects of Clinical Nutrition (G. Kleinberger, and E. Deutsch, eds) Karger; Basel; pp. 474–484.Google Scholar
  27. Hindfelt, B., Plum, F., and Duffy, T.E. (1977) Effects of acute ammonia intoxication on cerebral metabolism in rats with portacaval shunts. J. Clin. Invest. 59, 386–396.PubMedCrossRefGoogle Scholar
  28. Krebs, H.A., Hems, R., Lund, P., Halliday, D., and Read, W.W.C. (1978) Sources of ammonia for urea synthesis Biochem. J. 176, 733–737.PubMedGoogle Scholar
  29. Kvamme, E. (1983) Ammonia metabolism in the CNS. Prog. Neurobiol. 20, 109–132.PubMedCrossRefGoogle Scholar
  30. Lai, J.C.K., and Cooper, A.J.L. (1986) Brain a-ketoglutarate dehydrogenase complex: Kinetic properties, regional distribution and effects of inhibition. J. Neurochem. 47, 1376–1386.PubMedCrossRefGoogle Scholar
  31. Lockwood, A.H., Finn, R.D., Campbell, J.A., and Richman, T.B. (1980) Factors that affect the uptake of ammonia by the brain: the blood-brain pH gradient. Brain Res. 181, 259–266.PubMedCrossRefGoogle Scholar
  32. Lockwood, A.H., McDonald, J.M., Reiman, R.E., Gelbard, A.S., Laughlin, J.S., and Duffy, T.E. (1979) The dynamics of ammonia metabolism in man. Effects of liver disease and hyperammonemia. J. Clin. Invest. 63, 449–460.PubMedCrossRefGoogle Scholar
  33. Lowry, O.H., and Passonneau, J.V. (1966) Kinetic evidence for multiple binding sites on phosphofructokinase. J. Biol. Chem. 241, 2268–2279.PubMedGoogle Scholar
  34. Mans, A.M., Biebuyck, J.F., Davis, D.W., Bryan, R.M., and Hawkins, R.A. (1983) Regional cerebral glucose utilization in rats with portacaval anastamosis. J. Neurochem. 40, 986–991.PubMedCrossRefGoogle Scholar
  35. McCandless, D.W., and Schenker, S. (1981) Effect of acute ammonia intoxication on energy stores in the cerebral reticular activating system. Exp. Brain Res. 44, 325–330.PubMedCrossRefGoogle Scholar
  36. McKhann, G.M. and Tower, D.B. (1961) Ammonia toxicity and cerebral oxidative metabolism. Am. J. Physiol. 200 420–424.PubMedGoogle Scholar
  37. Meijer, A. (1985) Channeling of ammonia from glutaminase to carbamoyl-phosphate synthetase in liver mitochondria. FEBS Lett. 191, 249–251.PubMedCrossRefGoogle Scholar
  38. Meijer, A.J., Lof, C., Ramos, I.C. and Verhoeven, A. (1985) Control of ureogenesis. Eur. J. Biochem. 148, 189–196.PubMedCrossRefGoogle Scholar
  39. Norenberg, M.D., and Martinez-Hernandez, A. (1979) Fine structural localization of glutamine synthetase in astrocytes of rat brain. Brain Res. 161, 303–310.PubMedCrossRefGoogle Scholar
  40. Ochs, R.S. (1984) Glutamine metabolism of isolated rat hepatocytes. Evidence for catecholamine activation of α-ketoglutarate dehydrogenase. J. Biol. Chem. 259, 13004–13010.PubMedGoogle Scholar
  41. Pardrige, W.M. (1977) Unidirectional influx of glutamine and other neutral amino acids into liver of fed and fasted rat in vivo. Am. J. Physiol. 232, E492-E496.Google Scholar
  42. Pardridge, W.M. (1983) Brain Metabolism: A perspective from the blood-brain barrier. Physiol. Rev. 63, 1481–1535.PubMedGoogle Scholar
  43. Phelps, M.E., Hoffman, E.J., and Raybaud, C. (1977) Factors which affect cerebral uptake and retention of 13NH3. Stroke 8, 694–702.PubMedCrossRefGoogle Scholar
  44. Pitts, R.F. (1964) Renal production and excretion of ammonia. Am. J. Med. 36, 720–742.PubMedCrossRefGoogle Scholar
  45. Posner, J.B., and Plum, F. (1960) The toxic effects of carbon dioxide and acetazolamide in hepatic encephalopathy. J. Clin. Invest. 39, 1246–1258.PubMedCrossRefGoogle Scholar
  46. Quistorff, B. (1985) Gluconeogenesis in periportal and perivenous hepatocytes in rat liver, isolated by a new high-yield/collagenase perfusion technique. Biochem. J. 229, 221–226.PubMedGoogle Scholar
  47. Raichle, M.E., and Larson, K.B. (1981) The significance of the NH3-NH4 + equilibrium on the passage of 13N-ammonia from blood to brain. A new regional residue detection model. Circ. Res. 48, 913–937.PubMedGoogle Scholar
  48. Raijman, L. (1974) Citrulline synthesis in rat tissues and liver content of carbamoyl phosphate and ornithine. Biochem. J. 138, 225–232.PubMedGoogle Scholar
  49. Rognstad, R. (1977) Sources of ammonia for urea synthesis in isolated rat liver cells. Biochim. Biophys. Acta 496, 249–254.PubMedGoogle Scholar
  50. Ross, B.D. (1988) The current state of clinical magnetic resonance spectroscopy with phosphorus-31: An overview from Hammersmith. Mag. Res. Medicine Biol. 1, 81–98.Google Scholar
  51. Schultz, V., and Lowenstein, J.M. (1978) The purine nucleotide cycle. Studies of ammonia production and interconversions of adenine and hypoxanthine nucleotides and nucleosides by rat brain in vivo. J. Biol. Chem. 253, 1938–1943.PubMedGoogle Scholar
  52. Tatibana, M., and Shigesada, K (1976) Regulation of urea biosynthesis by the acetylglutamate-arginine system. In: The urea cycle (S. Grisolia, R. Baguena and F. Mayor, eds) John Wiley and Sons, Inc; New York; pp. 301–313.Google Scholar
  53. Taylor, P.M., and Rennie, M.J. (1987) Perivenous localization of Na-dependent glutamate transport in perfused rat liver. FEBS Lett. 221, 370–374.PubMedCrossRefGoogle Scholar
  54. Van Den Berg, C.J., Matheson, D.F., and Nijemanting, W.C. (1978) Compartmentation of amino acids in brain: The GABA-glutamine-glutamate cycle. In: Amino Acids and Chemical Transmitters (F. Fonnum, ed) Plenum Press; New York; pp. 709–723.Google Scholar
  55. Melbourne, T.C. (1988) Role of the lung in glutamine homeostasis. In: New Aspects of Renal Ammonia Metabolism. Contributions to Nephrology. Vol 63 (G. Baverel, A.C. Schoolwerth, H. Endou, M. Rengel, and A. Tizcanello, eds) Karger; Basel; pp. 178–182.Google Scholar
  56. Windmueller, H.G. and Spaeth, A.E. (1974) Uptake and metabolism of plasma glutamine by the small intestine. J. Biol. Chem. 249, 5070–5079.PubMedGoogle Scholar

Copyright information

© The Humana Press Inc. 1989

Authors and Affiliations

  • Arthur J. L. Cooper
    • 1
  • James C. K. Lai
    • 1
  • Alan S. Gelbard
    • 2
  1. 1.Departments of Biochemistry and NeurologyCornell University Medical CollegeNew YorkUSA
  2. 2.Biophysics LaboratoryMemorial Sloan Kettering Cancer CenterNew YorkUSA

Personalised recommendations