Skip to main content
SpringerLink
Log in

Ammonia Detoxication and Glutamine Metabolism in Severe Liver Disease and its Role in the Pathogenesis of Hepatic Encephalopathy

  • Conference paper
Glutamine Metabolism in Mammalian Tissues

Abstract

The term ammonia is used for the sum of the nonionized NH3 and the ionized NH +4 . Ammonia is mainly produced by degradation of amino acids in the human organism. About 1,100 mmol ammonia arise in the eatabolism of 100 g protein having an average amino acid composition. Other sources of ammonia are nucleosides and nucleotides by hydrolytic deamination of their purines and pyrimidines, further amines by oxidative deamination. In addition, enteral microorganisms produce ammonia, which can be reabsorbed from the gut.

Our research was supported by Deutsche Forschungsgemeinschaft and by SANDOZ-Stiftung für therapeutische Forschung

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 84.99
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 109.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Ansley JD, Isaaks JW, Rikkers LF, Kutner MH, Nordlinger BM, Rudman D (1978) Quantitative tests of nitrogen metabolism in cirrhosis: relation to other manifestation of liver disease. Gastroenterology 75: 570–579

    PubMed  CAS  Google Scholar 

  2. Atkinson DE, Camien MN (1982) The role of urea synthesis in the removal of metabolic bicarbonate and the regulation of blood pH. Curr Top Cell Regul 21: 261–302

    PubMed  CAS  Google Scholar 

  3. Berl S, Clarke DD (1969) Compartmentation of amino acid metabolism. In: Lajtha A (ed) Handbook of neurochemistry, vol II. Plenum Press, New York, pp 447–472

    Google Scholar 

  4. Bessman SP, Bessman AN (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

    Article  PubMed  CAS  Google Scholar 

  5. Cooper AJL, McDonald JM, Gelbard AS, Gledhill RF, Duffy TE (1979) The metabolic fate of 13N-labeled ammonia in rat brain. J Biol Chem 254: 4982–4992

    PubMed  CAS  Google Scholar 

  6. Cuilleret G, Pomier-Layrargues G, Pons F, Cadilhac J, Michel H (1980) Changes in brain catecholamine levels in human cirrhotic hepatic encephalopathy. Gut 21: 565–569

    Article  PubMed  CAS  Google Scholar 

  7. Cummings MG, Soeters PB, James JH, Keane JM, Fischer JE (1976) Regional brain indolamine metabolism following chronic portocaval anastomosis in the rat. J Neurochem 27: 501–509

    Article  PubMed  CAS  Google Scholar 

  8. Dahl DR (1968) Short chain fatty acid inhibition of rat brain Na-K-adenosine triphosphatase. J Neurochem 15: 815–820

    Article  PubMed  CAS  Google Scholar 

  9. Derr RF, Zieve L (1976) Effect of fatty acids on the disposition of ammonia. J Pharmacol Exp Ther 197: 675–680

    PubMed  CAS  Google Scholar 

  10. Deuel TF, Louie M, Lerner A (1978) Glutamine synthetase from rat liver. Purification, properties and preparation of specific antisera. J Biol Chem 253: 6111–6118

    PubMed  CAS  Google Scholar 

  11. Duffy TE, Plum F (1982) Hepatic encephalopathy. In: Arias I, Popper H, Schachter D, Shafritz DA (eds) The liver: Biology and pathobiology. Raven Press, New York, pp 693–715

    Google Scholar 

  12. Duffy TE, Vergara F, Plum F (1974) α-Ketoglutaramate in hepatic encephalopathy. Res Publ Assoc Nerv Ment Dis 53: 39–51

    CAS  Google Scholar 

  13. Ferenci P, Schafer DF, Shrager R, Jones EA (1981) Metabolism of the inhibitory neurotransmitter y-amino-butyric acid in a rabbit model of acute hepatic failure. Hepatology 1: 509

    Google Scholar 

  14. Fischer JE, Baldessarini RJ (1971) False neurotransmitters and hepatic failure. Lancet II: 75–80

    Article  Google Scholar 

  15. Ganda OP, Ruderman NB (1976) Muscle nitrogen metabolism in chronic hepatic insufficiency. Metabolism 25: 427–435

    Article  PubMed  CAS  Google Scholar 

  16. Häussinger D (1983) Hepatocyte heterogeneity in glutamine and ammonia metabolism and the role of an intercellular glutamine cycle during ureogenesis in perfused rat liver. Eur J Biochem 133: 269–275

    Article  PubMed  Google Scholar 

  17. Häussinger D, Gerok W (1984) Hepatocyte heterogeneity in ammonia metabolism: Impairment of glutamine synthesis in CCI4 induced liver cell necrosis with no effect on urea synthesis. Chem Biol Interact 48: 191–194

    Article  PubMed  Google Scholar 

  18. Häussinger D, Gerok W, Sies H (1983) Regulation of flux through glutaminase and glutamine synthetase in isolated perfused rat liver. Biochim Biophys Acta 775: 272–278

    Article  Google Scholar 

  19. Häussinger D, Gerok W, Sies H (1984) Hepatic role in pH regulation. Role of the intercellular glutamine cycle. TIBS (in press)

    Google Scholar 

  20. Hindtfelt B, Plum F (1975) L-Methionine-DL-sulphoximine and acute ammonia toxicity. J Pharm Pharmacol 27: 456–458

    Article  Google Scholar 

  21. Hindtfelt B, Plum F, Duffy TE (1977) Effect of acute ammonia intoxication on cerebral metabolism in rats with portocaval shunts. J Clin Invest 59: 386–396

    Article  Google Scholar 

  22. James JH, Hodgman JM, Funovics JM, Fischer JE (1976) Alterations in brain octopamine and brain tyrosine following portocaval anastomosis in rats. J Neurochem 27: 223–227

    Article  PubMed  CAS  Google Scholar 

  23. James JH, Ziparo V, Jeppson B, Fischer JE (1979) Hyperammonaemia, plasma amino acid imbalance, and blood-brain amino acid transport: A unified theory of portal systemic encephalopathy. Lancet II: 772–775

    Article  Google Scholar 

  24. Jellinger K, Riederer P (1977) Brain monoamines in metabolic endotoxic coma: A preliminary biochemical study in human postmortem material. J Neural Transm 41: 275–286

    Article  PubMed  CAS  Google Scholar 

  25. Imler M, Schlienger JL, Frick A (1978) Comparative study of ammonia and glutamine levels in blood and in cerebrospinal fluid in hepatic encephalopathy. In: Wewalka F, Dragosics B (eds) Aminosäuren, Ammoniak und hepatische Encephalopathie. G Fischer, Stuttgart, pp 105–117

    Google Scholar 

  26. Jones EA, Cain GD, Dickinson G (1972) Corticosteroid-induced changes in urea metabolism in patients with hepatocellular disease. Gastroenterology 62: 612–617

    PubMed  CAS  Google Scholar 

  27. Iqbai K, Ottoway JH (1970) Glutamine synthetase in muscle and kidney. Biochem J 119: 145–156

    Google Scholar 

  28. Klassen GA, Aronoff A, Karpati G (1969) Forearm metabolism in patients with chronic liver disease. Clin Sci 37: 455–470

    PubMed  CAS  Google Scholar 

  29. Krebs HA (1935) Metabolism of amino acids IV. The synthesis of glutamine from glutamic acid and ammonia, and the enzymatic hydrolysis of glutamine in animal tissues. Biochem J 29: 1951–1969

    PubMed  CAS  Google Scholar 

  30. Krebs HA, Henseleit K (1932) Untersuchungen über die Harnstoffbildung im Tierkörper. Hoppe-Seyler’s Z Physiol Chem 210: 33–71

    Article  CAS  Google Scholar 

  31. Lam KC, Tall AR, Goldstein GB, Mistiiis SP (1973) Role of false neurotransmitter, octopamine, in the pathogenesis of hepatic and renal encephalopathy. Scand J Gastroenterol 8: 465–472

    PubMed  CAS  Google Scholar 

  32. Lockwood AH, McDonald JM, Reiman RE, Gelbard AS, Laughlin JS, Duffy TE, Plum F (1979) The dynamics of ammonia metabolism in man. Effects of liver disease and hyperammonemia. J Clin Invest 63: 449–460

    Article  PubMed  CAS  Google Scholar 

  33. Lowenstein JM (1972) Ammonia production in muscle and other tissues: The purine nucleotide cycle. Physiol Rev 52: 382–414

    CAS  Google Scholar 

  34. Lunzer M, James IM, Weinman J, Sherlock S (1974) Treatment of chronic hepatic encephalopathy with levodopa. Gut 15: 555–561

    Article  PubMed  CAS  Google Scholar 

  35. Lusty CJ (1978) Carbamylphosphate synthetase I of rat-liver mitochondria. Purification, properties and polypeptidemolecular weight. Eur J Biochem 85: 373–383

    Article  PubMed  CAS  Google Scholar 

  36. Maier KP, Talke H, Gerok W (1978) Harnstoffzyklusenzyme und Harnstoffsynthese bei chronischen Lebererkrankungen. In: Wewalka F, Dragosics B (eds) Aminosäuren, Ammoniak und hepatische Encephalopathie. G. Fischer, Stuttgart, pp 33–38

    Google Scholar 

  37. Manghani KK, Lunzer MR, Billing BH, Sherlock S (1975) Urinary and serum octopamine in patients with portalsystemic encephalopathy. Lancet 11: 943–946

    Article  Google Scholar 

  38. Martinez-Hernandez A, Bell KP, Norenberg MD (1976) Glutamine synthetase: Glial localization in brain. Science 195: 1356–1358

    Article  Google Scholar 

  39. McClain CJ, Zieve L, Doizaki W, Gilberstadt S, Onstad G (1978) Mercaptans in portal systemic encephalopathy due to alcoholic liver disease. Gastroenterology 74: 1065

    Google Scholar 

  40. Moryan MH, Bolton CH, Morris JS, Read AE (1974) Medium chain triglycerides and hepatic encephalopathy. Gut 15: 180–184

    Article  Google Scholar 

  41. Norenberg MD, Martinez-Hernandez A (1979) Fine structural localization of glutamine synthetase in astrocytes of rat brain. Brain Res 161: 303–310

    Article  PubMed  CAS  Google Scholar 

  42. Oliver J, Koelz AM, Costello J, Bourke E (1977) Acid-base induced alterations in glutamine metabolism and ureogenesis in perfused muscle and liver of the rat. Eur J Clin Invest 7: 445–449

    Article  PubMed  CAS  Google Scholar 

  43. Quarfoth G, Ahmed K, Foster D, Zieve L (1976) Action of methanethiol on membrane Na+K+-ATPase of rat brain. Biochem Pharmacol 25: 1039–1044

    Article  PubMed  CAS  Google Scholar 

  44. Rabinowitz JL, Staeffen J, Blanquet P, Vincent JD, Terme R, Series C, Meyerson RM (1978) Sources of serum 14C-octanoate in cirrhosis of the liver and hepatic encephalopathy. J Lab Clin Med 91: 223–227

    PubMed  CAS  Google Scholar 

  45. Record CO, Al Mardini H, Bartlett K (1982) Blood and brain mercaptan concentrations in hepatic encephalopathy. Hepatology 2: 144

    Google Scholar 

  46. Rudman D, Difulco JTh, Galambos JT, Smith R, Salam A, Warren WD (1973) Maximal rates of excretion and synthesis of urea in normal and cirrhotic subjects. J Clin Invest 52: 2241–2249

    Article  PubMed  CAS  Google Scholar 

  47. Rypins EB, Henderson JM (1980) A tracer method for measuring rate of urea synthesis in normal and cirrhotic subjects. Gastroenterology 78: 1419–1424

    PubMed  CAS  Google Scholar 

  48. Schafer DF, Jones EA (1982) Potential neural mechanisms in the pathogenesis of hepatic encephalopathy. In: Popper H, Schaffner F (eds) Progress in Ever diseases, vol VII. Grane & Stratton, New York, pp 615–627

    Google Scholar 

  49. Schafer DF, Fowler JM, Jones EA (1981) Colonic bacteria: A source of γ -aminobutyric acid in blood. Proc Soc Exp Biol Med 167: 301–303

    PubMed  CAS  Google Scholar 

  50. Schafer DF, Ferenci P, Kleinberger G, Hoofnagle JH, Jones EA (1981) Elevated serum concentrations of the inhibitory neurotransmitter γ-aminobutyric acid in patients with hepatocellular disease. Hepatology 1: 543

    Google Scholar 

  51. Smith AR, Rossi-Fanelli F, Ziparo V, James JH, Perelle BA, Fischer JE (1978) Alterations in plasma and CSF amino acids, amines and metabolites in hepatic coma. An Surg 187: 343–350

    Article  CAS  Google Scholar 

  52. Teychenne PF, Walters I, Claveria LE, Calne DB, Price J, MacGillivary BB, Gompertz D (1976) The encephalopathic action of five-carbon-atom fatty acids in the rabbit. Clin Sci Mol Med 50: 463–472

    PubMed  CAS  Google Scholar 

  53. Vilstrup H (1980) Synthesis of urea after stimulation with amino acids: relation to liver function. Gut 21: 990–995

    Article  PubMed  CAS  Google Scholar 

  54. Walker CO, McCandless DW, McGarry JD, Schenker S (1970) Cerebral energy metabolism in short-chain fatty acid induced coma. J Lab Clin Med 76: 569–583

    PubMed  CAS  Google Scholar 

  55. Warren KS, Schenker S (1964) Effect of an inhibitor of glutamine synthesis (methionine sulfoximine) on ammonia toxicity and metabolism. J Lab Clin Med 64: 442–449

    PubMed  CAS  Google Scholar 

  56. Zieve L, Nicoloff DM (1975) Pathogenesis of hepatic coma. Ann Rev Med 26: 143–157

    Article  PubMed  CAS  Google Scholar 

  57. Zieve L, Olsen RL (1977) Can hepatic coma be caused by a reduction of brain noradrenaline or dopamine? Gut 18: 688–691

    Article  PubMed  CAS  Google Scholar 

  58. Zieve L, Doizaki WM, Derr RF (1979) Reversal of ammonia coma in rats by L-dopa: A peripheral effect. Gut 20: 28–32

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Medizinische Universitätsklinik Freiburg, Hugstetterstr. 55, D-7800, Freiburg, Germany

    D. Häussinger

Authors
  1. W. Gerok
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. D. Häussinger
    View author publications

    You can also search for this author in PubMed Google Scholar

Editor information

Editors and Affiliations

  1. Medizinische Universitätsklinik, Hugstetterstraße 55, 7800, Freiburg, Germany

    Dieter Häussinger

  2. Institut für Physiologische Chemie I, Universität Düsseldorf, Moorenstraβe 5, 4000, Düsseldorf, Germany

    Helmut Sies

Rights and permissions

Reprints and permissions

Copyright information

© 1984 Springer- Verlag Berlin Heidelberg

About this paper

Cite this paper

Gerok, W., Häussinger, D. (1984). Ammonia Detoxication and Glutamine Metabolism in Severe Liver Disease and its Role in the Pathogenesis of Hepatic Encephalopathy. In: Häussinger, D., Sies, H. (eds) Glutamine Metabolism in Mammalian Tissues. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-69754-8_17

Download citation

  • DOI: https://doi.org/10.1007/978-3-642-69754-8_17

  • Publisher Name: Springer, Berlin, Heidelberg

  • Print ISBN: 978-3-642-69756-2

  • Online ISBN: 978-3-642-69754-8

  • eBook Packages: Springer Book Archive

Publish with us

Policies and ethics

Search

Navigation