Skip to main content
NCBI home page
Proceedings of the National Academy of Sciences of the United States of America logoLink to Proceedings of the National Academy of Sciences of the United States of America
. 1972 Dec;69(12):3530–3533. doi: 10.1073/pnas.69.12.3530

Ammonia Intoxication in Rats: Protection by N-Carbamoyl-L-Glutamate Plus L-Arginine

Sangduk Kim *, Woon Ki Paik *, Philip P Cohen †,†
PMCID: PMC389814  PMID: 4509311

Abstract

Rats given a lethal dose (LD99.9) of ammonium acetate (10.8 mmol/kg of body weight) were protected to the extent of 85 and 76% when previously injected with N-carbamoyl glutamate or L-arginine, respectively, at a level of 4 mmol/kg of body weight. At a dose of 1 mmol/kg of body weight, L-arginine protected 24%, while N-carbamoyl-L-glutamate protected 61% of the animals. When a combination of N-carbamoyl-L-glutamate plus L-arginine (1 mmol each per kg of body weight) was injected, 100% of the rats were protected. The efficacy of N-carbamoyl-L-glutamate is related to its role as an activator of mitochondrial carbamoyl phosphate synthetase (EC 2.7.2.5) and its resistance to hydrolysis by tissue acylaminoacid acylase. N-Acetyl-L-glutamate, the naturally occurring and most effective activator of mitochondrial carbamoyl phosphate synthetase, was relatively ineffective in protection against lethal dose of ammonium acetate, because of its ready hydrolysis by acylaminoacid acylase.

The findings reported provide a rational basis for the use of N-carbamoyl-L-glutamate plus L-arginine in the prevention and treatment of hyperammonemia in clinical conditions of liver disease and parental infusion of amino acids, and in feeding of urea supplements to ruminants.

Keywords: hyperammonemia, mitochondrial carbamoyl phosphate synthetase, urea biosynthesis, acylaminoacid acylase

Full text

PDF
3530

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. ALLEN C. M., Jr, JONES M. E. DECOMPOSITION OF CARBAMYLPHOSPHATE IN AQUEOUS SOLUTIONS. Biochemistry. 1964 Sep;3:1238–1247. doi: 10.1021/bi00897a010. [DOI] [PubMed] [Google Scholar]
  2. BESSMAN S. P., SHEAR S., FITZGERALD J. Effect of arginine and glutamate on the removal of ammonia from the blood in normal and cirrhotic patients. N Engl J Med. 1957 May 16;256(20):941–943. doi: 10.1056/NEJM195705162562006. [DOI] [PubMed] [Google Scholar]
  3. BIRNBAUM S. M., DU RUISSEAU J. P., GREENSTEIN J. P., OTEY M. C., WINITZ M. Studies on the metabolism of amino acids and related compounds in vivo. V. Effects of combined administration of nonprotective compounds and subprotective levels of L-arginine. HCI on ammonia toxicity in rats. Arch Biochem Biophys. 1956 Oct;64(2):368–373. doi: 10.1016/0003-9861(56)90280-6. [DOI] [PubMed] [Google Scholar]
  4. BIRNBAUM S. M., DU RUISSEAU J. P., GREENSTEIN J. P., WINITZ M. Studies on the metabolism of amino acids and related compounds in vivo. IV. Blood ammonia and urea levels following intraperitoneal administration of amino acids and ammonium acetate, and the effect of arginine thereon. Arch Biochem Biophys. 1956 Oct;64(2):355–367. doi: 10.1016/0003-9861(56)90279-x. [DOI] [PubMed] [Google Scholar]
  5. BIRNBAUM S. M., GREENSTEIN J. P., GULLINO P., OTEY M. C., WINITZ M. Studies on the metabolism of amino acids and related compounds in vivo. III. Prevention of ammonia toxicity by arginine and related compounds. Arch Biochem Biophys. 1956 Oct;64(2):342–354. doi: 10.1016/0003-9861(56)90278-8. [DOI] [PubMed] [Google Scholar]
  6. BIRNBAUM S. M., GREENSTEIN J. P., GULLINO P., WINITZ M. Studies on the metabolism of amino acids and related compounds in vivo. II. Effect of toxic doses of essential amino acids on blood sugar, liver glycogen and muscle glycogen levels. Arch Biochem Biophys. 1956 Oct;64(2):333–341. doi: 10.1016/0003-9861(56)90277-6. [DOI] [PubMed] [Google Scholar]
  7. Chalupa W. Metabolic aspects of nonprotein nitrogen utilization in ruminant animals. Fed Proc. 1972 May-Jun;31(3):1152–1164. [PubMed] [Google Scholar]
  8. Chiosa L., Niculescu V., Bonciocat C., Stancu C. The protective action of N-acetyl and N-carbamyl derivatives of glutamic and aspartic acids against ammonia intoxication. Biochem Pharmacol. 1965 Nov;14(11):1635–1643. doi: 10.1016/0006-2952(65)90017-1. [DOI] [PubMed] [Google Scholar]
  9. FAHEY J. L., NATHANS D., RAIRIGH D. Effect of L-arginine on elevated blood ammonia levels in man. Am J Med. 1957 Dec;23(6):860–869. doi: 10.1016/0002-9343(57)90295-4. [DOI] [PubMed] [Google Scholar]
  10. FAHEY J. L. Toxicity and blood ammonia rise resulting from intravenous amino acid administration in man: the protective effect of l-arginine. J Clin Invest. 1957 Dec;36(12):1647–1655. doi: 10.1172/JCI103565. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. FAHIEN L. A., SCHOOLER J. M., GEHRED G. A., COHEN P. P. STUDIES ON THE MECHANISM OF ACTION OF ACETYLGLUTAMATE AS AN ACTIVATOR OF CARBAMYL PHOSPHATE SYNTHETASE. J Biol Chem. 1964 Jun;239:1935–1941. [PubMed] [Google Scholar]
  12. GRISOLIA S., COHEN P. P. Catalytic rôle of of glutamate derivatives in citrulline biosynthesis. J Biol Chem. 1953 Oct;204(2):753–757. [PubMed] [Google Scholar]
  13. GULLINO P., WINITZ M., BIRNBAUM S. M., CORNFIELD J., OTEY M. C., GREENSTEIN J. P. Studies on the metabolism of amino acids and related compounds in vivo. I. Toxicity of essential amino acids, individually and in mixtures, and the protective effect of L-arginine. Arch Biochem Biophys. 1956 Oct;64(2):319–332. doi: 10.1016/0003-9861(56)90276-4. [DOI] [PubMed] [Google Scholar]
  14. HALL L. M., METZENBERG R. L., COHEN P. P. Isolation and characterization of a naturally occurring cofactor of carbamyl phosphate biosynthesis. J Biol Chem. 1958 Feb;230(2):1013–1021. [PubMed] [Google Scholar]
  15. Harper A. E., Benevenga N. J., Wohlhueter R. M. Effects of ingestion of disproportionate amounts of amino acids. Physiol Rev. 1970 Jul;50(3):428–558. doi: 10.1152/physrev.1970.50.3.428. [DOI] [PubMed] [Google Scholar]
  16. Heird W. C., Nicholson J. F., Driscoll J. M., Jr, Schullinger J. N., Winters R. W. Hyperammonemia resulting from intravenous alimentation using a mixture of synthetic l-amino acids: a preliminary report. J Pediatr. 1972 Jul;81(1):162–165. doi: 10.1016/s0022-3476(72)80396-2. [DOI] [PubMed] [Google Scholar]
  17. Johnson J. D., Albritton W. L., Sunshine P. Hyperammonemia accompanying parenteral nutrition in newborn infants. J Pediatr. 1972 Jul;81(1):154–161. doi: 10.1016/s0022-3476(72)80395-0. [DOI] [PubMed] [Google Scholar]
  18. KORITZ S. B., COHEN P. P. The effect of diet on citrulline synthesis in vitro. J Biol Chem. 1953 Feb;200(2):551–557. [PubMed] [Google Scholar]
  19. Levin B., Russell A. Treatment of hyperammonemia. Am J Dis Child. 1967 Jan;113(1):142–145. doi: 10.1001/archpedi.1967.02090160192031. [DOI] [PubMed] [Google Scholar]
  20. Marshall M., Cohen P. P. Ornithine transcarbamylase from Streptococcus faecalis and bovine liver. II. Multiple binding sites for carbamyl-P and L-norvaline, correlation with steady state kinetics. J Biol Chem. 1972 Mar 25;247(6):1654–1668. [PubMed] [Google Scholar]
  21. RATNER S. Urea synthesis and metabolism of arginine and citrulline. Adv Enzymol Relat Subj Biochem. 1954;15:319–387. doi: 10.1002/9780470122600.ch8. [DOI] [PubMed] [Google Scholar]
  22. Shigesada K., Tatibana M. Enzymatic synthesis of acetylglutamate by mammalian liver preparations and its stimulation by arginine. Biochem Biophys Res Commun. 1971 Sep;44(5):1117–1124. doi: 10.1016/s0006-291x(71)80201-2. [DOI] [PubMed] [Google Scholar]
  23. Shigesada K., Tatibana M. Role of acetylglutamate in ureotelism. I. Occurrence and biosynthesis of acetylglutamate in mouse and rat tissues. J Biol Chem. 1971 Sep 25;246(18):5588–5595. [PubMed] [Google Scholar]
  24. Summerskill W. H., Wolpert E. Ammonia metabolism in the gut. Am J Clin Nutr. 1970 May;23(5):633–639. doi: 10.1093/ajcn/23.5.633. [DOI] [PubMed] [Google Scholar]
  25. Walker C. O., Schenker S. Pathogenesis of hepatic encephalopathy--with special reference to the role of ammonia. Am J Clin Nutr. 1970 May;23(5):619–632. doi: 10.1093/ajcn/23.5.619. [DOI] [PubMed] [Google Scholar]
  26. Wixom R. L., Reddy M. K., Cohen P. P. A concerted response of the enzymes of urea biosynthesis during thyroxine-induced metamorphosis of Rana catesbeiana. J Biol Chem. 1972 Jun 10;247(11):3684–3692. doi: 10.2172/4649772. [DOI] [PubMed] [Google Scholar]

Articles from Proceedings of the National Academy of Sciences of the United States of America are provided here courtesy of National Academy of Sciences

RESOURCES