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. 1983 Oct 15;216(1):233–236. doi: 10.1042/bj2160233

Inhibition of ureagenesis by valproate in rat hepatocytes. Role of N-acetylglutamate and acetyl-CoA.

F X Coude, G Grimber, P Parvy, D Rabier, F Petit
PMCID: PMC1152491  PMID: 6418145

Abstract

Valproate (0.5-5 mM) strongly inhibited urea synthesis in isolated rat hepatocytes incubated with 10 mM-alanine and 3 mM-ornithine. Valproate at the same concentrations markedly decreased concentrations of N-acetylglutamate, an essential activator of carbamoyl-phosphate synthetase I (EC 6.3.4.16), in parallel with the inhibition of urea synthesis by valproate. This compound also lowered the cellular concentration of acetyl-CoA, a substrate of N-acetylglutamate synthase (EC 2.3.1.1); glutamate, aspartate and citrulline were similarly decreased. Valproate in a dose up to 2 mM did not significantly affect the cellular concentration of ATP and had no direct effect on N-acetylglutamate synthesis, carbamoyl-phosphate synthetase I and ornithine transcarbamoylase (EC 2.1.3.3) activities.

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Selected References

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

  1. BROWN G. W., Jr, COHEN P. P. Comparative biochemistry of urea synthesis. I. Methods for the quantitative assay of urea cycle enzymes in liver. J Biol Chem. 1959 Jul;234(7):1769–1774. [PubMed] [Google Scholar]
  2. Berry M. N., Friend D. S. High-yield preparation of isolated rat liver parenchymal cells: a biochemical and fine structural study. J Cell Biol. 1969 Dec;43(3):506–520. doi: 10.1083/jcb.43.3.506. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Berry M. N., Kun E. Rate-limiting steps of gluconeogenesis in liver cells as determined with the aid of fluoro-dicarboxylic acids. Eur J Biochem. 1972 May 23;27(2):395–400. doi: 10.1111/j.1432-1033.1972.tb01850.x. [DOI] [PubMed] [Google Scholar]
  4. Ceriotti G., Spandrio L. Catalytic acceleration of the urea-diacetylmonoxime-phenazone reaction and its application to automatic analysis. Clin Chim Acta. 1965 Jun;11(6):519–522. doi: 10.1016/0009-8981(65)90007-0. [DOI] [PubMed] [Google Scholar]
  5. Cheung C. W., Raijman L. The regulation of carbamyl phosphate synthetase (ammonia) in rat liver mitochondria. Effects of acetylglutamate concentration and ATP translocation. J Biol Chem. 1980 Jun 10;255(11):5051–5057. [PubMed] [Google Scholar]
  6. Coude F. X., Ogier H., Grimber G., Parvy P., Pham Dinh D., Charpentier C., Saudubray J. M. Correlation between blood ammonia concentration and organic acid accumulation in isovaleric and propionic acidemia. Pediatrics. 1982 Jan;69(1):115–117. [PubMed] [Google Scholar]
  7. Coude F. X., Rabier D., Cathelineau L., Grimber G., Parvy P., Kamoun P. P. A mechanism for valproate-induced hyperammonemia. Pediatr Res. 1981 Jun;15(6):974–975. doi: 10.1203/00006450-198106000-00020. [DOI] [PubMed] [Google Scholar]
  8. Coude F. X., Sweetman L., Nyhan W. L. Inhibition by propionyl-coenzyme A of N-acetylglutamate synthetase in rat liver mitochondria. A possible explanation for hyperammonemia in propionic and methylmalonic acidemia. J Clin Invest. 1979 Dec;64(6):1544–1551. doi: 10.1172/JCI109614. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Coulter D. L., Allen R. J. Secondary hyperammonaemia: a possible mechanism for valproate encephalopathy. Lancet. 1980 Jun 14;1(8181):1310–1311. doi: 10.1016/s0140-6736(80)91773-0. [DOI] [PubMed] [Google Scholar]
  10. Gerber N., Dickinson R. G., Harland R. C., Lynn R. K., Houghton L. D., Antonias J. I., Schimschock J. C. Reye-like syndrome associated with valproic acid therapy. J Pediatr. 1979 Jul;95(1):142–144. doi: 10.1016/s0022-3476(79)80110-9. [DOI] [PubMed] [Google Scholar]
  11. Hensgens H. E., Verhoeven A. J., Meijer A. J. The relationship between intramitochondrial N-acetylglutamate and activity of carbamoyl-phosphate synthetase (ammonia). The effect of glucagon. Eur J Biochem. 1980;107(1):197–205. doi: 10.1111/j.1432-1033.1980.tb04640.x. [DOI] [PubMed] [Google Scholar]
  12. Kawamoto S., Ishida H., Mori M., Tatibana M. Regulation of N-acetylglutamate synthetase in mouse liver. Postprandial changes in sensitivity to activation by arginine. Eur J Biochem. 1982 Apr;123(3):637–641. [PubMed] [Google Scholar]
  13. Krebs H. A., Hems R., Lund P. Some regulatory mechanisms in the synthesis of urea in the mammalian liver. Adv Enzyme Regul. 1973;11:361–377. doi: 10.1016/0065-2571(73)90024-1. [DOI] [PubMed] [Google Scholar]
  14. Kuhara T., Matsumoto I. Metabolism of branched medium chain length fatty acid. I. Omega-oxidation of sodium dipropylacetate in rats. Biomed Mass Spectrom. 1974 Aug;1(4):291–294. doi: 10.1002/bms.1200010415. [DOI] [PubMed] [Google Scholar]
  15. Martin-Requero A., Corkey B. E., Cerdan S., Walajtys-Rode E., Parrilla R. L., Williamson J. R. Interactions between alpha-ketoisovalerate metabolism and the pathways of gluconeogenesis and urea synthesis in isolated hepatocytes. J Biol Chem. 1983 Mar 25;258(6):3673–3681. [PubMed] [Google Scholar]
  16. Matsumoto I., Kuhara T., Yoshino M. Metabolism of branched medium chain length fatty acid. II--beta-oxidation of sodium dipropylacetate in rats. Biomed Mass Spectrom. 1976 Oct;3(5):235–240. doi: 10.1002/bms.1200030509. [DOI] [PubMed] [Google Scholar]
  17. McGivan J. D., Bradford N. M., Mendes-Mourão J. The regulation of carbamoyl phosphate synthase activity in rat liver mitochondria. Biochem J. 1976 Feb 15;154(2):415–421. doi: 10.1042/bj1540415. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Meijer A. J., Gimpel J. A., Deleeuw G. A., Tager J. M., Williamson J. R. Role of anion translocation across the mitochondrial membrane in the regulation of urea synthesis from ammonia by isolated rat hepatocytes. J Biol Chem. 1975 Oct 10;250(19):7728–7738. [PubMed] [Google Scholar]
  19. Meijer A. J., Gimpel J. A., Deleeuw G., Tischler M. E., Tager J. M., Williamson J. R. Interrelationships between gluconeogenesis and ureogenesis in isolated hepatocytes. J Biol Chem. 1978 Apr 10;253(7):2308–2320. [PubMed] [Google Scholar]
  20. Meijer A. J., van Woerkom G. M. Control of the rate of citrulline synthesis by short-term changes in N-acetylglutamate levels in isolated rat-liver mitochondria. FEBS Lett. 1978 Feb 1;86(1):117–121. doi: 10.1016/0014-5793(78)80111-2. [DOI] [PubMed] [Google Scholar]
  21. Pande S. V., Caramancion M. N. A simple radioisotopic assay of acetylcarnitine and acetyl-CoA at picomolar levels. Anal Biochem. 1981 Mar 15;112(1):30–38. doi: 10.1016/0003-2697(81)90256-6. [DOI] [PubMed] [Google Scholar]
  22. Pinder R. M., Brogden R. N., Speight T. M., Avery G. S. Sodium valproate: a review of its pharmacological properties and therapeutic efficacy in epilepsy. Drugs. 1977 Feb;13(2):81–123. doi: 10.2165/00003495-197713020-00001. [DOI] [PubMed] [Google Scholar]
  23. Shigesada K., Aoyagi K., Tatibana M. Role of acetylglutamate in ureotelism. Variations in acetylglutamate level and its possible significance in control of urea synthesis in mammalian liver. Eur J Biochem. 1978 Apr 17;85(2):385–391. doi: 10.1111/j.1432-1033.1978.tb12250.x. [DOI] [PubMed] [Google Scholar]
  24. 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]
  25. Snodgrass P. J. The effects of pH on the kinetics of human liver Ornithine--carbamyl phosphate transferase. Biochemistry. 1968 Sep;7(9):3047–3051. doi: 10.1021/bi00849a004. [DOI] [PubMed] [Google Scholar]
  26. Stewart P. M., Walser M. Short term regulation of ureagenesis. J Biol Chem. 1980 Jun 10;255(11):5270–5280. [PubMed] [Google Scholar]
  27. Walajtys-Rode E., Williamson J. R. Effects of branched chain alpha-ketoacids on the metabolism of isolated rat liver cells. III. Interactions with pyruvate dehydrogenase. J Biol Chem. 1980 Jan 25;255(2):413–418. [PubMed] [Google Scholar]
  28. Williamson J. R., Browning E. T., Scholz R. Control mechanisms of gluconeogenesis and ketogenesis. I. Effects of oleate on gluconeogenesis in perfused rat liver. J Biol Chem. 1969 Sep 10;244(17):4607–4616. [PubMed] [Google Scholar]
  29. Young R. S., Bergman I., Gang D. L., Richardson E. P., Jr Fatal Reye-like syndrome associated with valproic acid. Ann Neurol. 1980 Apr;7(4):389–389. doi: 10.1002/ana.410070423. [DOI] [PubMed] [Google Scholar]
  30. Zollner H. Regulation of urea synthesis. The effect of ammonia on the N-acetylglutamate content of isolated rat liver cells. Biochim Biophys Acta. 1981 Aug 17;676(2):170–176. doi: 10.1016/0304-4165(81)90184-7. [DOI] [PubMed] [Google Scholar]

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