Skip to main content
SpringerLink
Log in

Ethyl Pyruvate: A Novel Anti-inflammatory Agent

  • Conference paper
Intensive Care Medicine

Abstract

Pyruvate, CH3COCOO−, plays a central role in intermediary metabolism, being the final product of glycolysis and the starting substrate for the tricarboxylic acid (TCA) cycle. Pyruvate probably also functions in cells as an endogenous antioxidant [1–3]. The capacity of pyruvate to function as an antioxidant was first described in 1904 by Holleman, who showed that simple aliphatic a-keto carboxylates reduce hydrogen peroxide (H2O2) nonenzymatically in a reaction that yields carbon dioxide and water [4]. In the case of pyruvate, this reaction is both rapid and stoichiometric [5–7].

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 39.99
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 54.99
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. O’Donnell-Tormey J, Nathan CF, Lanks K, DeBois CJ, de la Harpe J (1987) Secretion of pyruvate. An antioxidant defense of mammalian cells. J Exp Med 165: 500–514

    Article  PubMed  Google Scholar 

  2. Brand KA (1997) Aerobic glycolysis by proliferating cells: protection against oxidative stress at the expense of energy yield. J Bioenerg Biomembr 29: 355–364

    Article  PubMed  CAS  Google Scholar 

  3. Brand KA, Hermfisse U (1997) Aerobic glycolysis by proliferating cells: a protective strategy against reactive oxygen species. FASEB J 11: 388–395

    PubMed  CAS  Google Scholar 

  4. Holleman MAF (1904) Notice sur l’action de l’eau oxygénée sur les acétoniques et sur le dicétones 1.2. Red Tray Chim Pays-bas Belg 23: 169–171

    Article  CAS  Google Scholar 

  5. Adickes F, Andresen G (1943) Zur kenntnis der reihe der normalen aliphatischen ß-oxysauren und der a-ketosauren. Ann Chem 50: 41–57

    Google Scholar 

  6. Bunton CA (1949) Oxidation of a-diketones and a-keto-acids by hydrogen peroxide. Nature 163: 144

    Article  Google Scholar 

  7. Melzer E, Schmidt H (1988) Carbon isotope effects on the decarboxylation of carboxylic acids. Biochem J 252: 913–915

    PubMed  CAS  Google Scholar 

  8. Salahudeen AK, Clark EC, Nath KA (1991) Hydrogen peroxide-induced renal injury. A protective role for pyruvate in vitro and in vivo. J Clin Invest 88: 1886–1893

    Google Scholar 

  9. Bunger R, Mallet RT, Hartman DA (1989) Pyruvate-enhanced phosphorylation potential and inotropism in normoxic and postischemic isolated working heart. Near-complete prevention of reperfusion contractile failure. Eur J Biochem 180: 221–233

    Google Scholar 

  10. Cicalese L, Lee K, Schraut W, Watkins S, Borle A, Stanko R (1999) Pyruvate prevents ischemia-reperfusion mucosal injury of rat small intestine. Am J Surg 171: 97–100

    Article  Google Scholar 

  11. Sileri P, Schena S, Morini S, et al (2001) Pyruvate inhibits hepatic ischemia-reperfusion injury in rats. Transplantation 72: 27–30

    Article  PubMed  CAS  Google Scholar 

  12. Gupta SK, Mohanty I, Trivedi D, Tandon R, Srivastava S, Joshi S (2002) Pyruvate inhibits galactosemic changes in cultured cat lens epithelial cells. Ophthalmic Res 34: 23–28

    Article  PubMed  CAS  Google Scholar 

  13. Zhao W, Devamanoharan PS, Henein M, Ali AH, Varma SD (2000) Diabetes-induced biochemical changes in rat lens: attenuation of cataractogenesis by pyruvate. Diabetes Obes Metab 2: 165–174

    Article  PubMed  CAS  Google Scholar 

  14. Lee JY, Kim YH, Koh JY (2001) Protection by pyruvate against transient forebrain ischemia in rats. J Neurosci 21: 1–6

    Google Scholar 

  15. Slovin PN, Huang CJ, Cade JR, et al (2001) Sodium pyruvate is better than sodium chloride as a resuscitation solution in a rodent model of profound hemorrhagic shock. Resuscitation 50: 109–115

    Article  PubMed  CAS  Google Scholar 

  16. Varma SD, Devamanoharan PS, Rutzen AR, Ali AH, Henein M (1999) Attenuation of galactose-induced cataract by pyruvate. Free Rad Res 30: 253–263

    Article  CAS  Google Scholar 

  17. Zhao W, Devamanoharan PS, Varma SD (2000) Fructose induced deactivation of antioxidant enzymes: preventive effect of pyruvate. Free Rad Res 33: 23–30

    Article  CAS  Google Scholar 

  18. Varma SD, Devamanoharan PS, Ali AH (1998) Prevention of intracellular oxidative stress to lens by pyruvate and its ester. Free’Rad Res 28: 131–135

    CAS  Google Scholar 

  19. Montgomery CM, Webb JL (1956) Metabolic studies on heart mitochondria. II. The inhibitory action of parapyruvate on the tricarboxylic acid cycle. J Biol Chem 221: 359–368

    Google Scholar 

  20. Montgomery CM, Fairhurst AS, Webb JL (1956) Metabolic studies on heart mitochondria. III. The action of parapyruvate on a-ketoglutaric oxidase. J Biol Chem 221: 369–376

    Google Scholar 

  21. Willems JL, de Kort AFM, Vree TB, Trijbels JMF, Veerkamp JH, Monnens LAH (1978) Non-enzymatic conversion of pyruvate in aqueous solution to 2,4-dihydroxy-2-methylglutaric acid. FEBS Lett 86: 42–44

    Article  PubMed  CAS  Google Scholar 

  22. Margolis SA, Coxon B (1986) Identification and quantitation of the impurities in sodium pyruvate. Anal Biochem 58: 2504–2510

    CAS  Google Scholar 

  23. Sims CA, Wattanasirichaigoon S, Menconi MJ, Ajami AM, Fink MP (2001) Ringer’s ethyl pyruvate solution ameliorates ischemia/reperfusion-induced intestinal mucosal injury in rats. Crit Care Med 29: 1513–1518

    Article  PubMed  CAS  Google Scholar 

  24. Wattanasirichaigoon S, Menconi MJ, Delude RL, Fink MP (1999) Effect of mesenteric ischemia and reperfusion or hemorrhagic shock on intestinal mucosal permeability and ATP content in rats. Shock 12: 127–133

    Article  PubMed  CAS  Google Scholar 

  25. Wattanasirichaigoon S, Menconi MJ, Delude RL, Fink MP (1999) Lisofylline ameliorates intestinal mucosal barrier dysfunction caused by ischemia and ischemia/reperfusion. Shock 11: 269–275

    Article  PubMed  CAS  Google Scholar 

  26. Tawadrous ZS, Delude RL, Fink MP (2002) Resuscitation from hemorrhagic shock with Ringer’s ethyl pyruvate solution improves survival and ameliorates intestinal mucosal hyperpermeability in rats. Shock 17: 473–477

    Article  PubMed  Google Scholar 

  27. Yang R, Gallo DJ, Baust JJ, et al (2002) Ethyl pyruvate modulates inflammatory gene expression in mice subjected to hemorrhagic shock. Am J Physiol 283: G212 - G222

    CAS  Google Scholar 

  28. Meldrum DR, Shenkar R, Sheridan BC, Cain BS, Abraham E, Harken AH (1997) Hemorrhage activates myocardial NF-kappaB and increases TNF-alpha in the heart. J Mol Cell Cardiol 29: 2849–2854

    Article  PubMed  CAS  Google Scholar 

  29. Hierholzer C, Harbrecht B, Menezes JM, et al (1998) Essential role of induced nitric oxide in the initiation of the inflammatory response after hemorrhagic shock. J Exp Med 187: 917–928

    Article  PubMed  CAS  Google Scholar 

  30. Venkataraman R, Kellum JA, Song M, Fink MP (2002) Resuscitation with Ringer’s ethyl pyruvate solution prolongs survival and modulates plasma cytokine and nitrite/nitrate concentrations in a rat model of lipopolysaccharide-induced shock. Shock 18: 507–512

    Article  PubMed  Google Scholar 

  31. Ulloa L, Ochani M, Yang H, et al (2002) Ethyl pyruvate prevents lethality in mice with established lethal sepsis and systemic inflammation. Proc Natl Acad Sci USA 99: 12351–12356

    Article  PubMed  CAS  Google Scholar 

  32. Wang H, Bloom O, Zhang M, et al (1999) HMG-1 as a late mediator of endotoxin lethality in mice. Science 285: 248–251

    Article  PubMed  CAS  Google Scholar 

  33. Fink MP, Heard SO (1990) Research review: laboratory models of sepsis and septic shock. J Surg Res 49: 186–196

    Article  PubMed  CAS  Google Scholar 

  34. Unno N, Wang H, Menconi MJ, et al (1997) Inhibition of inducible nitric oxide synthase ameliorates lipopolysaccharide-induced gut mucosal barrier dysfunction in rats. Gastroenterology 113: 1246–1257

    Article  PubMed  CAS  Google Scholar 

  35. Sappington PL, Yang R, Yang H, Tracey KJ, Delude RL, Fink MP (2002) HMGB1 B box increases the permeability of Caco-2 enterocytic monolayers and impairs intestinal barrier function in mice. Gastroenterology 123: 790–802

    Article  PubMed  CAS  Google Scholar 

  36. Casellas F, Aguade S, Soriano B, Accarino A, Molero J, Guarner L (1986) Intestinal permeability to 99mTc-diethylenetriaminopentaacetic acid in inflammatory bowel disease. Am J Gastroenterol 81: 767–770

    PubMed  CAS  Google Scholar 

  37. Deitch EA, Specian RD, Berg RD (1991) Endotoxin-induced bacterial translocation and mucosal permeability: role of xanthine oxidase, complement activation, and macrophage products. Crit Care Med 19: 785–791

    Article  PubMed  CAS  Google Scholar 

  38. Sappington PL, Han X, Yang R, Delude RL, Fink MP (2003) Ethyl pyruvate ameliorates intestinal epithelial barrier dysfunction in endotoxemic mice and immunostimulated Caco-2 enterocytic monolayers. J Pharmacol Exp Ther 304: 464–476

    Article  PubMed  CAS  Google Scholar 

  39. Chavez A, Menconi MJ, Hodin RA, Fink MP (1999) Cytokine-induced epithelial hyperpermeability: role of nitric oxide. Crit Care Med 27: 2246–2251

    Article  PubMed  CAS  Google Scholar 

  40. Mertz RJ, Worley JFI, Spencer B, Johnson JH, Dukes ID (1996) Activation of stimulus-secretion coupling in pancreatic ß-cells by specific products of glucose metabolism. J Biol Chem 271: 4838–4845

    Article  PubMed  CAS  Google Scholar 

  41. Zawalich WS, Zawalich KC (1997) Influence of pyruvic acid methyl ester on rat pancreatic islets. Effects on insulin secretion, phosphoinositide hydrolysis, and sensitization of the beta cell. J Biol Chem 272: 3527–3531

    Google Scholar 

  42. Lembert N, Joos HC, Idahl L-A, Ammon HPT, Wahl MA (2001) Methyl pyruvate initiates membrane depolarization and insulin release by metabolic factors other than ATP. Biochem J 354: 345–350

    Article  PubMed  CAS  Google Scholar 

  43. Parikh AA, Moon MR, Pritts TA, et al (2000) IL-lbeta induction of NF-kappaB activation in human intestinal epithelial cells is independent of oxyradical signaling. Shock 13: 8–13

    Article  PubMed  CAS  Google Scholar 

  44. Salzman AL, Denenberg AG, Ueta I, O’Connor M, Linn SC, Szabo C (1996) Induction and activity of nitric oxide synthase in cultured human intestinal epithelial monolayers. Am J Physiol 270: G565 - G573

    PubMed  CAS  Google Scholar 

  45. Bowie AG, Moynagh PN, O’Neill LAJ (1997) Lipid peroxidation is involved in the activation of NF-KB by tumor necrosis factor but not interleukin-1 in the human endothelial cell line ECV304. J Biol Chem 272: 25941–25950

    Article  PubMed  CAS  Google Scholar 

  46. Chandel NS, Trzyna WC, McClintock DS, Schumacker PT (2000) Role of oxidants in NF-kappa B activation and TNF-alpha gene transcription induced by hypoxia and endotoxin. J Immunol 165: 1013–1021

    PubMed  CAS  Google Scholar 

  47. Lyss G, Knorre A, Schmidt TJ, Pahl HL, Merfort I (1998) The anti-inflammatory sesquiterpene lactone helenalin inhibits the transcription factor NF-kappaB by directly targeting p65. J Biol Chem 273: 33508–33516

    Article  PubMed  CAS  Google Scholar 

  48. Schmidt TJ, Lyss G, Pahl HL, Merfort I (1999) Helenanolide type sesquiterpene lactones. Part 5: the role of glutathione addition under physiological conditions. Bioorg Med Chem 7: 2849–2855

    Article  PubMed  CAS  Google Scholar 

  49. Garcia-Pineres AJ, Castro V, Mora G, et al (2001) Cysteine 38 in p65/NF-kappaB plays a crucial role in DNA binding inhibition by sesquiterpene lactones. J Biol Chem 276: 39713–39720

    Article  PubMed  CAS  Google Scholar 

  50. Dupuis G, Mitchell JC, Towers GH (1974) Reaction of alantolactone, an allergenic sesquiterpene lactone, with some amino acids. Resultant loss of immunologic reactivity. Can J Biochem 52: 575–581

    Google Scholar 

  51. Hay AJB, Hamburger M, Hostettmann K, Hoult JRS (1994) Toxic inhibition of smooth muscle contractility by plant-derived sesquiterpenes caused by their chemically reactive alpha-methylenebutyrolactone functions. Br J Pharmacol 112: 9–12

    Article  PubMed  CAS  Google Scholar 

  52. Schmidt TJ (1999) Toxic activities of sesquiterpene lactones: structural and biochemical aspects. Curr Org Chem 3: 577–608

    CAS  Google Scholar 

  53. Chiang Y, Kresge AJ, Pruszynski P (1992) Keto-enol equilibria in the pyruvic acid system: determination of the keto-enol equilibrium constants of pyruvic acid and pyruvate anion and the acidity constant of pyruvate enol in aqueous solution. J Am Chem Soc 114: 3103–3107

    Article  CAS  Google Scholar 

  54. Keeffe JR, Kresge AJ, Schepp NP (1990) Keto-enol equilibrium constants of simple mono-functional aldehydes and ketones in aqueous solution. J Am Chem Soc 112: 4862–4868

    Article  CAS  Google Scholar 

  55. Hynes MJ, O’Regan BD (1979) Kinetics and mechanisms of the reactions of nickel(II) and pentane-2,4-dione. J Chem Soc, Dalton Trans 162–166

    Google Scholar 

  56. Hynes MJ, O’Shea MT (1983) Kinetics and mechanisms of the reactions of nickel(II), cobalt(II), copper(II), and iron(III) with 1,1,1-trifluoropentane-2,4-dione. J Chem Soc, Dalton Trans 331–336

    Google Scholar 

  57. Brennan P, O’Neill LA (1998) Inhibition of nuclear factor kappaB by direct modification in whole cells–mechanism of action of nordihydroguaiaritic acid, curcumin and thiol modifiers. Biochem Pharmacol 55: 965–973

    Article  PubMed  CAS  Google Scholar 

Download references

Authors
  1. M. P. Fink
    View author publications

    You can also search for this author in PubMed Google Scholar

Editor information

Editors and Affiliations

  1. Department of Intensive Care, Erasme Hospital, Free University of Brussels, Route de Lennik 808, B-1070, Brussels, Belgium

    Jean-Louis Vincent MD, PhD, FCCM, FCCP (Head) (Head)

Rights and permissions

Reprints and permissions

Copyright information

© 2003 Springer-Verlag Berlin Heidelberg

About this paper

Cite this paper

Fink, M.P. (2003). Ethyl Pyruvate: A Novel Anti-inflammatory Agent. In: Vincent, JL. (eds) Intensive Care Medicine. Springer, New York, NY. https://doi.org/10.1007/978-1-4757-5548-0_57

Download citation

  • DOI: https://doi.org/10.1007/978-1-4757-5548-0_57

  • Publisher Name: Springer, New York, NY

  • Print ISBN: 978-1-4757-5550-3

  • Online ISBN: 978-1-4757-5548-0

  • eBook Packages: Springer Book Archive

Publish with us

Policies and ethics

Search

Navigation