Inhibition of Prostaglandin H2 Synthases by Salicylate is Dependent on the Oxidative State of the Enzymes

  • David M. Aronoff
  • Olivier Boutaud
  • Lawrence J. Marnett
  • John A. Oates
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 525)


Salicylic acid (SA) is an effective antipyretic and analgesic agent, yet at therapeutic concentrations exerting these effects SA lacks antiinflammatory action, distinguishing it from non-steroidal antiinflammatory drugs (NSAIDs) and selective inhibitors of prostaglandin H synthase-2 (PGHS-2). Only at concentrations much greater than are required for antipyresis does SA demonstrate antiinflammatory effects. In contrast to acetylsalicylic acid (aspirin), which irreversibly inhibits platelet PGHS-1 by acetylating a serine in the cyclooxygenase active site, SA is a weak inhibitor of platelet PGHS. The distinctive pharmacologic behavior of SA suggests that the molecular basis for its action differs from that of NSAIDs and PGHS-2 inhibitors.


Salicylic Acid Lipid Hydroperoxide Inhibitory Potency Sodium Salicylate Salicylic Acid Level 
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  1. 1.
    Humes JL, Winter CA, Sadowski SJ and Kuehl FA, Jr. Multiple sites on prostaglandin cyclooxygenase are determinants in the action of nonsteroidal antiinflammatory agents. Proc Natl Acad Sci USA 1981; 78:2053–6.PubMedCrossRefGoogle Scholar
  2. 2.
    Mitchell JA, Akarasereenont P, Thiemermann C, Flower RJ and Vane JR. Selectivity of nonsteroidal antiinflammatory drugs as inhibitors of constitutive and inducible cyclooxygenase. Proc Natl Acad Sci USA 1994; 90:11693–7CrossRefGoogle Scholar
  3. 3.
    Mitchell JA, Saunders M, Barnes PJ, Newton R and Belvisi MG. Sodium salicylate inhibits cyclo-oxygenase-2 activity independently of transcription factor (nuclear factor kappaB) activation: role of arachidonic acid. Molecular Pharmacology 1997; 51:907–12PubMedGoogle Scholar
  4. 4.
    Riendeau D, Charleson S, Cromlish W, Mancini JA, Wong E and Guay J. Comparison of the cyclooxygenase-1 inhibitory properties of nonsteroidal antiinflammatory drugs (NSAIDs) and selective COX-2 inhibitors, using sensitive microsomal and platelet assays. Can J Physiol Pharmacol 1997; 75:1088–95PubMedCrossRefGoogle Scholar
  5. 5.
    Amann R, Egger T, Schuligoi R, Heinemann A and Peskar BA. Sodium salicylate enhances the expression of cyclooxygenase-2 in endotoxin-stimulated human mononuclear cells. Eur J Pharmacol 2001; 433:129–34.PubMedCrossRefGoogle Scholar
  6. 6.
    Giuliano F, Mitchell JA and Warner TD. Sodium salicylate inhibits prostaglandin formation without affecting the induction of cyclooxygenase-2 by bacterial lipopolysaccharide in vivo. J Pharmacol Exp Ther 2001; 299:894–900.PubMedGoogle Scholar
  7. 7.
    Boutaud O, Aronoff DM, Richardson JH, Marnett LJ and Oates JA. Determinants of the cellular specificity of acetaminophen as an inhibitor of prostaglandin H2 synthases. Proceedings of the National Academy of Sciences 2002; 99:7130–7135CrossRefGoogle Scholar
  8. 8.
    Hemler ME, Lands WE. Evidence for a peroxide-initiated free radical mechanism of Prostaglandin biosynthesis. J Biol Chem 1980; 255:6253–61.PubMedGoogle Scholar
  9. 9.
    Hanel AM, Lands WE. Modification of anti-inflammatory drug effectiveness by ambient lipid peroxides. Biochem Pharmacol 1982; 31:3307–11.PubMedCrossRefGoogle Scholar
  10. 10.
    Ouellet M, Percival MD. Mechanism of acetaminophen inhibition of cyclooxygenase isoforms. Archives of Biochemistry and Biophysics 2001; 387:273–280PubMedCrossRefGoogle Scholar
  11. 11.
    Markey CM, Alward A, Weiler PE and Marnett LJ. Quantitative studies of hydroperoxide reduction by prostaglandin H synthase. Reducing substrate specificity and the relationship of peroxidase to cyclooxygenase activities. J Biol Chem 1987; 262:6266–79.PubMedGoogle Scholar
  12. 12.
    Odenwaller R, Chen YN and Marnett LJ. Preparation and proteolytic cleavage of apoprostaglandin endoperoxide synthase. Methods in Enzymology 1990; 187:479–85PubMedCrossRefGoogle Scholar
  13. 13.
    Odenwaller R, Maddipati KR and Marnett LJ. Detection of a higher oxidation state of manganese-prostaglandin endoperoxide synthase. Journal of Biological Chemistry 1992; 267:13863–9.PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2003

Authors and Affiliations

  • David M. Aronoff
    • 1
  • Olivier Boutaud
    • 2
  • Lawrence J. Marnett
    • 3
  • John A. Oates
    • 4
  1. 1.Divisions of Infectious Diseases & Pulmonary/Critical Care MedicineAnn ArborUSA
  2. 2.Division of Clinical PharmacologyVanderbilt UniversityNashvilleUSA
  3. 3.Vanderbilt Institute of Chemical BiologyVanderbilt UniversityNashvilleUSA
  4. 4.Division of Clinical PharmacologyVanderbilt University School of Medicine, The Vanderbilt-Ingram Cancer CenterNashvilleUSA

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