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Is aspirin a prodrug for antioxidant and cytokine-modulating oxymetabolites

  • Inflammation
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Abstract

Aspirin and salicylate are transformed by stimulated human polymorphonuclear leucocytes (PMN), likely to be found at inflammatory sites, into both 2,3- and 2,5-dihydroxybenzoates (DHB). These DHB inhibit both the production of hydrogen peroxide by stimulated human PMN and prostaglandin (PG) E2 by activated rat macrophages. In contrast, DHB stimulated production of interleukin (IL)-1 and tumour necrosis factor (TNF) but inhibited IL-6 production by rat macrophages. These effects were probably a consequence of PGE2 inhibition. Gentisate (2,5-DHB) and homogentisate (a tyrosine metabolite) inhibited the lymphoproliferative action of IL-1. Some related phenols, e.g. 5-aminosalicylate, inhibited H2O2 production but had little effect on PGE2 production.

These findings suggest that the local synthesis of DHB may contribute to the overall anti-inflammatory activity of salicylate, which (unlike aspirin) has little direct effect on PG production.

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References

  1. J. R. Vane,The mode of action of aspirin-like drugs. Agents and Actions8, 430–431 (1978).

    Google Scholar 

  2. B. M. Babior,The respiratory burst oxidase. Trends Biochem. Sci.12, 241–243 (1987).

    Google Scholar 

  3. T. R. Green and K. L. Pratt,A reassessment of the product specificity of the NADPH:O 2 oxidoreductase of human neutrophils. J. Biol. Chem.261, 6010–6015 (1987).

    Google Scholar 

  4. C. E. Cross,Oxygen radicals in human disease. Ann. Internatl. Med.107, 526–545 (1987).

    Google Scholar 

  5. E. Shacter, R. L. Lopez and S. Pati,Inhibition of the myeloperoxidase-H 2 O 2 −Cl − system of neutrophils by indomethacin and other non-steroidal antiinflammatory drugs. Biochem. Pharmacol.41, 975 984 (1991).

    Google Scholar 

  6. C. A. Dinarello,Interleukin-1 and its biologically related cytokines. Adv. Immunol.44, 153–205 (1989).

    Google Scholar 

  7. S. Akira, T. Hirano, T. Taga and T. Kishimoto,Biology of multifunctional cytokines: IL 6 and related molecules (IL 1 and TNF). FASEB J.4, 2860–2867 (1990).

    Google Scholar 

  8. S. B. Mizel, J. M. Dayer, S. M. Karne and S. E. Mergenhagen,Stimulation of rheumatoid synovial cell collagensae and prostaglandin production by partially purified lymphocyte-activating factor (Interleukin-1). Proc. Natl. Acad. Sci. USA78, 2474–2477 (1981).

    Google Scholar 

  9. A. Ferrante, M. Nandoskar, A. Walz, D. H. B. Goh and I. C. Kowanko,Effects of tumour necrosis factor alpha and interleukin-1 alpha and beta on human neutrophil migration, respiratory burst and degranulation. Int. Archs. Allergy Appl. Immun.86, 82–91 (1988).

    Google Scholar 

  10. T. Y. Shen,Prostaglandin synthetase inhibitors I. InAntiinflammatory Drugs. (Eds. J. R. Vane and S. H. Ferrera) pp. 306–407, Springer, Berlin (1979).

    Google Scholar 

  11. P. F. A. Wright and B. G. Priestly,An HPLC-ECD assay of hydroxylated salicylate for the detection of hydroxyl radicals. Clin. Exp. Pharm. Physiol. (Suppl.)10, (1987).

  12. A. L. Sagone, R. M. Husney, M. S. O'Dorosio and E. M. Metz,Mechanisms for the oxidation of reduced glutathione by stimulated granulocytes. Blood63, 96–104 (1984).

    Google Scholar 

  13. N. P. Hurst, J. K. French, A. Bell, G. Nuki, M. L. O'Donnell, W. H. Betts and L. G. Cleland,Differential effects of mepacrine, chloroquine and hydroxychloroquine on superoxide anion generation, phospholipid methylation and arachidonic acid release by human blood monocytes. Biochem. Pharmacol.35, 3083–3089 (1986).

    Google Scholar 

  14. D. R. Haynes, I. R. Garrett and B. Vernon-Roberts,Effect of gold salt treatment on receptor binding activity of monocytes and macrophages isolated from rats with adjuvant arthritis. Rheumatol. Int.8, 159–164 (1988).

    Google Scholar 

  15. D. R. Haynes, 1. R. Garrett, M. W. Whitehouse and B. Vernon-Roberts,Do gold drugs inhibit interleukin-1? Evidence from an in vitro lymphocyte activating factor assay. J. Rheumatol.15, 775–778 (1988).

    Google Scholar 

  16. S. Nakai, K. Mizuno, M. Kaneta and Y. Hirai,A simple, sensitive bioassay for the detection of interleukin-1 using human melanoma A375 cell line. Biochem. Biophys. Res. Comm.154, 1189–1196 (1988).

    Google Scholar 

  17. N. Matthews and M. L. Neale, Cytotoxicity assays for tumour necrosis factor and lymphotoxin. InLymphokines and Interferons, a Practical Approach (Eds. M. J. Clements, A. G. Morris and A. J. H. Ghearing) pp. 221–225, IRL Press, Oxford 1987.

    Google Scholar 

  18. P. M. Bartold and D. R. Haynes,Interleukin-6 production by human gingival, fibroblast. J. Peridont. Res.26, 339–345 (1991).

    Google Scholar 

  19. R. W. Kelly, S. Deam, M. J. Cameron and R. F. Seamark,Measurement by radioimmunoassay of prostaglandins as their methyl oximes. Prostaglandins Leukotr. Med.24, 1–14 (1978).

    Google Scholar 

  20. D. A. Bass, J. W. Parce, L. R. Dechatelet, P. Szejda, M. C. Seeds and M. Thomas,Flow cytometric studies of oxidative product formation by neutrophils: A graded response to membrane stimulation. J. Immunol.126, 1910–1917 (1983).

    Google Scholar 

  21. G. W. Snedecor and W. G. Cochran, Statistical Methods, 8th Edition pp. 84–86, Iowa State University Press, Ames, Iowa 1989.

    Google Scholar 

  22. P. M. Brooks, W. F. Keen and W. W. Buchanan,Salicylates. InThe Clinical Pharmacology of Anti-Inflammatory Agents, pp. 46–58. Taylor and Francis, London. 1986.

    Google Scholar 

  23. L. G. Cleland, M. W. Whitehouse and W. H. Betts,Gentisate, a salicylate metabolite with antioxidant properties. Drugs Exp. Clin. Res.XI, 273–280 (1985).

    Google Scholar 

  24. M. Grootveld and B. Halliwell,Aromatic hydroxylation as a measure of hydroxyl radical formation in vivo. Biochem. J.237, 499–504 (1986).

    Google Scholar 

  25. E. M. Kapp and A. F. Coburn,Urinary metabolites of sodium salicylate. J. Biol. Chem.145, 549–565 (1942).

    Google Scholar 

  26. M. Grootveld and B. Halliwell,2,3-Dihydroxybenzoic acid is a product of human aspirin metabolism. Biochem. Pharmacol.37, 271–280 (1988).

    Google Scholar 

  27. M. S. Alexander, R. M. Husney and A. L. Sagone,Metabolism of benzoic acid by stimulated polymorphonuclear cells. Biochem. Pharmacol.35, 3649–3651 (1986).

    Google Scholar 

  28. A. L.Sagone and R. M. Husney,Oxidation of salicylates by stimulated granulocytes. J. Immunol.138, 2177–2183 (1987).

    Google Scholar 

  29. B. Halliwell and J. M. C. Gutteridge,Detection of hydroxyl radicals in biological systems. InFree Radicals in Biology and Medicine, pp. 35–37. Oxford University Press, Oxford 1986.

    Google Scholar 

  30. D. R. Haynes, M. W. Whitehouse and B. Vernon-Roberts,The prostaglandin E 1 analogue, Misoprostol, regulates inflammatory cytokines and immune functions in vitro like the natural E-prostaglandins (1,2 and 3). Immunology76, 251–257 (1992).

    Google Scholar 

  31. S. Endres, R. Ghorbani, V. E. Kelley, K. Georgilis, G. Lonnemann, J. W. M. van der Meer, J. G. Cannon, T. S. Rogers, M. S. Klempner, P. C. Weber, Schaefer, S. M. Wolff and C. A. Dinarello,The effect of dietary supplementation with n-3 polyunsaturated fatty acids on the synthesis of interleukin-1 and tumor necrosis factor by mononuclear cells. New Engl. J. Med.320, 265–271 (1989).

    Google Scholar 

  32. D. R. Haynes, P. F. Wright, M. W. Whitehouse and B. Vernon-Roberts,The cyclooxygenase inhibitor, piroxicam, enhances cytokine-induced lymphocyte proliferation in vitro and in vivo. Immunol. Cell Biol.68, 225–230 (1990).

    Google Scholar 

  33. W. E. Scales, S. W. Chensue, I. Otterness and S. L. Kunkel, Regulation of monokine gene expression: prostaglandin E2 suppresses tumor necrosis factor but not interleukin-1 alpha or beta-mRNA and cell-associated bioactivity. J. Leukoc. Biol.45, 416–421 (1989).

    Google Scholar 

  34. I. G. Otterness, M. L. Bliven, J. D. Eskra, M. Reinke and D. C. Hanson,Regulation of Interleukin-1 production: The role of prostaglandins. Cell Immunol.114, 385–397 (1988).

    Google Scholar 

  35. Y. Zhang, J. Lin and J. Vilack,Synthesis of Interleukin-6 (Interferon-beta 2 /B cell stimulatory factor 2) in human fibroblasts is triggered by an increase in intracellular cyclic AMP. J. Biol. Chem.263, 6177–6182 (1988).

    Google Scholar 

  36. J. L. Webb, InEnzyme and Metabolic Inhibitors, Vol. III, pp. 520–538. Academic Press, New York 1966.

    Google Scholar 

  37. R. K. Rosenthal, T. B. Bayles and K. Fremont-SmithSimultaneous salicylate concentrations in synovial fluid and plasma in rheumatoid arthritis. Arth. Rheum.7, 103–109 (1964).

    Google Scholar 

  38. M. J. H. Smith,Editorial: Prostaglandins and aspirin: an alternative view. Agents and Actions.5, 315–317 (1975).

    Google Scholar 

  39. M. J. H. Smith, A. W. Ford-Hutchinson, J. R. Walker and J. A. Slack,Aspirin, salicylate and prostaglandins. Agents and Actions9, 483–487 (1979).

    Google Scholar 

  40. E. M. Glenn, B. J. Bowman and N. A. Rohloff,Anomalous biological effects of salicylates and prostaglandins. Agents and Actions9, 257–264 (1979).

    Google Scholar 

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Authors and Affiliations

  1. Department of Pathology, University of Adelaide, 5001, South Australia

    D. R. Haynes, S. J. Gadd, M. W. Whitehouse & B. Vernon-Roberts

  2. Key Centre for Applied and Nutritional Toxicology, Royal Melbourne Institute of Technology, 30001, Melbourne, Australia

    P. F. A. Wright

  3. Division of Tissue Pathology, Institute of Medical and Veterinary Science, 5001, Adelaide, South Australia

    M. W. Whitehouse & B. Vernon-Roberts

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  1. D. R. Haynes
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Additional information

The term “oxymetabolites” refers to those diphenols and other products formed primarily by oxygenation, in contrast to other normal metabolites formed by conjugation (with glucuronate, glycine and sulphate), recognising that some oxymetabolites may in turn be conjugated (e.g. gentisate to gentisurate). Production of oxymetabolites is not necessarily mediated by cytochrome-P450 oxygenases: as this report indicates, they may also be formed by interactions, possibly non-enzymatic, with reactive oxygen-derived species generated by inflammatory cells.

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Haynes, D.R., Wright, P.F.A., Gadd, S.J. et al. Is aspirin a prodrug for antioxidant and cytokine-modulating oxymetabolites. Agents and Actions 39, 49–58 (1993). https://doi.org/10.1007/BF01975714

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  • DOI: https://doi.org/10.1007/BF01975714

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