Abstract
25 years ago, Vane proposed that the mechanism of action of the aspirin-like drugs (non-steroid anti-inflammatory drugs; NSAIDs) was through the inhibition of prostaglandin biosynthesis1 and, there is now a general acceptance of the theory. The inhibition by aspirin is due to the irreversible acetylation of the cyclooxygenase (COX) site of prostaglandin endoperoxide synthase, leaving the peroxidase activity of the enzyme unaffected. In contrast to this unique irreversible action of aspirin, other NSAIDs such as ibuprofen or indomethacin produce reversible or irreversible COX inhibition by competing with the substrate, arachidonic acid, for the active site of the enzyme.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
Preview
Unable to display preview. Download preview PDF.
Similar content being viewed by others
References
Vane JR. Inhibition of prostaglandin synthesis as a mechanism of action for the aspirin-like drugs. Nature; 231: 232–235 (1971).
Xie W, Robertson DL and Simmons DL. Mitogen-inducible prostaglandin G/H synthase: a new target for nonsteroidal antiinflammatory drugs. Drug Devel Res; 25: 249–265 (1992).
Picot D, Loll PJ, Garavito RM. The x-ray crystal structure of the membrane protein prostaglandin H2synthase-1. Nature; 367: 243–249 (1994).
Luong, C., Miller, A., Barnett, J., Chow, J., Ramesha, C., and Browner, M.F. Flexibility of the NSAID binding site in the structure of human cyclooxygenase-2. Nature Structural Biology; 3: 927–933 (1996).
Gierse, J.K., McDonald, J.J., Hauser, S.D., Rangwala, S.H., Koboldt, C.M., and Seibert, K. A single amino acid difference between cyclooxygenase-1 (COX-1) and-2 (COX-2) reverses the selectivity of COX-2 specific inhibitors. J. Biol.Chem. 271: 15810–15814 (1996).
Moncada S, Gryglewski R, Bunting S, Vane JR. An enzyme isolated from arteries transforms prostaglandin endoperoxides to an unstable substance that inhibits platelet aggregation. Nature; 263: 663–665 (1976).
Whittle BJR, Higgs GA, Eakins KE, Moncada S, Vane JR. Selective inhibition of prostaglandin production in inflammatory exudates and gastric mucosa. Nature; 284: 271–273 (1980).
Funk, C.D., Funk, L.B., Kennedy, M.E., Pong, A.S., and Fitzgerald, G.A. Human platelet/erythroleukemia cell prostaglandin G/H synthase: cDNA cloning, expression, and gene chromosomal assignment. FASEB J; 5: 2304–2312 (1991).
Raz, A., Wyche, A., and Needleman, P. Temporal and pharmacological division of fibroblast cyclooxygenase expression into transcriptional and translational phases. Proc Natl. Acad Sci USA; 86: 1657–1661 (1989).
Fu JY, Masferrer JL, Seibert K, Raz A and Needleman P. The induction and suppression of prostaglandin H2 synthase (cyclooxygenase) in human monocytes. J Biol Chem; 265: 16737–16740 (1990).
Masferrer JL, Zweifel BS, Seibert K and Needleman P. Selective regulation of cellular cyclooxygenase by dexamethasone and endotoxin in mice. J Clin Invest; 86: 1375–1379 (1990).
Xie W, Chipman JG, Robertson DL, Erikson RL and Simmons DL Expression of a mitogen-responsive gene encoding prostaglandin synthase is regulated by mRNA splicing. Proc Natl. Acad Sci USA; 88: 2692–2696 (1991).
O’Banion MK, Sadowski HB, Winn V and Young DA. A serum-and glucocorticoid-regulated 4-kilobase mRNA encodes a cyclooxygenase-related protein. J Biol Chem; 266: 23261–23267 (1991).
Kujubu DA, Fletcher BS, Varnum BC, Lim RW and Herschman HR. TIS10, a phorbol ester tumor promoter-inducible mRNA from swiss 3T3 cells, encodes a novel prostaglandin synthase/cyclooxygenase homologue. J Biol Chem; 26: 12866–12872 (1991).
DeWitt, D.L. Prostaglandin endoperoxide synthase: Regulation of enzyme expression. Biochim.Biophys.Acta 1083: 121–134 (1991).
Wu, K.K., Sanduja, R., Tsai, A.-L., Ferhanoglu, B., and Loose-Mitchell, D.S. Aspirin inhibits interleukin 1-induced prostaglandin H synthase expression in cultured endothelial cells. Proc Natl. Acad Sci USA; 88: 2384–2387 (1991).
Kargman, S., Charleson, S., Cartwright, M., Frank, J., Riendeau, D., Mancini, J., Evans, J., and O’Neill, G.P. Characterization of prostaglandin G/H synthase 1 and 2 in rat, dog, monkey and human gastrointestinal tracts. Gastroenterology; 111: 445–454 (1996).
Langenbach R, Morham SG, Tiano HF, Loftin CD, Ghanayem BI, Chulada PC, Mahler JF, Lee CA, Goulding EH, Kluckman KD, Kim HS and Smithies O. Prostaglandin synthase 1 gene disruption in mice reduces arachidonic acid-induced inflammation and indomethacin-induced gastric ulceration. Cell; 83: 483–492 (1995).
Kutchera, W., Jones, D.A., Matsunami, N., Groden, J., McIntyre, T.M., Zimmerman, G.A., White, R.L., and Prescott, S.M. Prostaglandin H synthase 2 is expressed abnormally in human colon cancer: Evidence for a transcriptional effect. Proc Natl Acad Sci USA; 93: 4816–4820 (1996).
Gustafson-Svärd, C., Lilja, I., Hallböök, O., and Sjödahl, R. Cyclooxygenase-1 and cyclooxygenase-2 gene expression in human colorectal adenocarcinomas and in azoxymethane induced colonie tumours in rats. Gut; 38: 79–84 (1996).
Thun, M.J., Namboodiri, M.M., and Heath, C.W.J. Aspirin use and reduced risk of fatal colon cancer. New England Journal of Medicine; 325: 1593–1596 (1991).
Luk, G.D. Prevention of gastrointestinal cancer-the potential role of NS AIDs in colorectal cancer. Schweiz Med Wochenschr; 126: 801–812 (1996).
Nugent, K.P., Spigelman, A.D., and Phillips, R.K.S. Tissue prostaglandin levels in familial adenomatous polyposis patients treated with sulindac. Dis Colon Rectum; 39: 659–662 (1996).
Oshima, M., Dinchuk, J.E., Kargman, S.L., Oshima, H., Hancock, B., Kwong, E., Trzaskos, J.M., Evans, J.F., Taketo, M.M. Suppression of intestinal polyposis in Apc Δ716 knockout mice by inhibition of cyclooxygenase 2 (COX-2). Cell; 87: 803–809 (1996).
Harris, R.C., McKanna, I.A., Akai, Y., Jacobson, H.R., Dubois, R.N., and Breyer, M.D. Cyclooxygenase-2 is associated with the macula densa of rat kidney and increases with salt restriction. J. Clin. Invest.; 94: 2504–2510 (1994).
Nüsing, R.M., Klein, T., Pfeilschifter, J., and Ullrich, V. Effect of cyclic AMP and prostaglandin E2 on the induction of nitric oxide-and prostanoid-forming pathways in cultured rat mesangial cells. Biochem. J.; 313: 617–623 (1996).
Morham, S.G., Langenbach, R., Loftin, C.D., Tiano, H.F., Vouloumanos, N., Jenette, J.C., Mahler, J.F., Kluckman, K.D., Ledford, A., Lee, C.A., and Smithies, O. Prostaglandin synthase 2 gene disruption causes severe renal pathology in the mouse. Cell; 83: 473–482 (1995).
Garcia Rodriguez LA, Jick H. Risk of upper gastrointestinal bleeding and perforation associated with individual non-steroidal anti-inflammatory drugs. Lancet; 343: 769–772 (1994).
Langman MJS, Weil J, Wainwright P, Lawson DH, Rawlins MD, Logan RFA, Murphy M, Vessey MP, Colin-Jones DG. Risks of bleeding peptic ulcer associated with individual non-steroidal anti-inflammatory drugs. Lancet; 343: 1075–1078 (1994).
Henry D, Lim LL-Y, Rodriguez LAG, Gutthann SP, Carson JL, Griffin M, Savage R, Logan R, Moride Y, Hawkey C, Hill S, Fries JT. Variability in risk of gastrointestinal complications with individual non-steroidal anti-inflammatory drugs: results of a collaborative meta-analysis. Br Med J; 312: 1563–1566 (1996).
Vane JR and Botting RM. New insights into the mode of action of anti-inflammatory drugs. Inflamm Res; 44: 1–10 (1995).
Grossman CJ, Wiseman J, Lucas FS, Trevethick MA, Birch P.J. Inhibition of constitutive and inducible cyclooxygenase activity in human platelets and mononuclear cells by NSAIDs and Cox 2 inhibitors. Inflamm Res; 44: 253–257 (1995).
Mitchell JA, Akarasereenont P, Thiemermann C, Flower RJ, Vane JR. Selectivity of nonsteroidal antiinflammatory drugs as inhibitors of constitutive and inducible cyclooxygenase. Proc Natl. Acad Sci USA; 90: 11693–11697 (1993).
Laneuville O, Breuer DK, DeWitt DL, Hla T, Funk CD and Smith WL. Differential inhibition of human prostaglandin endoperoxide H synthases-1 and-2 by nonsteroidal anti-inflammatory drugs. J Pharmacol Exp Therap; 271: 927–934 (1994).
Churchill L, Graham AG, Shih C-K, Pauletti D, Farina PR, Grob PM. Selective inhibition of human cyclo-oxygenase-2 by meloxicam. Inflammopharmacology; 4: 125–135 (1996).
Barner A. Review of clinical trials and benefit/risk ratio of meloxicam. Scand J Rheumatol; 25(Suppl 102): 29–37 (1996).
Rabasseda, X. Nimesulide: a selective cyclooxygenase 2 inhibitor antiinflammatory drug. Drugs of Today; 32(Suppl D): 1–23 (1996).
Glaser, K., Sung, M.-L., O’Neill, K., Belfast, M., Hartman, D., Carlson, R., Kreft, A., Kubrak, D., Hsiao, C.-L. and Weichman, B. Etodolac selectively inhibits human prostaglandin G/H synthase 2 (PGHS-2) versus human PGHS-l. Eur J Pharmacol; 281: 107–111 (1995).
Laine, L., Sloane, R., Ferretti, M. and Comincili, F. A randomized double-blind comparison of placebo, etodolac and naproxen on gastrointestinal injury and prostaglandin production. Gastrointest Endosc; 42: 428–433 (1995).
Cummings, D.M. and Amadio, P. Jr. A review of selected newer nonsteroidal anti-inflammatory drugs. Am Fam Physician; 49: 1197–1202 (1994).
Hubbard RC, Mehlisch DR, Jasper DR, Nugent MJ, Yu S, Isakson PC. SC-58635, a highly selective inhibitor of COX-2, is an effective analgesic in an acute post-surgical pain model. J Invest Med; 44: 293A (1996).
Parnham, M.J. COX-2 inhibitors at the 8th International Conference of the Inflammation Research Association. Exp. Opin. Invest. Drugs; 6: 79–82 (1997).
Ford-Hutchinson, A. New highly selective COX-2 inhibitors. In: Selective COX-2 Inhibitors: Pharmacology, Clinical Effects and Therapeutic Potential. Abstracts of the William Harvey Research Conference, Cannes, p 23 (1997).
Author information
Authors and Affiliations
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 1997 Springer Science+Business Media New York
About this chapter
Cite this chapter
Vane, J.R., Botting, R.M. (1997). Mechanism of Action of Anti-Inflammatory Drugs. In: Sinzinger, H., Samuelsson, B., Vane, J.R., Paoletti, R., Ramwell, P., Wong, P.YK. (eds) Recent Advances in Prostaglandin, Thromboxane, and Leukotriene Research. Advances in Experimental Medicine and Biology, vol 433. Springer, Boston, MA. https://doi.org/10.1007/978-1-4899-1810-9_27
Download citation
DOI: https://doi.org/10.1007/978-1-4899-1810-9_27
Publisher Name: Springer, Boston, MA
Print ISBN: 978-1-4899-1812-3
Online ISBN: 978-1-4899-1810-9
eBook Packages: Springer Book Archive