Novel 5-Lipoxygenase Inhibitors in Inflammation and Asthma

  • G. A. Higgs
Conference paper
Part of the NATO ASI Series book series (NSSA, volume 177)


The discovery of mammalian lipoxygenases which convert arachidonic acid to oxygenated products with potent inflammatory and anaphylactic properties has led to growing speculation that these enzymes are central to certain disease processes (Samuelsson, 1983; Higgs, Moncada and Vane, 1984). This speculation has been supported by the demonstration of lipoxygenase activity in a number of different tissues following stimulation. For example, pulmonary tissues synthesize the peptido-leukotrienes (LTC4, D4 and E4), which are products of 5-lipoxygenase, in response to immunological challenge. These leukotrienes comprise the activity originally referred to as ‘slow reacting substance of anaphylaxis’ (SRSA), they are powerful constrictors of airway smooth muscle and are thought to be mediators of anaphylactic bronchoconstriction. Phagocytic leukocytes also convert arachidonic acid to leukotrienes and the major product in polymorphonuclear leukocytes (PMNs) is the di-hydroxy acid LTB4. Leukotriene B4, along with some of the mono-hydroxy lipoxygenase products is chemotactic and it has been suggested that LTB4 production by activated PMNs represents a local control mechanism for the accumulation of leukocytes at inflammatory sites.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Bhattacherjee, P., Boughton-Smith, N.K., Follenfant, R.L., Garland, L.G., Higgs, G.A., Hodson, H.F., Islip, P.J., Jackson, W.P., Moncada, S., Payne, A.N., Randall, R.W., Reynolds, C.H., Salmon, J.A., Tateson, J.E. and Whittle, B.J.R., 1988. The effects of a novel series of selective inhibitors of arachidonate 5-lipoxygenase on anaphylactic and inflammatory responses. Ann. N.Y. Acad. Sci., 524: 307–320.Google Scholar
  2. Corey, E.J., Cashman, J.R., Kantner, S.S. and Wright, S.W., 1984. Rationally designed, potent competitive inhibitors of leukotriene biosynthesis. J. Am. Chem. Soc., 106: 1503–1504.Google Scholar
  3. Ford-Hutchinson, A.W., Bray, M.A., Doig, M.V., Shipley, M.W. and Smith, M.J.H., 1980. Leukotriene B, a potent chemokinetic and aggregating substance released from polymorphonuclear leukocytes. Nature, 286: 264–265.CrossRefGoogle Scholar
  4. Hamberg, M. and Samuelsson, B., 1974. Prostaglandin endoperoxides. Novel transformations of arachidonic acid in human platelets. Proc. Natl. Acad. Sci. USA, 71: 3400–3404.Google Scholar
  5. Higgs, G.A., Follenfant, R.L. and Garland, L.G., 1988. Selective inhibition of arachidonate 5-lipoxygenase by novel acetohydroxamic acids III. Effects on acute inflammatory responses. Br. J. Pharmacol., 94: 547–551.Google Scholar
  6. Higgs, G.A., Moncada, S. and Vane, J.R., 1984. Eicosanoids in inflammation. Ann. Clin. Res. 16: 287–299.Google Scholar
  7. Jackson, W.P., Islip, P.J., Kneen, G., Pugh, A. and Wates, P.J., 1988. Acetohydroxamic acids as potent, selective, orally active 5-lipoxygenase inhibitors. J. Med. Chem., 31: 499–500.Google Scholar
  8. Payne, A.N., Garland, L.G., Lees, I.W. and Salmon, J.A., 1988. Selective inhibition of arachidonate 5-lipoxygenase by novel acetohydroxamic acids: II. Effects on bronchial anaphylaxis in anaesthetised guinea-pigs. Br. J. Pharmacol., 94: 540–546.Google Scholar
  9. Samuelsson, B., 1983. Leukotrienes: mediators of immediate hypersensitivity reactions and inflammation. Science, 220: 568–575.CrossRefGoogle Scholar
  10. Tateson, J.E., Randall, R.W., Reynolds, C.H., Jackson, W.P.,Bhattacherjee, P., Salmon, J.A. and Garland, L.G., 1988. Selective inhibition of arachidonate 5-lipoxygenase by novel acetohydroxamic acids: I. Biochemical assessment in vitro and ex vivo Br. J. Pharmacol., 94: 528–539.CrossRefGoogle Scholar

Copyright information

© Plenum Press, New York 1989

Authors and Affiliations

  • G. A. Higgs
    • 1
  1. 1.Wellcome Research LabsBeckenham, KentUK

Personalised recommendations