Lipoxygenase Metabolites

Chemistry and Biochemistry
  • Joshua Rokach
  • Brian J. Fitzsimmons
Part of the New Horizons in Therapeutics book series (NHTH)


The lipoxygenase-derived metabolites of arachidonic acid have been the subject of intense interest and research over the last decade, since the discovery of this pathway in mammals (Borgeat and Samuelsson, 1979). This important biochemical pathway is summarized in Fig. 1. The initial step in the lipoxygenase reaction is the conversion of a Z, Z1,4 diene to E, Z1,3 diene with the introduction of a molecule of oxygen to give a hydroperoxide (Fig. 2). In the case of arachidonic acid, this reaction can result in the incorporation of oxygen at C-5, -8, -9, -11, -12, or -15. In humans and other mammals, products of lipoxygenation at C-5, -11, -12, and -15 have been detected, with those that result from the 11-lipoxygenase reaction being known as products of the cyclooxygenase pathway. The products of the other three lipoxygenase enzymes retain the linear backbone of arachidonic acid and are referred to as the lipoxygenase products.


Arachidonic Acid Lipoxygenase Product Eicosatetraenoic Acid Lipoxygenase Metabolite Stereospecific Synthesis 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Adams, J., Fitzsimmons, B. J., and Rokach, J., 1984, Synthesis of lipoxins: Total synthesis of conjugated trihydroxy eicosatetraenoic acids, Tetrahedron Lett. 25: 4713–4716.CrossRefGoogle Scholar
  2. Adams, J., Fitzsimmons, B. J., Girard, Y., Leblanc, Y., Evans, J. F., and Rokach J., 1985, Enantiospecific and stereospecific synthesis of lipoxin A. Stereochemical assignment of the natural lipoxin A and its possible biosynthesis, J. Am. Chem. Soc. 107: 464 469.Google Scholar
  3. Borgeat, P., and Samuelsson, B., 1979, Arachidonic acid metabolism in polymorphonuclear leukocytes: Effects of ionophore A23187, Proc. Natl. Acad. Sci. U.S.A. 76: 2148–2152.PubMedCrossRefGoogle Scholar
  4. Bray, M. A., Cunningham, F. M., Ford-Hutchinson, A. W., and Smith, M. J. H., 1981a, Leukotriene B4: A mediator of vascular permeability, Br. J. Pharmacol. 72: 483–486.PubMedGoogle Scholar
  5. Bray, M. A., Ford-Hutchinson, A. W., and Smith, M. J. H., 1981b, Leukotriene B4: An inflammatory mediator in vivo, Prostaglandins 22: 213–222.PubMedCrossRefGoogle Scholar
  6. Brocklehurst, W. E., 1960, The release. of histamine and formation of a slow-reacting substance (SRS-A) during anaphylactic shock, J. Physiol. (Lond.) 151: 416–435.Google Scholar
  7. Charleson, S., Evans, J. F., Zamboni, R. J., Leblanc., Y., Fitzsimmons, B. J., Léveillé, C., Dupuis, P., and Ford-Hutchinson, A. W., 1986, Leukotriene B3, leukotriene B4 and leukotriene B5; binding to leukotriene B4 receptors on rat and human leucocyte membranes, Prostaglandins 32: 503–516.PubMedCrossRefGoogle Scholar
  8. Evans, J. F., Dupuis, P., and Ford-Hutchinson, A. W., 1985, Purification and characterisation of leukotriene A4 hydrolase from rat neutrophils, Biochim. Biophys. Acta 840: 43–50.PubMedCrossRefGoogle Scholar
  9. Feinmark, S. J., Lindgren, J. A., Claesson, H. E., Malmsten, C., and Samuelsson, B., 1981, Stimulation of human leukocyte degranulation by leukotriene B4 and its omega-oxidized metabolites, FEBS Lett. 136: 141–144.PubMedCrossRefGoogle Scholar
  10. Fitzsimmons, B. J., and Rokach, J., 1985, On the biosynthesis and the structure of lipoxin B, Tetrahedron Lett. 26: 3939–3942.CrossRefGoogle Scholar
  11. Fitzsimmons, B. J., Adams, J., Evans, J. F., Leblanc, Y., and Rokach, J., 1985, The lipoxins. Stereochemical identification and determination of their biosynthesis, J. Biol. Chem. 260: 13008–13012.PubMedGoogle Scholar
  12. Ford-Hutchinson, A. W., 1983, The role of leukotriene B4 as a mediator of leukocyte function, Agents Actions [Suppl.] 12: 154–166.Google Scholar
  13. Ford-Hutchinson, A. W., 1985, Leukotrienes as mediators of human disease, Adv. Prostaglandin Thromboxane Leukotriene Res. 15: 353–355.Google Scholar
  14. Ford-Hutchinson, A. W., and Letts, L. G., 1986, Biological actions of leukotrienes, Hypertension Suppl. II 8: 1144–1149.Google Scholar
  15. Ford-Hutchinson, A. W., Bray, M. A., Doig, M. V., Shipley, M. E., and Smith, M. J. H., 1980, Leukotriene B, a potent chemokinetic and aggregating substance released from polymorphonuclear leukocytes, Nature 286: 264–265.PubMedCrossRefGoogle Scholar
  16. Foster, A., Fitzsimmons, B., and Letts, L. G., 1986, The synthesis of N-acetyl-leukotriene E4 and its effects on cardiovascular and respiratory function of the anesthetized pig, Prostaglandins 31 (6): 1077–1086.PubMedCrossRefGoogle Scholar
  17. Goldman, D. W., and Goetzl, E. J., 1982, Specific binding of leukotriene B 4 to receptors on human polymorphonuclear leukocytes, J. Immunol. 129: 1600–1604.PubMedGoogle Scholar
  18. Goldman, D. W., and Goetzl, E. J., 1984, Heterogeneity of human polymorphonuclear leukocyte receptors for leukotriene B4. Identification of a subset of high affinity receptors that transduce the chemotactic response. J. Exp. Med. 159: 1027–1041.PubMedCrossRefGoogle Scholar
  19. Grabbe, J., Czarnetzki, B. M., Rosenbach, T., and Mardin, M., 1984, Identification of chemotactic lipoxygenase products of arachidonate metabolism in psoriatic skin, J. Invest. Dermatol. 82: 477–479.PubMedCrossRefGoogle Scholar
  20. Guindon, Y., Zamboni, R., Lau, C. K., and Rokach. J. 1982, Stereospecific synthesis of leukotriene B4 (LTB4), Tetrahedron Lett. 23: 739–742.CrossRefGoogle Scholar
  21. Hagmann, W., Denzlinger, C., Rapp, S., Weckbecker, G., and Keppler, D., 1986, Identification of the major endogenous leukotriene metabolite in the bile of rats as N-acetyl leukotriene E4, Prostaglandins 31 (2): 239–251.PubMedCrossRefGoogle Scholar
  22. Hedqvist, P., Dahlén, S. E., and Palmertz, U., 1985, Leukotrienes as mediators of airway anaphylaxis, Adv. Prostaglandin Thromboxane Leukotriene Res. 15: 345–348.Google Scholar
  23. Hoffstein, S. T., Manzi, R. M., Razgaitis, K. A., Bender, P. E., and Gleason, J., 1986, Structural requirements for chemotactic activity of leukotriene B4 (LTB4), Prostaglandins 31: 205–215.PubMedCrossRefGoogle Scholar
  24. Kellaway, C. H., and Trethewie, E. R., 1940, The liberation of a slow-reacting smoothmuscle-stimulating substance in anaphylaxis, Q. J. Exp. Physiol. 30: 121–145.Google Scholar
  25. Klickstein, L. B., Shapleigh, C., and Goetzl, E. J., 1980, Lipoxygenation of arachidonic acid as a source of polymorphonuclear leukocyte chemotactic factors in synovial fluid and tissue in rheumatoid arthritis and spondylarthritis, J. Clin. Invest. 66: 1166–1170.PubMedCrossRefGoogle Scholar
  26. Kreisle, R. A., and Parker, C. W.. 1983, Specific binding of leukotriene, B4 to a receptor on human polymorphonuclear leukocytes, J. Exp. Med. 157: 628–641.PubMedCrossRefGoogle Scholar
  27. Kreisle, R. A., Parker, C. W., Griffin, G. L., Senior, R. M., and Stenson, W. F., 1985, Studies of leukotriene B4—specific binding and function in rat polymorphonuclear leukocytes: Absence of a chemotactic response. J. Immunol. 134: 3356–3363.PubMedGoogle Scholar
  28. Leblanc, Y.. Fitzsimmons, B.. Adams, J., and Rokach, J., 1985. Total synthesis of lipoxin B: Assignment of stereochemistry, Tetrahedron Lett. 26: 1399–1402.Google Scholar
  29. Lewis, R. A., Austen, K. F., Drazen, J. M., Clark, D. A., Marfat, A., and Corey, E. J., 1980, Slow reacting substances of anaphylaxis: Identification of leukotrienes C-I and D from human and rat sources, Proc. Natl. Acad. Sci. U.S.A. 77: 3710–3314.PubMedCrossRefGoogle Scholar
  30. Lewis, R. A., Goetzl, E. J., Drazen, J. M., Soter, N. A., Austen, K. F., and Corey, E. J., 1981, Functional characterization of synthetic leukotriene B and its stereochemical isomers, J. Exp. Med. 154: 1243–1248.Google Scholar
  31. Lin, A. H., Ruppel, P. L., and Gorman, R. R., 1984, Leukotriene B4 binding to human neutrophils, Prostaglandins 28: 837–849.PubMedCrossRefGoogle Scholar
  32. Mannervik, B., Jensson, H., Alin, P., Orning, L., and Hammarstrom, S., 1984, Transformation of leukotriene A4 methyl ester to leukotriene C4 mono methyl ester by cytosolic rat glutathione transferases, FEBS Lett. 175: 287–293.CrossRefGoogle Scholar
  33. Morris, H. R., and Taylor, G. W., Piper, P. J., and Tippins, J. R., 1980, Structure of slow-reacting substance of anaphylaxis from guinea-pig lung, Nature 285: 104–106.PubMedCrossRefGoogle Scholar
  34. Namiki, M., Igarashi, Y., Sakamoto, K., Nakamura, T., and Koga, Y., 1986, Pharmacological profiles of a potential LTB4-antagonist, SM-9064, Biochem. Biophys. Res. Commun. 138: 540.PubMedCrossRefGoogle Scholar
  35. O’Flaherty, J., Kosfeld, S., and Nishihira, J., 1986, Binding and metabolism of leukotriene B4 by neutrophils and their subcellular organelles, J. Cell. Physiol. 126: 359–370.PubMedCrossRefGoogle Scholar
  36. Orning, L., 1987, co-Hydroxylation of N-acetylleukotriene E4 by rat liver microsomes, Bio-chem. Biophys. Res. Commun. 143: 337–344.Google Scholar
  37. Orning, L., Norin, E., Gustafsson, B., and Hammarstrom, S., 1986, In vivo metabolism of leukotriene C4 in germ-free and conventional rats. Fecal excretion of N-acetylleukotriene E4, J. Biol. Chem. 261 (2): 766–771.Google Scholar
  38. Rokach, J., Zamboni, R., Lau, C. K., and Guindon, Y., 1981, The stereospecific synthesis of leukotriene A4 (LTA4), 5-epi-LTA4, 6-epi-LTA4, and 5-epi, 6-epi-LTA4, Tetrahedron Lett. 22: 2759–2762.CrossRefGoogle Scholar
  39. Rokach, J., Fitzsimmons, B. J., Leblanc, Y., Ueda, N., and Yamamoto, S., 1987. Recent progress in the Chemistry and Biochemistry of Lipoxygenase Products: The Lipoxins, Adv. Prostaglandin Thromboxane Leukotriene Res. 17: 761–767Google Scholar
  40. Samuelsson, B., 1983, Leukotrienes: A new class of mediators of immediate hypersensitivity reactions and inflammations, Adv. Prostaglandin Thromboxane Leukotriene Res. 11: 113.Google Scholar
  41. Serhan, C. N., Hamberg, M., and Samuelsson, B., 1984a, Trihydroxytetraenes: A novel series of compounds formed from arachidonic acid in human leukocytes, Biochem. Biophys. Res. Commun. 118: 943–949.PubMedCrossRefGoogle Scholar
  42. Serhan, C. N., Hamberg, M., and Samuelsson, B., 1984b, Lipoxins: A novel series of biolog-ically active compounds formed from arachidonic acid in human leukocytes, Proc. Natl. Acad. Sci. U.S.A. 81: 5335–5339.PubMedCrossRefGoogle Scholar
  43. Serhan, C. N., Hamberg, M., Samuelsson, B., Morris, J., and Wishka, D. G., 1986a, On the stereochemistry and biosynthesis of lipoxin B, Proc. Natl. Acad. Sci. U.S.A. 83: 19831987.Google Scholar
  44. Serhan, C. N., Nicolaou, K. C., Webber, S. E., Veale, C. A., Dahlén, S. E., Puustinen, T. J., and Samuelsson, B., 1986b, Lipoxin A stereochemistry and biosynthesis, J. Biol. Chem. 261: 16340–16345.PubMedGoogle Scholar
  45. Showell, H. J., Otterness, I. G., Marfat, A., and Corey, E. J., 1982, Inhibition of leukotriene B4-induced neutrophil degranulation by leukotriene B4—dimethylamide, Biochem. Biophys. Res. Commun. 106: 741–747.PubMedCrossRefGoogle Scholar
  46. Stenson, W. F., and Lobos, E., 1982, Sulfasalazine inhibits the synthesis of chemotactic lipids by neutrophils, J. Clin. Invest. 69: 494–497.PubMedCrossRefGoogle Scholar

Copyright information

© Plenum Press, New York 1988

Authors and Affiliations

  • Joshua Rokach
    • 1
  • Brian J. Fitzsimmons
    • 1
  1. 1.Merck Frosst Canada, Inc.Pointe-Claire-Dorval-QuebecCanada

Personalised recommendations