Summary
Arachidonic acid is normally stored in membrane-bound phospholipids and released by the action of phospholipases. Enzymatic conversion of released arachidonic acid into biologically active derivatives proceeds through one of several routes. Cyclo-oxygenase converts arachidonic acid to unstable cyclic endoperoxides from which prostaglandins, prostacyclin and thromboxanes are derived. Formation of the leukotrienes from arachidonic acid is initiated by the action of 5-lipoxygenase producing leukotriene A4. Hydrolysis of leukotriene A4, or the incorporation of glutathione results in the formation of leukotriene B4 and C4, respectively. In addition, 12- and 15-lipoxygenase can catalyse arachidonic acid conversion and lipoxins A and B are amongst the possible products. Many of these metabolites of arachidonic acid feature prominently in the development of inflammation. Prostaglandin E2 and prostacyclin are potent vasodilators, while leukotriene D4 causes cellular adhesion, chemotaxis of neutrophils and degranulation. Leukotrienes C4, D4 and E4 contribute to inflammation by increasing vascular permeability. Leukotrienes are also believed to play an important pathophysiological role in allergic bronco-constriction of asthma.
Through pharmacological intervention in the arachidonic acid cascade various anti-inflammatory agents have been developed. These include aspirin-like drugs, which inhibit cyclooxygenase. Corticosteroids appear to indirectly inhibit phospholipases thus preventing release of arachidonic acid. Future progress in this field is likely to produce drugs which antagonise arachidonic acid derivatives or inhibit the enzymes involved in their synthesis with greater specificity.
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References
Bergström S, Danielsson H, Samuelsson B. The enzymatic formation of prostaglandin E2 from arachidonic acid. Biochimica et Biophysica Acta 90: 207–210, 1964
Borgeat P, Samuelsson B. Arachidonic acid metabolism in polymorphonuclear leukocytes: unstable intermediate in formation of dihydroxy acids. Proceedings of National Academy of Sciences, Vol. 76, pp. 3213–3217, 1979
Borgeat P, Hamberg M, Samuelsson B. Transformation of arachidonic acid and homo-γ-linolenic acid by rabbit polymorphonuclear leukocytes: monohydroxy acids from novel lipoxygenase. Journal of Biological Chemistry 251: 7816–7820, 1976
Borgeat P, Fruteau de Laclos B, Maclouf J. New concepts in the modulation of leukotriene synthesis. Biochemical Pharmacology 32: 381–387, 1983
Dahlen SE, Hansson G, Medquist P, Björcke T, Granthöm E, et al. Allergen challenge of lung tissue from asthmatic elicits bronchial contraction that correlates with the release of leukotrienes C4, D4 and E4. Proceedings of National Academy of Sciences, Vol. 80, pp. 1712–1716, 1983
Dorp DA van, Beerthuis RK, Nugteren DH, Vonkeman H. The biosynthesis of prostaglandins. Biochimica et Biophysica Acta 90: 204–207, 1964
Euler US von. Zur Kenntnis der pharmakologischen Wirkungen von Nativsekreten und Extrakten männlicher accessorischer Geßlechtsdrüsen. Naunyn-Schmiedebergs Archiv für experimentelle Pathologie und Pharmakologie 175: 78–84, 1934
Euler US von. Über die spezifische blutdrucksenkende Substanz des menschlichen Prostata- und Samenblasensekretes. Klinische Wochenschrift 14: 1182–1183, 1935
Godard P, Damon M, Michel FB, Corey EJ, Austen KF, et al. Leukotriene B4 production from human alveolar macrophages. Clincal Research 31: 548A, 1983
Goldblatt MW. A depressor substance in seminal fluid. Journal Soc. chem. Ind. Lond. 52: 1056–1057, 1933
Hamberg M, Samuelsson B. Prostaglandin endoperoxides. Novel transformations of arachidonic acid in human platelets. Proceedings of the National Academy of Sciences USA 71: 3400–3404, 1974
Hamberg M, Svensson J, Samuelsson B. Tromboxanes: a new group of biologically active compounds derived from prostaglandin endoperoxides. Proceedings of the National Academy of Sciences USA 72: 2994–2998, 1975
Hamberg M, Svensson J, Wakabayashi T, Samuelsson B. Isolation and structure of two prostaglandin endoperoxides that cause platelet aggregation. Proceedings of the National Academy of Sciences USA 71: 345–349, 1974
Holroyde MC, Altounyan REC, Cole M, Dixon M, Elliott EV. Bronchoconstriction produced in man by leukotrienes C and D. Lancet 2: 17–18, 1981
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
Rouzer CA, Samuelsson B. On the nature of the 5-lipoxygenase reaction in human leukocytes: enzyme purification and requirement for multiple stimulatory factors. Proceedings of National Academy of Sciences, Vol. 82, pp. 6040–6044, 1985
Rouzer CA, Matsumoto T, Samuelsson B. Single protein from human leukocytes possesses both 5-lipoxygenase and leukotriene A4 synthase activity. Proceedings of National Academy of Sciences, Vol. 83, pp. 857–861, 1986
Samuelsson B. The leukotrienes; mediators of immediate hypersensitivity reactions and inflammation. Proceedings of National Academy of Sciences, Vol. 220, pp. 568–55, 1983
Serhan CN, Hamberg M, Samuelsson B. Lipoxins: Novel series of biologically active compounds formed from arachidonic acid in human leukocytes. Proceedings of the National Academy of Sciences USA 81: 5335–5339, 1984
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Samuelsson, B. An Elucidation of the Arachidonic Acid Cascade. Drugs 33 (Suppl 1), 2–9 (1987). https://doi.org/10.2165/00003495-198700331-00003
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DOI: https://doi.org/10.2165/00003495-198700331-00003