[Pharmacology of the leukotrienes]

Leukotrienes are a new family of metabolites of arachidonic acid produced by a C-5 lipoxygenase. As shown on figure 1, leukotriene A4, the key compound in their biosynthesis could either be hydrolysed to form leukotriene B4 or combine with glutathione to form leukotriene C4. Removal of glycine from the glutathione substituent or removal of glycine and gamma-glutamic acid yields the leukotriene D4 and E4 respectively. Leukotriene C4, D4 and E4 are the main bioactive components of the long elusive "Slow Reacting Substance of Anaphylaxis" (SRS-A). They induce powerful contractions of lung parenchyma strips and trachea in vitro (fig. 2) as well as powerful bronchoconstriction in vivo. They also favor mucus production from airways and slow its transport. Leukotrienes exhibit vasoconstrictor activity both on large blood vessels and on the microcirculation and induce marked increases in blood pressure followed by long lasting slight decreases (fig. 3). Injections of leukotriene B4 produce erythema, neutrophil migration and, in association with prostaglandin E2, increase vascular permeability and cause oedema. Leukotriene B4 is a powerful chemoattractant for polymorphonuclear leukocytes, stimulates cellular aggregation, degranulation and the release of lysosomal enzymes. It is also involved in the modulation of the immune response by inducing the formation of suppressor and of cytotoxic cells. The pharmacological actions of leukotriene B4 are mediated by very specific receptors while the actions of leukotriene C4, D4 and E4 are mediated by another type of receptors which are blocked by the selective SRS-A antagonist FPL-55712. The actions of leukotrienes depend partly upon the formation of prostaglandins and thromboxanes in the guinea-pig lungs while in man, their actions appear mostly a direct myotropic effect (fig. 4). Leukotriene formation has been stimulated in lungs and in various leukocyte populations by inflammatory or hypersensitivity reactions and by non specific stimuli such as the ionophore A-23187 and the C5a-anaphylatoxin. Inhibitors of lipoxygenases and corticosteroids could inhibit their release while non-steroid anti-inflammatory drugs such as aspirin may potentiate their formation by rechanneling their substrate from the cyclooxygenase cascade (fig. 5). The activity and potency of leukotrienes, their putative role in various important diseases as well as the explanations which they may give to old problems are good reasons to justify our interest on these novel compounds.