Leucotrienes

Leukotrienes (from Greek leukos =white, and treis =three) are highly active substances which, like prostaglandins, are derived from arachidonic acid and other unsaturated C20 fatty acids. They have three double bonds and belong to the substance group of eicosanoids (C20 fatty acids).

The following leukotrienes play a pathophysiological role:

• Leukotrien A4 (LTA4)
• Leukotriene B4 (LTB4)
• Leukotriene C4 (LTC4)
• Leukotriene D4 (LTD4)
• Leukotriene E4 (LTE4)

The biosynthesis of leukotrienes is dependent on the enzyme 5'-lipoxygenase. In the 5'-lipoxygenase reaction, 5-hydroperoxy eicosatetraenoic acid (5-HPTE) is formed first, which is converted into leukotrien A4 by rearrangement of the double bonds. This leads to the formation of leukotriene B4 (LTB4) by epoxyhydrolase or leukotriene C4 (LTC4) by linking with the tripeptide glutathione. The cleavage of a glutamyl residue leads to leukotriene D4 (LTD4). Elimination of a glycyl residue leads to leukotriene E4 (LTE4) (the index "4" indicates the number of double bonds in the molecule).

The leukotrienes LTC4, LTD4, LTE4 are called cysteinyl leukotrienes. They bind with different affinity to 2 G-protein bound receptors: CYSLTR1 and CYSLTR2 (CYSLTR = acronym for "cysteinyl leukotriene receptor"). These receptors play an essential role in the endocrine and cardiovascular system. Mast cells and monocytes, among others, express this type of receptor. The stimulation of mast cells by LTD4 increases the c-kit induced proliferation of mast cells

In contrast to the wider distribution of fatty acid cyclocygenases, lipoxygenase activity is found only in a limited number of cell types, such as neutrophil and eosinophil granulocytes, reticulocytes, platelets and macrophages. The different cell types differ in the specificity of their lipoxygenases. For example, platelet lipoxygenase catalyses the biosynthesis of 12-HPETE. In reticulocytes and neutrophilic granulocytes, 15-HPETE is produced by a 5-lipoxygenase.

Leukotrienes (e.g. leukotrienes B, C, D etc.) are sometimes highly effective mediators of inflammatory and allergic reactions. The highly bronchoconstrictive and secretion-promoting cysteinyl leukotrienes LTC4-LTE4 can trigger allergic and anaphylactic reactions in the lungs. LTB4 causes the adhesion of the leukocytes to the blood vessel wall by chemotaxis. It also causes the aggregation of leukocytes, the release of oxidizing enzymes and the formation of superoxide radicals with pro-inflammatory and tissue-destroying effects. Leukotrienes interact with interleukins and interferons.