Leukotrienes.

Abstract

The leukotrienes are a family of biologically active molecules, formed by leukocytes, mastocytoma cells, macrophages, and other tissues and cells in response to immunological and nonimmunological stimuli. They exhibit a number of biological effects such as contraction of bronchial smooth muscles, stimulation of vascular permeability, and attraction and activation of leukocytes. Compared to histamine, which causes constriction of airways and edema formation, the leukotrienes are three to four orders of magnitude more potent and the effects have longer duration. The leukotrienes were discovered in 1938 as a smooth muscle-contracting factor in lung perfusates. It was referred to as "slow reacting substance" (SRS) or "slow reacting substance of anaphylaxis" (SRS-A) until 1979 when its structure was reported. The term "leukotriene" was introduced at that time as a trivial name for the new type of compound. Leukotrienes C4 and D4 are glutathione and cysteinylglycine conjugates, respectively, of arachidonic acid. After hydrolytic release from phospholipids of the cell membrane, arachidonic acid is oxygenated by a lipoxygenase to 5-hydroperoxy-6,8,11,14-eicosatetraenoic acid. This product is further converted to leukotrienes by elimination of the 10-pro-R hydrogen and OH from the hydroperoxy group to give 5,6-oxido-7,9,11, 14-eicosatetraenoic acid (leukotriene A4). Nucleophilic opening of the epoxide at C-6 by the sulfhydryl group of glutathione gives leukotriene C4, which is metabolized to leukotrienes D4 and E4 by sequential elimination of glutamic acid and glycine. The latter reactions are catalyzed by gamma-glutamyl transpeptidase and a particulate dipeptidase from kidney. Alternatively, water may add at C-12 of leukotriene A4, leading also to opening of the epoxide at C-6 with formation of 5,12-dihydroxy-6,8,10,14-eicosatetraenoic acid (leukotriene B4). Leukotriene B4 is metabolized by omega-hydroxylation to 20-hydroxy and 20-carboxy leukotriene B4. Leukotrienes are also formed from eicosatrienoic acid (n-9) and eicosapentaenoic acid (n-3) after oxygenation at C-5 and from eicosatrienoic acid (n-6) and arachidonic acid after oxygenation at C-8 (eicosatrienoic acid) and C-12 or C-15 (arachidonic acid). Although they are formed from the same and additional fatty acids as prostaglandins and thromboxanes [reviewed in this series in (1)], the structures and the reactions involved in biosynthesis and catabolism of leukotrienes are completely separate from those required for prostaglandin formation and metabolism. The leukotrienes seem to provide a new system of biological regulators that are important in many diseases involving inflammatory or immediate hypersensitivity reactions.