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.

Eicosanoids, Mesangial Contraction, and Intracellular Signal Transduction.

“…Alternative sources of increased TxA2 are glomerular epithelial and mesangial cells, also capable of metabolizing AA to TxA2, although the synthesis of other prostaglandins (PG), such as PGE2 and PGE2a predominates (Kreisberg et al 1982;Scharschmidt and Dunn 1983). Lipooxygenase metabolites of AA also have potent effects on vascular smooth muscle and chemotactic properties on leukocytes (Hammarstrom 1983;Lewis and Austen 1984). Leukotrienes (LT) are abundantly produced by leukocytes and possibly resident cells in certain forms of experimental glomerulonephritis (Lianos et al 1985;Stork et al 1986).…”

Action sites of antiallergic drugs on human neutrophils.

“…Leukotrienes including LTB4, LTC4 and LTD4 and LTE4 can be produced in mast cells, basophils as well as neutrophils, and they are released from human or guinea pig lungs upon immunological challenge (2). Since they possess a potent vasoconstricting activity and cause contraction of bronchial air way (3,4), LTs may play an important role in immediate hypersensitivity responses as mediators of allergic bronchocontraction and vascular per meability (5).…”

Inhibition of leukotriene D4 catabolism by D‐penicillamine

“…LTC3 [14,19,26, 271 as well as LTC,, LTD,, LTE, and N-acetyl-LTE4 [S, 9,10,15,28,291 are rapidly eliminated from the circulating blood and taken up mainly by the liver. Uptake of cysteinyl leukotrienes into hepatocytes [17, 301 and subsequent elimination into bile predominates over renal excretion in the rat [28, 291.…”