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.