Leukotrienes are naturally produced eicosanoid lipid mediators, which may be responsible for the effects of an inflammatory response. Leukotrienes use both autocrine signalling and paracrine signalling to regulate the body's response. Leukotrienes are produced in the body from arachidonic acid by the enzyme 5-lipoxygenase. Their production by the body is part of a complex response that usually includes the production of histamine.
LTC4, LTD4 and LTE4 are often called cysteinyl leukotrienes due to the presence of the amino acid in their structure. Collectively, the cysteinyl leukotrienes make up the slow reacting substance of anaphylaxis (SRS-A).
There has also been postulated the existence of LTG4, a metabolite of LTE4 in which the cysteinyl moiety has been oxidized to an alpha-keto-acid (i.e., the cysteine has been replaced by a pyruvate). Very little is known about this putative leukotriene.
Leukotrienes are commercially available to the research community.
Leukotrienes are synthesized in the cell from arachidonic acid by 5-lipoxygenase. The catalytic mechanism involves the insertion of an oxygen moiety at a specific position in the arachidonic acid backbone.
The lipoxygenase pathway is active in leukocytes, including mast cells, eosinophils, neutrophils, monocytes and basophils. When such cells are activated, arachidonic acid is liberated from cell membrane phospholipids by phospholipase A2, and donated by the 5-lipoxygenase activating protein (FLAP) to 5-lipoxygenase.
5-lipoxygenase (5-LO) uses FLAP to convert arachidonic acid into 5-hydroperoxyeicosatetraenoic acid (5-HPETE), which spontaneously reduces to 5-hydroxyeicosatetraenoic acid (5-HETE). The enzyme 5-LO acts again on 5-HETE to convert it into leukotriene A4 (LTA4), an unstable epoxide.
In cells equipped with LTA4 hydrolase, such as neutrophils and monocytes, LTA4 is converted to the dihydroxy acid leukotriene LTB4, which is a powerful chemoattractant for neutrophils acting at BLT1 and BLT2 receptors on the plasma membrane of these cells.
In cells that express LTC4 synthase, such as mast cells and eosinophils, LTA4 is conjugated with the tripeptide glutathione to form the first of the cysteinyl-leukotrienes, LTC4. Outside the cell, LTC4 can be converted by ubiquitous enzymes to form successively LTD4 and LTE4, which retain biological activity.
The cysteinyl-leukotrienes act at their cell-surface receptors CysLT1 and CysLT2 on target cells to contract bronchial and vascular smooth muscle, to increase permeability of small blood vessels, to enhance secretion of mucus in the airway and gut, and to recruit leukocytes to sites of inflammation.
Both LTB4 and the cysteinyl-leukotrienes (LTC4, LTD4, LTE4) are partly degraded in local tissues, and ultimately become inactive metabolites in the liver.
Leukotrienes are very important agents in the inflammatory response. Some such as LTB4 have a chemotactic effect on migrating neutrophils, and as such help to bring the necessary cells to the tissue. Leukotrienes also have a powerful effect in bronchoconstriction, they also increase vascular permeability.
In excess, the cysteinyl leukotrienes can induce anaphylactic shock.
Zileuton blocks 5-lipoxygenase inhibiting the synthetic pathway of leukotriene metabolism. Zileuton affects the LTB4 pathway, montelukast doesn't.
Should leukotriene inhibitors be a single, first line asthma therapy in children?(Brief Article)(Statistical Data Included)
Jan 01, 2000; Dr. Robert Wood YES The Leukotriene-inhibiting drugs montelukast and zafirlukast are highly efficacious as single,...