Leukotriene

[loo-kuh-trahy-een]

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.

Types

Examples of leukotrienes are LTA₄, LTB₄, LTC₄, LTD₄, LTE₄, and LTF₄.

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a metabolite of LTE4 in which the cysteinyl moiety has been oxidized to an alpha-keto-acid (i.e., the cysteine has been replaced by a pyruvate).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.

History and name

The name leukotriene, introduced by Swedish biochemist Bengt Samuelsson in 1979, comes from the words leukocyte and triene (indicating the compound's three conjugated double bonds). What would be later named leukotriene C, "slow reaction smooth muscle-stimulating substance" (SRS) was originally described between 1938 and 1940 by Feldberg and Kellaway. The researchers isolated SRS from lung tissue after a prolonged period following exposure to snake venom and histamine.

Leukotrienes are commercially available to the research community.

Biochemistry

Synthesis

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.

Function

Leukotrienes act principally on a subfamily of G protein coupled receptors. They may also act upon peroxisome proliferator-activated receptors. Leukotrienes are involved in asthmatic and allergic reactions and act to sustain inflammatory reactions; several leukotriene receptor antagonists (e.g. montelukast and zafirlukast) are used to treat asthma. Recent research points to a role of 5-lipoxygenase in cardiovascular and neuropsychiatric illnesses.

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.

Leukotrienes in asthma

Leukotrienes assist in the pathophysiology of asthma, causing or potentiating the following symptoms:

airflow obstruction
increased secretion of mucus
mucosal accumulation
bronchoconstriction
infiltration of inflammatory cells in the airway wall

Role of cysteinyl leukotrienes

Cysteinyl leukotriene receptors CysLT1 and CysLT2 are present on mast cells, eosinophil and endothelial cells. During cysteinyl leukotriene interaction, they can stimulate proinflammatory activities such as endothelial cell adherence and chemokine production by mast cells. As well as mediating inflammation, they induce asthma and other inflammatory disorders, thereby reducing the airflow to the alveoli.

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.

Leukotriene modifiers

See leukotriene antagonist

Notes

References

Lipkowitz, Myron A. and Navarra, Tova (2001) The Encyclopedia of Allergies (2nd ed.) Facts on File, New York, p. 167, ISBN 0-8160-4404-X
Samuelsson, Bengt (ed.) (2001) Advances in prostaglandin and leukotriene research: basic science and new clinical applications: 11th International Conference on Advances in Prostaglandin and Leukotriene Research: Basic Science and New Clinical Applications, Florence, Italy, June 4-8, 2000 Kluwer Academic Publishers, Dordrecht, ISBN 1-4020-0146-0
Bailey, J. Martyn (1985) Prostaglandins, leukotrienes, and lipoxins: biochemistry, mechanism of action, and clinical applications Plenum Press, New York, ISBN 0-306-41980-7