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{{Short description|Class of inflammation mediator molecules}}

'''Leukotrienes''' are autocrine and paracrine eicosanoid lipid mediators derived from [[arachidonic acid]] by 5-lipoxygenase.

[[Image:Leukotriene A4.svg|thumb|right|[[Leukotriene A4|LTA₄]] Note the four double bonds, three of them conjugated. This is a common property of A4, B4, C4, D4, and E4.]]

[[Image:Leukotriene B4.svg|right|thumb|[[Leukotriene B4|LTB₄]]]]

[[Image:Leukotriene C4.svg|thumb|right|[[Leukotriene C4|LTC₄]] is a cysteinyl leukotriene, as are D4 and E4.]]

[[Image:Leukotriene D4.svg|thumb|right|[[Leukotriene D4|LTD₄]]]]

[[Image:Leukotriene E4.svg|thumb|right|[[Leukotriene E4|LTE₄]]]]

'''Leukotrienes''' are a family of [[eicosanoid]] [[inflammation|inflammatory mediators]] produced in [[leukocyte]]s by the [[redox|oxidation]] of [[arachidonic acid]] (AA) and the [[essential fatty acid]] [[eicosapentaenoic acid]] (EPA) by the [[enzyme]] [[arachidonate 5-lipoxygenase]].<ref>{{cite journal |last1=Loick |first1=H. |last2=Theissen |first2=J. |title=Die Eicosanoide als Mediatoren beim ARDS |trans-title=Eicosanoids as mediators in ARDS |language=de |journal= Anästhesiologie, Intensivmedizin, Notfallmedizin, Schmerztherapie|volume=29 |issue=1 |pages=3–9 |year=1994 |pmid=8142566 |doi=10.1055/s-2007-996677 }}</ref><ref>{{cite journal |last1=Salmon |first1=John A |last2=Higgs |first2=Gerald A |title=Prostaglandins and leukotrienes as inflammatory mediators |journal=British Medical Bulletin |volume=43 |issue=2 |pages=285–96 |year=1987 |pmid=2825898 |doi=10.1093/oxfordjournals.bmb.a072183 }}</ref><ref>{{cite journal |last1=O'Byrne |first1=Paul M. |last2=Israel |first2=Elliot |last3=Drazen |first3=Jeffrey M. |title=Antileukotrienes in the treatment of asthma |journal=Annals of Internal Medicine |volume=127 |issue=6 |pages=472–80 |year=1997 |pmid=9313005 |doi=10.7326/0003-4819-127-6-199709150-00009 |s2cid=21480605 }}</ref>

Leukotrienes use [[lipid signaling]] to convey information to either the cell producing them ([[autocrine signaling]]) or neighboring cells ([[paracrine signaling]]) in order to regulate immune responses. The production of leukotrienes is usually accompanied by the production of [[histamine]] and [[prostaglandin]]s, which also act as inflammatory mediators.<ref>

{{cite journal | title=Mediators of inflammation and the inflammatory process

|first1=Martha

|last1=White

|journal=The Journal of Allergy and Clinical Immunology

|volume=103

|url=https://www.jacionline.org/article/S0091-6749(99)70215-0/pdf

|date=1999

|issue=3 Pt 2

|pages=S378-81

|doi=10.1016/S0091-6749(99)70215-0

|pmid=10069896

|access-date=8 June 2019|doi-access=free

}}

</ref>

One of their roles (specifically, [[Leukotriene D4|leukotriene D₄]]) is to trigger contractions in the smooth muscles lining the bronchioles; their overproduction is a major cause of inflammation in [[asthma]] and allergic [[rhinitis]].<ref>{{cite book |first1=David L. |last1=Nelson |first2=Michael M. |last2=Cox |chapter=Leukotrienes |page=[https://archive.org/details/lehningerprincip00lehn_1/page/359 359] |chapter-url={{Google books|5Ek9J4p3NfkC|page=359|plainurl=yes}} |year=2008 |title=Lehninger Principles of Biochemistry |edition=5th |publisher=Macmillan |isbn=978-0-7167-7108-1 |url=https://archive.org/details/lehningerprincip00lehn_1/page/359 }}</ref> [[Leukotriene antagonist]]s are used to treat these disorders by inhibiting the production or activity of leukotrienes.<ref name="Antileukotriene">{{cite journal |vauthors=Scott JP, Peters-Golden M | title = Antileukotriene agents for the treatment of lung disease | journal = Am. J. Respir. Crit. Care Med. | volume = 188 | issue = 5 | pages = 538–544 | date = September 2018| pmid = 23822826 | doi = 10.1164/rccm.201301-0023PP }}</ref>

== 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 system|conjugated double bonds]]).

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

What would be later named leukotriene C, "slow reaction smooth muscle-stimulating substance" ([[Slow-reacting substance of anaphylaxis|SRS]]) was originally described between 1938 and 1940 by Feldberg and Kellaway.<ref>{{cite journal |last1=Feldberg |first1=W. |last2=Kellaway |first2=C. H. |title=Liberation of histamine and formation of lysocithin-like substances by cobra venom |journal=The Journal of Physiology |volume=94 |issue=2 |pages=187–226 |year=1938 |pmid=16995038 |pmc=1393616 |doi=10.1113/jphysiol.1938.sp003674 }}</ref><ref>{{cite journal |last1=Feldberg |first1=W. |last2=Holden |first2=H. F. |last3=Kellaway |first3=C. H. |title=The formation of lysocithin and of a muscle-stimulating substance by snake venoms |journal=The Journal of Physiology |volume=94 |issue=2 |pages=232–48 |year=1938 |pmid=16995040 |pmc=1393612 |doi=10.1113/jphysiol.1938.sp003676 }}</ref><ref name= Kellaway >{{cite journal |last1=Kellaway |first1=C.H. |last2=Trethewie |first2=E.R. |title=The Liberation of a Slow-Reacting Smooth Muscle-Stimulating Substance in Anaphylaxis |journal=Quarterly Journal of Experimental Physiology and Cognate Medical Sciences |volume=30 |issue=2 |year=1940 |pages=121–145 |doi=10.1113/expphysiol.1940.sp000825 |doi-access=free |issn=1469-445X}}</ref> The researchers isolated SRS from lung tissue after a prolonged period following exposure to snake [[venom]] and histamine.{{r|Kellaway}}

==Types==

===Cysteinyl leukotrienes===

[[leukotriene C4|LTC₄]], [[leukotriene D4|LTD₄]], [[leukotriene E4|LTE₄]] and LTF₄ are often called '''cysteinyl leukotrienes''' due to the presence of the amino acid [[cysteine]] in their structure. The cysteinyl leukotrienes make up the [[slow-reacting substance of anaphylaxis]] (SRS-A). LTF₄, like LTD₄, is a metabolite of LTC₄, but, unlike LTD₄, which lacks the [[glutamate|glutamic]] residue of [[glutathione]], LTF₄ lacks the [[glycine]] residue of glutathione.<ref>[http://www.caymanchem.com/app/template/Product.vm/catalog/20520 internet] checked April 24, 2012{{full citation needed|date=April 2016}}</ref>

===LTB₄===

{{main|Leukotriene B4}}

[[leukotriene B4|LTB₄]] is synthesized ''in vivo'' from [[leukotriene A4|LTA₄]] by the enzyme [[leukotriene-A4 hydrolase|LTA₄ hydrolase]]. Its primary function is to recruit neutrophils to areas of tissue damage, though it also helps promote the production of inflammatory cytokines by various immune cells. Drugs that block the actions of LTB₄ have shown some efficacy in slowing the progression of neutrophil-mediated diseases.<ref>{{cite journal |last1=Crooks |first1=S.W |last2=Stockley |first2=R.A |title=Leukotriene B4 |journal=The International Journal of Biochemistry & Cell Biology |volume=30 |issue=2 |pages=173–8 |year=1998 |pmid=9608670 |doi=10.1016/S1357-2725(97)00123-4 |s2cid=45983006 }}</ref>

===LTG₄===

There has also been postulated the existence of LTG₄, a metabolite of LTE₄ in which the cysteinyl [[functional group|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.{{citation needed|date=April 2016}}

===LTB₅===

Leukotrienes originating from the omega-3 class eicosapentanoic acid (EPA) have diminished inflammatory effects. In human subjects whose diets have been supplemented with eicosapentaenoic acid, leukotrine B5, along with leukotrine B4, is produced by neutrophils.<ref>{{cite journal |last1=von Schacky |first1=C |last2=Fahrer |first2=C |last3=Fischer |first3=S |title=Catabolism of leukotriene B5 in humans |journal=Journal of Lipid Research |date=October 1990 |volume=31 |issue=10 |pages=1831–1838 |doi=10.1016/S0022-2275(20)42326-0 |pmid=1964169 |url=https://www.jlr.org/article/S0022-2275(20)42326-0/pdf |access-date=16 January 2023|doi-access=free }}</ref> LTB₅ induces aggregation of rat [[neutrophils]], chemokinesis of human polymorphonuclear neutrophils (PMN), lysosomal enzyme release from human PMN and potentiation of bradykinin-induced plasma exudation, although compared to LTB₄, it has at least 30 times less potency.<ref>{{cite journal |last1=Terano |first1=Takashi |last2=Salmon |first2=John A. |last3=Moncada |first3=Salvador |title=Biosynthesis and biological activity of leukotriene B5 |journal=Prostaglandins |volume=27 |issue=2 |pages=217–32 |year=1984 |pmid=6326200 |doi=10.1016/0090-6980(84)90075-3 }}</ref>

== Biochemistry ==

=== Synthesis === <!--Leukotriene synthesis redirects here-->

[[Image:Eicosanoid synthesis.svg|thumb|320px|Eicosanoid synthesis. (Leukotrienes at right.)]]

Leukotrienes are synthesized in the cell from [[arachidonic acid]] by [[5-lipoxygenase]]. The lipoxygenase pathway is active in [[leukocyte]]s and in [[macrophage]]s and synthesizes leukotrines.

Leukotrienes are synthesized in the cell from [[arachidonic acid]] by [[arachidonate 5-lipoxygenase]]. The catalytic mechanism involves the insertion of an oxygen moiety at a specific position in the arachidonic acid backbone.{{citation needed|date=April 2016}}

The lipoxygenase pathway is active in leukocytes and other immunocompetent cells, including [[mast cell]]s, [[eosinophil]]s, [[neutrophil]]s, [[monocyte]]s, and [[basophil]]s. 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.{{citation needed|date=April 2016}}

5-[[Lipoxygenase]] (5-LO) uses FLAP to convert arachidonic acid into 5-hydroperoxyeicosatetraenoic acid (5-HPETE), which spontaneously [[redox|reduces]] to [[5-hydroxyeicosatetraenoic acid]] (5-HETE). The enzyme 5-LO acts again on 5-HETE to convert it into [[leukotriene A4|leukotriene A₄]] (LTA₄), an unstable epoxide. 5-HETE can be further metabolized to 5-oxo-ETE and 5-oxo-15-hydroxy-ETE, all of which have pro-inflammatory actions similar but not identical to those of LTB₄ and mediated not by LTB₄ receptors but rather by the OXE receptor (see [[5-Hydroxyeicosatetraenoic acid]] and [[5-Oxo-eicosatetraenoic acid]]).<ref>{{cite journal |last1=O'Flaherty |first1=Joseph T. |last2=Taylor |first2=Jennifer S. |last3=Thomas |first3=Michael J. |title=Receptors for the 5-oxo class of eicosanoids in neutrophils |journal=The Journal of Biological Chemistry |volume=273 |issue=49 |pages=32535–41 |year=1998 |pmid=9829988 |doi=10.1074/jbc.273.49.32535|doi-access=free }}</ref><ref>{{cite journal |last1=Powell |first1=William S. |last2=Rokach |first2=Joshua |title=The eosinophil chemoattractant 5-oxo-ETE and the OXE receptor |journal=Progress in Lipid Research |volume=52 |issue=4 |pages=651–65 |year=2013 |pmid=24056189 |doi=10.1016/j.plipres.2013.09.001 |pmc=5710732}}</ref>

In cells equipped with [[leukotriene A4 hydrolase|LTA 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.{{citation needed|date=April 2016}}

In cells that express [[leukotriene C4 synthase|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]].{{citation needed|date=April 2016}}

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.{{citation needed|date=April 2016}}

Both LTB₄ and the cysteinyl-leukotrienes (LTC₄, LTD₄, LTE₄) are partly degraded in local tissues, and ultimately become inactive metabolites in the liver.{{citation needed|date=April 2016}}

=== Function ===

Leukotrienes act principally on a subfamily of [[G protein -coupled receptor]]s. They may also act upon [[peroxisome proliferator-activated receptor]]s. Leukotrienes are involved in asthmatic and allergic reactions and act to sustain inflammatory reactions;. severalSeveral [[leukotriene receptor antagonist]]s such as [[montelukast]] and [[zafirlukast]] are used to treat [[asthma]]. Recent research points to a role of 5-lipoxygenase in cardiovascular and neuropsychiatric illnesses.<ref>{{cite journal |last1=Manev |first1=Radmila |last2=Manev |first2=Hari |title=5-Lipoxygenase as a Putative Link Between Cardiovascular and Psychiatric Disorders |journal=Critical Reviews in Neurobiology |volume=16 |issue=1–2 |pages=181–6 |year=2004 |pmid=15581413 |doi=10.1615/CritRevNeurobiol.v16.i12.190 }}</ref>

Leukotrienes are very important agents in the [[inflammation|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]] and increase [[vascular permeability]].<ref name="lppl">{{cite journal |last1=Dahlén |first1=Sven-Erik |last2=Björk |first2=Jakob |last3=Hedqvist |first3=Per |last4=Arfors |first4=Karl-E. |last5=Hammarström |first5=Sven |last6=Lindgren |first6=Jan-Åke |last7=Samuelsson |first7=Bengt |title=Leukotrienes promote plasma leakage and leukocyte adhesion in postcapillary venules: in vivo effects with relevance to the acute inflammatory response |journal=Proceedings of the National Academy of Sciences |volume=78 |issue=6 |pages=3887–91 |year=1981 |pmid=6267608 |pmc=319678 |jstor=10943 |doi=10.1073/pnas.78.6.3887 |bibcode=1981PNAS...78.3887D |doi-access=free }}</ref>

==Leukotrienes in asthma==

Leukotrienes contribute to the [[pathophysiology]] of [[asthma]], especially in patients with [[aspirin-exacerbated respiratory disease]] (AERD), and cause or [[Potentiator|potentiate]] the following [[symptom]]s:<ref>{{cite journal |last1=Berger |first1=A. |title=Science commentary: What are leukotrienes and how do they work in asthma? |journal=BMJ |volume=319 |issue=7202 |pages=90 |year=1999 |pmid=10398630 |pmc=1116241 |doi=10.1136/bmj.319.7202.90 }}</ref>

* Airflow obstruction

* Increased secretion of mucus

* Mucosal accumulation

* Bronchoconstriction

* Infiltration of inflammatory cells in the airway wall

===Role of cysteinyl leukotrienes===

Cysteinyl leukotriene receptors [[CYSLTR1]] and [[CYSLTR2]] 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 [[Pulmonary alveolus|alveoli]]. The levels of cysteinyl leukotrienes, along with [[isoprostane|8-isoprostane]], have been reported to be increased in the [[Exhaled breath condensate|EBC]] of patients with [[asthma]], correlating with disease severity.<ref name="Samitas">{{cite journal |last1=Samitas |first1=Konstantinos |last2=Chorianopoulos |first2=Dimitrios |last3=Vittorakis |first3=Stelios |last4=Zervas |first4=Eleftherios |last5=Economidou |first5=Erasmia |last6=Papatheodorou |first6=George |last7=Loukides |first7=Stelios |last8=Gaga |first8=Mina |title=Exhaled cysteinyl-leukotrienes and 8-isoprostane in patients with asthma and their relation to clinical severity |journal=Respiratory Medicine |volume=103 |issue=5 |pages=750–6 |year=2009 |pmid=19110408 |doi=10.1016/j.rmed.2008.11.009 |doi-access=free }}</ref> Cysteinyl leukotrienes may also play a role in adverse drug reactions in general and in contrast medium induced adverse reactions in particular.<ref>{{cite journal |last1=Böhm |first1=Ingrid |last2=Speck |first2=Ulrich |last3=Schild |first3=Hans |title=A possible role for cysteinyl-leukotrienes in non-ionic contrast media induced adverse reactions |journal=European Journal of Radiology |volume=55 |issue=3 |pages=431–6 |year=2005 |pmid=16129253 |doi=10.1016/j.ejrad.2005.01.007 }}</ref>

In excess, the cysteinyl leukotrienes can induce [[Anaphylaxis|anaphylactic shock]].<ref>{{cite journal |last1=Brocklehurst |first1=W. E. |title=The release of histamine and formation of a slow-reacting substance (SRS-A) during anaphylactic shock |journal=The Journal of Physiology |volume=151 |issue= 3|pages=416–35 |year=1960 |pmid=13804592 |pmc=1363273 |doi=10.1113/jphysiol.1960.sp006449 }}</ref>

== See also ==

* [[Wittig reaction#Examples of use|A chemical synthesis of Leukotriene A methyl ester]]

* [[Eoxin]]s (14,15-leukotrienes)

==References==

{{reflist}}

==Further reading==

* Bailey, J. Martyn (1985) ''Prostaglandins, leukotrienes, and lipoxins: biochemistry, mechanism of action, and clinical applications'' Plenum Press, New York, {{ISBN|0-306-41980-7}}<!-- Template not ready for prime time yet.

* {{Cite Q|Q27863436}}-->

* Lipkowitz, Myron A. and Navarra, Tova (2001) ''The Encyclopedia of Allergies'' (2nd ed.) Facts on File, New York, p.&nbsp;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}}

==External links==

* {{MeshName|Leukotrienes}}

{{Eicosanoids}}

{{Leukotrienergics}}

{{Authority control}}

[[Category:Eicosanoids]]

{{stub}}

[[Category:Immunology]]

[[Category:Polyenes]]