Leukotriene C4 Explained

Leukotriene C₄ (LTC₄) is a leukotriene. LTC₄ has been extensively studied in the context of allergy and asthma.^{[1] [2]} In cells of myeloid origin such as mast cells, its biosynthesis is orchestrated by translocation to the nuclear envelope along with co-localization of cytosolic phospholipase A2 (cPLA2), arachidonate 5-lipoxygenase (5-LO), 5-lipoxygenase-activating protein (FLAP) and LTC₄ synthase (LTC₄S), which couples glutathione to an LTA₄ intermediate. The MRP1 transporter then secretes cytosolic LTC₄ and cell surface proteases further metabolize it by sequential cleavage of the γ-glutamyl and glycine residues off its glutathione segment, generating the more stable products LTD₄ and LTE₄. All three leukotrienes then bind at different affinities to two G-protein coupled receptors: CYSLTR1 and CYSLTR2, triggering pulmonary vasoconstriction and bronchoconstriction.^[3]

In cells of non-haematopoietic lineage, endoplasmic reticulum (ER) stress and chemotherapy induce LTC₄ biosynthesis by transcriptionally upregulating and activating the enzyme microsomal glutathione-S-transferase 2 (MGST2). ER stress and chemotherapy also trigger nuclear translocation of the two LTC₄ receptors. Acting in an intracrine manner, LTC₄ then elicits nuclear translocation of NADPH oxidase 4 (NOX4), ROS accumulation and oxidative DNA damage.^[4] Besides being a potent lipid mediator in asthma and inflammation, LTC₄ was reported to be involved in several other diseases, such as allergic airway diseases, dermatological diseases, cardiovascular diseases, liver injury, atherosclerosis and colon cancer.^{[5] [6] [7]}

Notes and References

1. Identification and Characterization of a Novel Human Microsomal Glutathione S-Transferase with Leukotriene C4 Synthase Activity and Significant Sequence Identity to 5-Lipoxygenase-activating Protein and Leukotriene C4 Synthase . Journal of Biological Chemistry . 1996-09-06 . 0021-9258 . 8703034 . 22203–22210 . 271 . 36 . 10.1074/jbc.271.36.22203 . Per-Johan . Jakobsson . Joseph A. . Mancini . Anthony W. . Ford-Hutchinson. free.
2. Book: Chapter Two - The Leukotrienes: Immune-Modulating Lipid Mediators of Disease . Academic Press . 2012-01-01 . 51–92 . 116 . 10.1016/b978-0-12-394300-2.00002-8 . 23063073 . Antonio . Di Gennaro . Jesper Z. . Haeggström . Frederick W. . Alt. The Leukotrienes: Immune-Modulating Lipid Mediators of Disease . Advances in Immunology . 9780123943002 .
3. Lipoxygenase and Leukotriene Pathways: Biochemistry, Biology, and Roles in Disease . Chemical Reviews . 2011-09-22 . 5866–5898 . 111 . 10 . 10.1021/cr200246d . Jesper Z. . Haeggström . Colin D. . Funk . 21936577.
4. Leukotriene C4 is the major trigger of stress-induced oxidative DNA damage . Nature Communications . 2015-12-11 . 4682057 . 26656251 . 10112 . 6 . 10.1038/ncomms10112 . Efrat . Dvash . Michal . Har-Tal . Sara . Barak . Ofir . Meir . Menachem . Rubinstein. 2015NatCo...610112D .
5. Enhanced expressions and activations of leukotriene C4 synthesis enzymes in D-galactosamine/lipopolysaccharide-induced rat fulminant hepatic failure model . World Journal of Gastroenterology . 2008-05-07 . 1007-9327 . 2709038 . 18461660 . 2748–2756 . 14 . 17 . Kui-Fen . Ma . Hong-Yu . Yang . Zhe . Chen . Luo-Yang . Qi . Dan-Yan . Zhu . Yi-Jia . Lou . 10.3748/wjg.14.2748 . free .
6. Altered eicosanoid levels in human colon cancer . Rigas . B. . 1993 . J Lab Clin Med . 8228569 . 122 . 5 . 518–23.
7. Expanding expression of the 5-lipoxygenase pathway within the arterial wall during human atherogenesis . Proceedings of the National Academy of Sciences of the United States of America . 2003-02-04 . 0027-8424 . 298757 . 12552108 . 1238–1243 . 100 . 3 . 10.1073/pnas.242716099 . Rainer . Spanbroek . Rolf . Grabner . Katharina . Lotzer . Markus . Hildner . Anja . Urbach . Katharina . Ruhling . Michael P. W. . Moos . Brigitte . Kaiser . Tina U. . Cohnert. 2003PNAS..100.1238S . free .