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Leukotriene C4 Synthase A -444 CLeukotriene C4 Synthase is the first committed enzyme in the pathway leading from Leukotriene A4 to the Sulfido-Leukotrienes C4, D4 and E4, formerly known as "Slow Reacting Substances of Anaphylaxis (SRS-A)". Leukotrienes C4, D4 and E4 are potent stimulators of smooth muscle constriction and strong chemoattractants for inflammatory cells and play a major pathogenetic role in inflammation, particularly Acute Allergy, Pseudoallergy, Anaphylaxis and Anaphylactic shock. Recently, the A-444C promoter variant of the Leukotriene C4 Synthase gene has been described (1). This variant promoter (-444C) interacts more efficiently with transcription factors and thus leads to overexpression of active enzyme and to enhanced Leukotriene C4 synthesis in vivo (2). Clinically, an association with Aspirin-induced asthma has been described (1,3). Importantly, Variant LTC(4) synthase allele apparently modifies cysteinyl leukotriene synthesis in eosinophils and predicts clinical response to the anti-asthma drug zafirlukast, a cysteinyl-leukotriene-receptor-antagonist (4).References (1) Sanak M, Simon HU, Szczeklik A. Leukotriene C4 synthase promoter polymorphism and risk of aspirin-induced asthma. Lancet 1997 Nov 29;350(9091):1599-600 (2) Sanak M, Pierzchalska M, Bazan-Socha S, Szczeklik A. Enhanced expression of the leukotriene C(4) synthase due to overactive transcription of an allelic variant associated with aspirin-intolerant asthma. Am J Respir Cell Mol Biol 2000 Sep;23(3):290-6 (3) Penrose JF, Baldasaro MH. Leukotriene C4 synthase: a candidate gene for the aspirin-intolerant asthmatic phenotype. Allergy Asthma Proc 1999 Nov-Dec;20(6):353-60 (4) Sampson AP, Siddiqui S, Buchanan D, Howarth PH, Holgate ST, Holloway JW, Sayers I. Variant LTC(4) synthase allele modifies cysteinyl leukotriene synthesis in eosinophils and predicts clinical response to zafirlukast. Thorax 2000 Oct;55 Suppl 2:S28-31 |