Leukotriene pathway genetics and pharmacogenetics in allergy

Abstract

Leukotrienes (LT) are a family of potent eicosanoid lipid mediators with central importance in disease processes such as inflammation and proliferation most notably observed in allergic conditions like asthma (1). There are two general classes of LT according to the presence of a cysteine residue in their amino acid chain: the cysteinyl leukotrienes (CysLTs) including LTC 4 , LTD 4 and LTE 4 and the dihydroxyleukotriene LTB 4 (2). The 5-lipoxygenase pathwayLeukotrienes are produced in a multi-step enzyme pathway called the 5-lipoxygenase (5-LO) pathway, which is active in leucocytes such as neutrophils, eosinophils, mast cells and monocytes (Fig. 1). Arachidonic acid is the precursor for LT synthesis and is hydrolysed from the plasma membrane by cytosolic phospholipase A 2 (and other isoforms) (3, 4) in a calcium-dependent process (5). Upon activation, the rate-limiting enzyme 5-LO oxygenates first free arachidonic acid into the unstable intermediate 5-hydroperoxyeicosatetraenoic acid (5-HPETE) which is then either hydrolysed to 5-hydroxyeicosatetraenoic acid (5-HETE) or transformed into the unstable epoxide leukotriene A 4 (LTA 4 ) by forming a conjugated triene system through dehydration (6). 5-LO translocates from either the nucleus (in macrophages) or cyotosol (in neutrophils) to the nuclear envelope in response to cell activation (7,8). This movement occurs as 5-LO is dependent on a 5-LO activating protein (FLAP) for its function. FLAP remains associated with the nuclear membrane (9) and acts as a Ôtransfer proteinÕ presenting arachidonic acid to 5-LO, a system which allows the favourable conversion of 5-HPETE to LTA 4 compared to 5-HETE (10). Both 5-LO and FLAP are expressed in cells of myeloid lineage (11) restricting the pathway to these cell types. LTA 4 can be further metabolised to the cysteinyl leukotrienes (CysLTs) or LTB 4 . The specific glutathione S-transferase leukotriene C 4 synthase (LTC 4 S) conjugates LTA 4 to form LTC 4 which can then be rapidly converted to LTD 4 by a gammaglutamyl transpeptidase and to LTE 4 by a dipeptidase once exported out the cell by membrane transport proteins such as multi-drug related protein 1 (MRP1) (12-15). A specific zinc metallohydrolase, LTA 4 hydrolase (LTA 4 H) is responsible for the conversion of LTA 4 to LTB 4 (16). CysLTs and LTB 4 act on different G-protein coupled receptors (GPCRs). Each bind to at least two different receptors: CysLTs to CYSLTR1 and CYSLTR2 and LTB 4 to LTB 4 R1 and LTB 4 R2 (or BLT1 and BLT2) (17).Leukotrienes (LT) are biologically active lipid mediators known to be involved in allergic inflammation. Leukotrienes have been shown to mediate diverse features of allergic conditions including inflammatory cell chemotaxis/activation and smooth muscle contraction. Cysteinyl leukotrienes (LTC 4 , LTD 4 and, LTE 4 ) and the dihydroxy leukotriene LTB 4 are generated by a series of enzymes/ proteins constituting the LT synthetic pathway or 5-lipoxygenase (5-LO) pathway. Their function is mediated by interacting with multiple receptors. Leukotr...

Anti-inflammatory constituents fromPerovskia atriplicifolia

“…Leukotrienes including LTC 4 are lipid mediators found elevated in various inflammatory diseases such as allergic rhinitis, asthma, and atopic dermitis. Currently, antileukotrienes are being prescribed for the treatment of asthma and have been approved for the treatment of allergic rhinitis (Duroudier et al, 2009). …”

Arresting supporters: targeting neutrophils in metastasis

“…LTs are eicosanoids that belong to a family of molecules that are derived from arachidonic acid. LTs mediate inflammatory processes and increase vasodilation and vascular permeability [12]. Interestingly, LT stimulation of mouse MMTV-PyMT + breast cancer cells enhanced tumor initiation potential of these cancer cells both in vitro and in vivo.…”

“…In summary, the study by Wculek and Malanchi addresses the functional contribution of a key player, neutrophils, in the metastatic microenvironment, and provides a targeted approach to prevent pro-metastatic activity of these cells in breast cancer models. LTs are important mediators of inflammatory and allergic responses [12]. As such, Alox5 inhibitors such as Zileuton (Zil) are in use for treating asthma.…”

Effects of Leukotriene Receptor Antagonists on Peripheral Eosinophil Counts and Serum IgE Levels in Children with Food Allergy

“…montelukast or pranlukast] blocks the effects of Cys-LTs and alleviates the symptoms of many chronic allergic diseases, including bronchial asthma. [12] The clinical effect of montelukast for pediatric asthma was first reported in 1998. [13] It has been used since that time, and its effectiveness is recognized worldwide.…”