Regulation of leukotriene and 5oxoETE synthesis and the effect of 5-lipoxygenase inhibitors: a mathematical modeling approach

Tatiana A Karelina,David Fairman,Oleg O Demin,Oleg V Demin,Kirill V Zhudenkov,Balaji Agoram,Dmitry V Svetlichny

doi:10.1186/1752-0509-6-141

Abstract

Background5-lipoxygenase (5-LO) is a key enzyme in the synthesis of leukotrienes and 5-Oxo-6E,8Z,11Z,14Z-eicosatetraenoic acid (oxoETE). These inflammatory signaling molecules play a role in the pathology of asthma and so 5-LO inhibition is a promising target for asthma therapy. The 5-LO redox inhibitor zileuton (Zyflo IR/CR®) is currently marketed for the treatment of asthma in adults and children, but widespread use of zileuton is limited by its efficacy/safety profile, potentially related to its redox characteristics. Thus, a quantitative, mechanistic description of its functioning may be useful for development of improved anti-inflammatory targeting this mechanism.ResultsA mathematical model describing the operation of 5-LO, phospholipase A2, glutathione peroxidase and 5-hydroxyeicosanoid dehydrogenase was developed. The catalytic cycles of the enzymes were reconstructed and kinetic parameters estimated on the basis of available experimental data. The final model describes each stage of cys-leukotriene biosynthesis and the reactions involved in oxoETE production. Regulation of these processes by substrates (phospholipid concentration) and intracellular redox state (concentrations of reduced glutathione, glutathione (GSH), and lipid peroxide) were taken into account. The model enabled us to reveal differences between redox and non-redox 5-LO inhibitors under conditions of oxidative stress. Despite both redox and non-redox inhibitors suppressing leukotriene A4 (LTA4) synthesis, redox inhibitors are predicted to increase oxoETE production, thus compromising efficacy. This phenomena can be explained in terms of the pseudo-peroxidase activity of 5-LO and the ability of lipid peroxides to transform 5-LO into its active form even in the presence of redox inhibitors.ConclusionsThe mathematical model developed described quantitatively different mechanisms of 5-LO inhibition and simulations revealed differences between the potential therapeutic outcomes for these mechanisms.

Highlights

Leukotrienes are key inflammatory mediators associated with pathological states of inflammation in diseases such as asthma and allergic rhinitis and play a pivotal role in normal host defense [1]
The main purpose of this paper is to summarize the development of a detailed mathematical model of 5-LO operation, its application to describe the production of leukotriene A4 (LTA4) and oxoETE, and to study the differences between redox and non-redox inhibitors
Model construction The “LOS model” describing LTA4 and oxoETE production in leukocytes includes reactions catalyzed by 5-LO, cytosolic phospholipase A2 (cPLA2), glutathione peroxidase (GPx), hydroxyeicosanoid dehydrogenase (HEDH) and degradation of hydroxyeicosatetraenoic acid (HT), oxoETE and LTA4

Summary

Introduction

Leukotrienes are key inflammatory mediators associated with pathological states of inflammation in diseases such as asthma and allergic rhinitis and play a pivotal role in normal host defense [1]. They have been shown to promote leukocyte chemotaxis and activation, vascular tone and permeability, smooth muscle contractility and immune function. There are two steps in this reaction: oxygenation of arachidonic acid (AA) using O2 to produce HP and the dehydration of the hydroperoxide intermediate, to produce the epoxide, leukotriene A4 (LTA4). HT, in turn, can be converted to 5-Oxo-6E,8Z,11Z,14Z-eicosatetraenoic acid (oxoETE) by 5-hydroxyeicosanoid dehydrogenase (HEDH) [9]. 5oxoETE stimulates eosinophil migration and tissue infiltration 30 fold more potently than leukotriene B4 (LTB4) [11], and increases intracellular calcium (Ca2+) concentration and actin polymerization in eosinophils [10]

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