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

A 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.The mathematical model developed described quantitatively different mechanisms of 5-LO inhibition and simulations revealed differences between the potential therapeutic outcomes for these mechanisms.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. 5-lipoxygenase (5-LO) is the key enzyme of leukotriene biosynthesis and so is a promising target for drug development [2,3].5-LO is expressed predominantly in leukocytes and is responsible for the synthesis of both leukotriene A4 (LTA4) and 5(S)-hydroperoxy-6,8,1l,14-(E,Z,Z,Z)-eicosatetraenoic acid (HP) [4-6]. The reaction scheme is given in F