Untitled

Abstract

Oxidation of low density lipoprotein (LDL) has been postulated as the main cause of atherogenesis, resulting in formation of foam cells, triggering of various pathways, and leading to the development of the disease. Therefore, antioxidants would naturally be expected to attenuate the progress of atherosclerosis. α-Tocopherol (α-TocH) is the most abundant form of vitamin E in nature and the major antioxidant of biological membranes. α-TocH is also present at a much higher concentration than other antioxidants in plasma lipoproteins. The large amount of α-TocH present in LDL leads to the expectation that lipid peroxidation would be strongly inhibited by α-TocH. However, advanced atherosclerotic plaques are not deficient in the presence of antioxidants such as vitamins C and E, despite the occurrence of massive lipid oxidation. Thus conventional mechanism associated with the antioxidant properties of α-TocH cannot explain why lipid peroxidation occurs in atherosclerotic lesions in the presence of compounds that are usually considered to be antioxidants. A kinetic model was developed and applied to explore the mechanism of lipid peroxidation process under various conditions and to examine the possible occurrence of lipid peroxidation in the presence of α-tocopherol. The model incorporated many factors, that were not included in previous models but we believe to play important roles in the different outcome of the process. As a result, the numerical simulation illustrated that lipid peroxidation in the lipoprotein particle could occur in the presence of vitamins E (α-TocH) and C under certain conditions, including high initiation rate, high initial α-TocH level, low ratio of [vitamin C]/[α-TocH], and small lipoprotein particles. The kinetic scheme developed in this study defined the type of relationship that α-TocH in an environment exhibits either pro-or antioxidative property. Thus, antioxidant and pro-oxidant effects of tocopherol merely depend on the condition in which its properties are exhibited.

Analysis of Lipid Peroxidation Kinetics. 1. Role of Recombination of Alkyl and Peroxyl Radicals

“…The data presented in ref imply that the “oxidizability” Z LO 2 • = k 3 2 k 6 ≈ 0.04 M − 1 / 2 s − 1 which is within the range 0.02−0.08 M −1/ 2 s −1 given in ref , while refs and yield Z LO 2 • ≈ 0.7 M −1/ 2 s −1 and Z LO 2 • ≈ 4.5 × 10 3 M −1/2 s −1 , respectively. The oxidizability determines the peroxidation rate under continuous initiation when only recombination between peroxyl radicals is important. , …”

“…It can only change the kinetic law from exponential, in the absence of recombination [ LOOH ] t = [ LOOH ] 0 + [ LH ] 0 false{ 1 − exp ( − k 3 [ LO 2 • ] 0 t ) false} to the slower algebraic form of eq . This is clearly seen for the situation described in refs and , i.e., when k 3 ≪ 2 k 6 When this condition is satisfied, eq can be expanded and rewritten as [ LOOH ] t = [ LOOH ] 0 + [ LH ] 0 k 3 2 k 6 ln false( 1 + 2 k 6 [ LO 2 • ] 0 t false) For short tim...…”

“…Reference , on the other hand, only included the recombination of alkyl radicals, i.e., reaction . The argument was that the rate constant of the peroxyl recombination reaction ( k 6 ) is 5 or 6 orders of magnitude smaller than the recombination rate constant of alkyl radicals ( k 4 ) and therefore only the latter recombination needs to be included. However, the rate constant k 5 of the recombination between alkyl and peroxyl radicals, eq , is large enough to influence the recombination kinetics.…”

“…The oxidizability Z LO 2 • for the reaction of LO 2 • was introduced in eq as the ratio of the decay rate constant k 3 and the square root of 2 times the recombination rate constant k 6 . By analogy, we introduce oxidizability for the reaction of alkyl radicals as Z L • = k 2 2 k 4 > 10 3 M − 1 / 2 s − 1 for the published rate constants. , The corresponding dimensionless parameter, cf. eq , is ξ = k 2 ′ 2 k 4 I ≡ Z L • [ O 2 ] I ≫ 1 From eqs and it follows that η ≪ ξ or Z LO 2 • [ LH ] t ≪ Z ...…”

“…Previous attempts to describe the kinetics – have used numerical simulations and approximate analytical descriptions of the lipid peroxidation kinetics to interpret experimental data in terms of rate constants of the individual stages of the process. However, the derived reaction rates and the concentrations of the reactants are rather scattered in the literature and differ, sometimes by orders of magnitude, from each other.…”