Thermodynamic and Kinetic Aspects of the Lipid Peroxidation of Arachidonic Acid

Lipid peroxidation is the oxidative modification of polyunsaturated fatty acids (PUFA) that leads to hydroperoxides. Hydroperoxides that are derived from the lipid arachidonic acid serve as regulators of the enzymes involved in prostaglandin synthesis. Further oxidation of these hydroperoxides produces short chain aldehydes, such as 4- hydroxynonenal. The mechanism of lipid peroxidation is well established, yet it is difficult to predict the ratio of aldehydes produced. Since these aldehydes are markers of biological activity, quantitative prediction of product ratios is desirable. Density functional calculations are used to study the thermodynamic and kinetic aspects of the first three steps in the mechanism of lipid peroxidation of arachidonic acid. It is found that the relative stability of peroxyl radical intermediates resulting from hydrogen abstraction and subsequent oxidation correlates with localization of the valence molecular orbitals on the peroxyl group. In addition, simple diene models are used to show that the most stable isomers of the peroxyl radicals are trans, trans, where the peroxyl group is located away from the bis-allylic carbon. Finally, the most stable peroxyl radicals originating from arachidonic acid are identified: these arise from hydrogen abstraction at the C13 position and exhibit trans, trans stereochemistry around the site of peroxidation.