RADICAL-INITIATED LIPID-PEROXIDATION IN LOW-DENSITY LIPOPROTEINS - INSIGHTS OBTAINED FROM KINETIC MODELING

We present kinetic models of various complexity for radical-initiated lipid peroxidation in low density lipoproteins (LDL). The models, comp rised of simultaneous differential equations programmed in Mathematica , were used to evaluate the concentration profiles of the reactants of interest. Single-phase reaction schemes describing lipid peroxidation and antioxidation according to the ''conventional'' and tocopherol-me diated peroxidation (TMP) model were simulated for conditions of low a nd high radical fluxes produced by thermolabile azo initiators. The re sults show that the particular dependencies of the rates of lipid pero xidation (R(p)) on the rates of initiation (R(i)) for the two reaction schemes were accurately predicted by the simulations. Both models qua litatively predicted inhibition of lipid peroxidation in the presence of alpha-tocopherol (alpha-TOH) under high radical flux conditions, su ggesting that both can describe inhibited lipid peroxidation in soluti on under these conditions. TMP, but not the conventional model, could also predict the experimentally observed complex behavior of LDL lipid peroxidation induced with different concentrations of azo initiators. Specifically, TMP faithfully reproduced the observed kinetic chain le ngth of lipid peroxidation of much greater than 1 at low and much less than 1 at high concentration of the initiator (i.e., 0.2 and 10 mM, r espectively for LDL at 1 mu mol apoB-100/L) during the alpha-TOH-conta ining period of oxidation. It also demonstrated the experimentally obs erved nondependence of R(p)(TMP) On R(i). Kinetic analysis of radical generation and initiation of lipid peroxidation in an extended, two-co mpartment model of TMP showed that phase separation of bimolecular rea ctions in a suspension of LDL particles can lead to a similar to 400-f old increase in the rate of lipid hydroperoxide formation. The experim entally observed co-antioxidant action of water-soluble ascorbate and lipid-soluble ubiquinol-10 were verified using this model. A simple bi ophysical model constituting the reactions of TMP and incorporating th e compartmental nature of an LDL suspension is proposed. Together, the results demonstrate that TMP is the only model that fits the experime ntal data describing the early stages of LDL lipid peroxidation under various oxidizing conditions. The implications of our findings are dis cussed in relation to atherogenesis and a recently proposed alternativ e model of LDL lipid peroxidation (Abuja and Esterbauer (1995) Chem. R es. Toxicol. 8, 753).