SIMULATION OF THE INDUCTION OF OXIDATION OF LOW-DENSITY-LIPOPROTEIN BY HIGH COPPER CONCENTRATIONS - EVIDENCE FOR A NONCONSTANT RATE OF INITIATION

Kinetic simulation can help obtain deeper insight into the molecular m echanisms of complex processes, such as lipid peroxidation (LPO) in lo w-density lipoprotein (LDL). We have previously set up a single-compar tment model of this process, inititating with radicals generated exter nally at a constant rate to show the interplay of radical scavenging a nd chain propagation. Here we focus on the initiating events, substitu ting constant rate of initiation (R-i) by redox cycling of Cu2+ and Cu +. Our simulation reveals that early events in copper-mediated EDL oxi dation include (1) the reduction of Cu2+ by tocopherol (TocOH) which g enerates tocopheroxyl radical (TocO(.)), (2) the fate of TocO(.) which either is recycled or recombines with lipid peroxyl radical. (LOO.), and (3) the reoxidation of Cu+ by lipid hydroperoxide which results in alkoxyl radical (LO.) formation. So TocO(.), LOO., and LO. can be reg arded as primordial radicals, and the sum of their formation rates is the total rate of initiation, R-i. As experimental information of thes e initiating events cannot be obtained experimentally, the whole model was validated experimentally by comparison of LDL oxidation in the pr esence and absence of bathocuproine as predicted by simulation, Simula tion predicts that R-i decreases by 2 orders of magnitude during lag t ime. This has important consequences for the estimation of oxidation r esistance in copper-mediated LDL oxidation: after consumption of tocop herol, even small amounts of antioxidants may prolong the lag phase fo r a considerable time.