REDUCTION OF CU(II) BY LIPID HYDROPEROXIDES - IMPLICATIONS FOR THE COPPER-DEPENDENT OXIDATION OF LOW-DENSITY-LIPOPROTEIN

The Cu(II)-promoted oxidation of lipids is a lipid hydroperoxide (LOOH )-dependent process that has been used routinely to assess the oxidiza bility of low-density lipoprotein (LDL) in human subjects. Metal-depen dent redox reactions, including those mediated by copper, have been im plicated in the pathogenesis of atherosclerosis. Despite its widesprea d use and possible biological significance, key elements of the mechan ism are not clear. For example, although it is evident that copper act s as a catalyst, which implies a redox cycle between the Cu(II) and Cu (I) redox states, the reductants remain uncertain. In LDL these could include alpha-tocopherol, amino acid residues on the protein and LOOH. However, both alpha-tocopherol and amino acid residues are probably c onsumed before the most rapid phase of lipid peroxidation occurs, sugg esting that another reductant must be donating electrons to Cu(II), th e most likely candidate being LOOH. This role has been disputed, since LDLs nominally devoid of LOOH are still capable of reducing Cu(II) to Cu(I) and thermodynamic calculations for this reaction are not favour able. Direct investigation of the role of LOOH as reductant has not be en reported and in the present study, using simple lipid systems and L DL, we have re-examined this issue using the Cu(I) chelator bathocupro ine. We have shown that Cu(II) may promote lipid peroxidation in lipos omes, which do not contain either protein or alpha-tocopherol, and tha t this is associated with reduction to Cu(I). The data also indicate t hat an equilibrium between free Cu(II) and LOOH exists, which only in the presence of an oxidizable substrate, i.e. unsaturated fatty acids, is shifted towards formation of Cu(I) and lipid-derived peroxyl radic als. We propose that reduction of Cu(II) by LOOH is a necessary compon ent in sustaining the propagation of lipid peroxidation and that the f ormation of peroxyl radicals and their products in a lipid environment is sufficient to overcome thermodynamic barriers to the reaction.