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Pro-oxidant effects of lipoxygenase-derived peroxides on the copper-initiated oxidation of low-density lipoprotein.

ABSTRACT: It has been proposed that lipoxygenases, specifically 15-lipoxygenase, may play an important role in promoting the oxidation of low-density lipoprotein (LDL) in the artery wall. It is well known that peroxides are unstable in the presence of transition metals, decomposing to form the alkoxy and peroxy radicals, and so initiating lipid peroxidation. To test whether lipoxygenase-derived peroxides may promote the oxidation of LDL in the presence of copper, the lipoprotein was enriched with lipid peroxides derived from the enzymic action of 5- and 15-lipoxygenases on either linoleic or arachidonic acid. All of these products were found to promote oxidation, whereas the related hydroxy fatty acids had no effect. This suggests that lipoxygenase-derived peroxides associated with the LDL particle may promote peroxidation in the presence of a suitable transition metal catalyst. This result has implications both for the mechanism of the potential pro-oxidant action of lipoxygenases in vivo and for the ex vivo assessment of the oxidizability of LDL samples isolated from different donors.

SUBMITTER: O'Leary VJ

PROVIDER: S-EPMC1130833 | biostudies-other | 1992 Mar

REPOSITORIES: biostudies-other

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Project description:The Cu(II)-promoted oxidation of lipids is a lipid hydroperoxide (LOOH)-dependent process that has been used routinely to assess the oxidizability of low-density lipoprotein (LDL) in human subjects. Metal-dependent redox reactions, including those mediated by copper, have been implicated in the pathogenesis ofatherosclerosis. Despite its widespread use and possible biological significance, key elements of the mechanism are not clear. For example, although it is evident that copper acts 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 consumed before the most rapid phase of lipid peroxidation occurs, suggesting that another reductant must be donating electrons to Cu(II), the 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 favourable. Direct investigation of the role of LOOH as reductant has not been reported and in the present study, using simple lipid systems and LDL, we have re-examined this issue using the Cu(I) chelator bathocuproine. We have shown that Cu(II) may promote lipid peroxidation in liposomes, which do not contain either protein or alpha-tocopherol, and that this is associated with reduction to Cu(I). The data also indicate that 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 radicals. We propose that reduction of Cu(II) by LOOH is a necessary component in sustaining the propagation of lipid peroxidation and that the formation of peroxyl radicals and their products in a lipid environment is sufficient to overcome thermodynamic barriers to the reaction.

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Pro-oxidant effects of lipoxygenase-derived peroxides on the copper-initiated oxidation of low-density lipoprotein.

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