Alpha-tocopherol is ineffective in preventing the decomposition of preformed lipid peroxides and may promote the accumulation of toxic aldehydes: a potential explanation for the failure of antioxidants to affect human atherosclerosis.

The decomposition of peroxidized lipids of low-density lipoprotein (LDL) has been suggested to be involved in atherosclerosis. In this study, an in vitro system with 13-hydroperoxylinoleic acid (13-HPODE) was used to determine the effects of antioxidants on its decomposition. Decomposition of 13-HPODE was not affected by alpha-tocopherol, several other antioxidants, or antioxidant enzymes. Moreover, the inclusion of alpha-tocopherol during the decomposition of 13-HPODE resulted in an accumulation of aldehydes. Further oxidation of aldehydes to carboxylic acids by a number of oxidases was prevented by alpha-tocopherol. Conversely, the formation of carboxylic acids may be conducive to plaque stabilization via immunomodulation, rapid degradation, and by calcium sequestration. Thus, the inhibition of formation of carboxylic acids could be a serious deleterious effect of antioxidant treatment. In contrast, alpha-keto acids, like pyruvic acid, promoted the conversion of 13-HPODE to 13-hydroxylinoleic acid (13-HODE) by readily undergoing decarboxylation into acetate. These observations suggest that agents that promote the reduction of lipid peroxides into lipid hydroxides could be far more effective in treating cardiovascular diseases as opposed alpha-tocopherol-like antioxidants that could affect additional steps in the oxidation cascade.