Reaction rate calculations indicate that α-tocopherol primarily acts as a membrane protein antioxidant in vivo

Lipid peroxidation is a complex free radical chain reaction in which lipid peroxyl radicals serially attack other components of the lipid bilayer. As a condensed phase, the lipid bilayer contains numerous potentially reactive substrates beyond unsaturated fatty acids, including membrane proteins and dissolved small molecules like α-tocopherol, the major lipid-soluble antioxidant. Despite a long history of investigation, the reaction cascades that do succeed in vivo to produce tocopherol's pronounced antioxidant effect are still arguable. Here, we have revisited the tocopherol reaction cascade problem from a quantitative perspective, by analyzing published rate constants and stereologically derived intramembrane reactant concentrations of various lipid bilayer components. Applying chemical rate laws, we find that in native biological membrane systems, less than 1% - 5% of all radical flux from lipid peroxyl radicals directly attacks α-tocopherol owing to its low concentration. Most radical flux rather attacks aromatic amino acid side chains, whose radical forms are then repaired very efficiently by even highly diluted α-tocopherol. Although tocopherol can also forestall fatty acid oxidation in protein-free oils and artificial lipid-only bilayers, its in vivo activity is predominantly that of a membrane protein antioxidant. Our data provide a potential explanation for the relaxed resorption of nutritional vitamin E by animals.