TOCOPHEROL-MEDIATED PEROXIDATION - THE PROOXIDANT EFFECT OF VITAMIN-E ON THE RADICAL-INITIATED OXIDATION OF HUMAN LOW-DENSITY-LIPOPROTEIN

Oxidation of human low-density lipoprotein (LDL) is implicated as an initiator of athcrosclerosis. Alpha-tocopherol (alpha-TocH) may thus inhibit atherosclerosis because it is the major and most active chain-breaking antioxidant in extracted LDL lipid. Our studies show, however, that alpha-TocH can bc a strong prooxidant for the LDL itself, i.e., an aqueous dispersion of lipid-bearing particles. Thus, a steady flux (R(g)) of alkylperoxyl radicals (ROO.) generated from a water-soluble azo initiator induced lipid peroxidation in LDL which was faster in the presence of alpha-TocH than in its absence (for R(g) < 2 nM s-1), insensitive to R(g) and [O2], and inhibited by vitamin C, ubiquinol-10 (normally present in fresh LDL), and small phenolic antioxidants but not inhibited by the aqueous radical scavenger uric acid. Furthermore, LDL peroxidation induced by a water- or lipid-soluble azo initiator or by transition metals in Ham's F-10 cell culture medium was accelerated by increasing the concentration of alpha-TocH in LDL. We propose that LDL peroxidation is initiated by the reaction of ROO. with alpha-TocH and that the inability of the alpha-Toc. formed in this reaction to escape from an LDL particle then forces alpha-Toc. to propagate a radical chain via its reaction with PUFA lipid (LH) within the particle (alpha-Toc. + LH + O2 --> alpha-TocH + LOO.). Termination of a radical chain occurs when a peroxidizing LDL particle captures a second radical from the aqueous medium (ROO. + alpha-Toc. --> nonradical products). Steady-state kinetic analysis of this mechanism yields a theoretical model for tocopherol-mediated peroxidation (TMP) in lipid dispersions which fully explains our findings for LDL. We conclude that peroxidation of LDL lipid can (only) be prevented by agents which eliminate the alpha-Toc. radical: vitamin C and LDL-associated ubiquinol-10 do so by ''exporting the radical'' into the aqueous medium, whereas small phenolic antioxidants (e.g., butylated hydroxytoluene) accelerate the transfer of radicals between particles. The theoretical and practical implications of TMP in LDL, dispersions, and bulk lipids are discussed.