Prevention of tocopherol-mediated peroxidation in ubiquinol-10-free human low density lipoprotein

Oxidation of low density lipoprotein (LDL) may be involved in the development of atherosclerosis. It has recently been shown that alpha-tocopherol (alpha-TOH) can act either as an antioxidant or prooxidant for isolated low density lipoprotein (LDL). In the absence of an effective co-antioxidant, alpha-TOH is a prooxidant and this activity is evidently due to reaction of the alpha-tocopheroxyl radical (alpha-TO.) with the LDL's polyunsaturated lipids (Bowry, V. B., and Stocker, R. (1993) J. Am. Chem. Soc. 115, 6029-6045). Herein we examined the effectiveness of selected natural and synthetic radical scavengers as co-antioxidants for inhibiting peroxyl radical-induced peroxidation in LDL that is devoid of ubiquinol-10 (an effective endogenous co-antioxidant) but still contains most of its natural complement of alpha-TOH. Various quinols, catechols, and aminophenols, as well as ascorbate, 6-palmityl ascorbate, and bilirubin, were very effective co-antioxidants under our test conditions, whereas ordinary phenolic antioxidants, including short-tailed alpha-TOH homologues, were less effective. Reduced glutathione, urate, and Probucol were ineffective. These findings confirm that the prooxidant activity of alpha-TOH in LDL relies heavily on the segregation of water-insoluble radicals (particularly alpha-TO.) into individual LDL particles, since it was those compounds that are expected to either irreversibly reduce alpha-TO. or accelerate the diffusion of radicals between particles which most effectively inhibited the tocopherol-mediated phase of peroxidation. Theoretical and practical implications of these findings are discussed, as is their relevance to the "LDL oxidation" hypothesis of atherogenesis.