Vitamins E and C do not effectively inhibit low density lipoprotein oxidation by ferritin at lysosomal pH

Abstract

Low density lipoprotein (LDL) might be oxidized by iron in the lysosomes of macrophages in atherosclerotic lesions. We have shown previously that the iron-storage proteinferritin can oxidize LDL at lysosomal pH. We have now investigated the roles of the most important antioxidant contained in LDL, a-tocopherol (the main form of vitamin E) and of ascorbate (vitamin C), a major water-soluble antioxidant, on LDL oxidation by ferritin at lysosomal pH (pH 4.5). We incubated LDL with ferritin at pH 4.5 and 37 C and measured its oxidation by monitoring the formation of conjugated dienes at 234 n min a spectrophotometer. a-Tocopherol is well known to inhibit LDL oxidation at pH 7.4, but enrichment of LDL with a-tocopherol was unable to inhibit LDL oxidation by ferritin at pH 4.5. Ascorbate had a complex effect on LDL oxidation by ferritin at lysosomal pH and exhibited both antioxidant and pro-oxidant effects. It had no antioxidant effect on partially oxidized LDL, only a pro-oxidant effect. Ascorbate completely inhibited LDL oxidation by copper at pH 7.4 for a long period, but in marked contrast did not inhibit LDL oxidation by copper at lysosomal pH. Dehydroascorbate, the oxidation product of ascorbate, had a pronounced pro-oxidant effect on LDL incubated with ferritin at pH 4.5. The inability of a-tocopherol and ascorbate to effectively inhibit LDL oxidation by ferritin at lysosomal pH might help to explain why the large clinical trials with these vitamins failed to show protection against cardiovascular diseases.

Enhancement of Antioxidant and Anti-Glycation Properties of Beeswax Alcohol in Reconstituted High-Density Lipoprotein: Safeguarding against Carboxymethyllysine Toxicity in Zebrafish

“…Although vit C inhibited LDL oxidation by myeloperoxidase in vitro, the dosage was too high to use practical applications, such as 50, 100, 150, and 200 mM [44]. In addition, vit C and E could not inhibit LDL oxidation by ferritin at lysosomal pH, which might help to explain why vit C and E did not reduce CVD in large clinical trials [45], which is in good agreement with the current results (Supplementary Figures S2 and S3). Several phenolic compounds and flavonoids have been developed as inhibitors of LDL oxidation [46].…”

Enhanced Antioxidant and Anti-Glycation Abilities of Beeswax Alcohol in Reconstituted High-Density Lipoprotein with Potent Wound-Healing Activity and Protection of Embryo from Acute Toxicity of Carboxymethyllysine in Zebrafish

“…Although vit C inhibited LDL oxidation by myeloperoxidase in vitro, the dosage was too high to use practical application, such as 50, 100, 150, and 200 mM [42]. In addition, vit C and E could not inhibit LDL oxidation by ferritin at lysosomal pH, which might help to explain why vit C and E did not reduce CVD in large clinical trials [43]. Several phenolic compounds and flavonoids were developed as inhibitors of LDL oxidation [44]; new pharmaceutical agents are needed to maximize the antioxidant, anti-glycation, protection of HDL, and stabilization of apoA-I via an interaction of amphipathic helix domain.…”