alpha-Tocopherol as a reductant for Cu(II) in human lipoproteins - Triggering role in the initiation of lipoprotein oxidation

Initiation of lipid peroxidation by Cu(II) requires reduction of Cu(II) to Cu(I) as a first step. It is unclear, however, whether this reaction occurs in the course of lipoprotein oxidation. It is also unknown which reductant, if any, can drive the reduction of Cu(II) in this case. We found that Cu(II) was rapidly reduced to Cu(I) by all major human lipoproteins (high, low and very low density lipoproteins (HDL, LDL, and VLDL), and chylomicrons). Cu(II)-reducing activity was associated with a lipid moiety of the lipoproteins. The rates of Cu(II) reduction by different lipoproteins were similar when the lipoproteins were adjusted to similar alpha-tocopherol concentrations, Enriching lipoproteins with alpha-tocopherol considerably increased the rate of Cu(II) reduction. Cu(II) reduction by alpha-tocopherol-deficient LDL isolated from a patient with familial inherited vitamin E deficiency was found to occur much slower in comparison with LDL isolated from a donor with a normal plasma level of alpha-tocopherol. Initial rate of Cu(II) reduction by alpha-tocopherol-deficient LDL was found to be zero. Enriching LDL with ubiquinol-10 to concentrations close to those of alpha-tocopherol did not influence the reaction rate. When LDL was treated with ebselen to eliminate preformed lipid hydroperoxides, the reaction rate was also not changed significantly, Cu(II) reduction was accompanied by a consumption of lipoprotein alpha-tocopherol and accumulation of conjugated dienes in the samples. Increasing alpha-tocopherol content in lipoproteins slightly decreased the rate of conjugated diene accumulation in LDL and HDL and considerably increased it in VLDL. The results suggest that alpha-tocopherol plays a triggering role in the lipoprotein oxidation by Cu(II), providing its initial step as follows: alpha TocH + Cu(II) --> alpha Toc(.) + Cu(I) + H+. This reaction appears to diminish or totally eliminate the antioxidative activity of alpha-tocopherol in the course of lipoprotein oxidation.