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 -tocopherol concentrations. Enriching lipoproteins with -tocopherol considerably increased the rate of Cu(II) reduction. Cu(II) reduction by -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 -tocopherol. Initial rate of Cu(II) reduction by -tocopherol-deficient LDL was found to be zero. Enriching LDL with ubiquinol-10 to concentrations close to those of -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 -tocopherol and accumulation of conjugated dienes in the samples. Increasing -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 -tocopherol plays a triggering role in the lipoprotein oxidation by Cu(II), providing its initial step as follows: TocH + Cu(II) Toc + Cu(I) + H. This reaction appears to diminish or totally eliminate the antioxidative activity of -tocopherol in the course of lipoprotein oxidation.

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