Vitamin E in human low-density lipoprotein. When and how this antioxidant becomes a pro-oxidant

Abstract

Uptake of oxidatively modified low-density lipoprotein (LDL) by cells in the arterial wall is believed to be an important early event in the development of atherosclerosis. Because vitamin E is the major antioxidant present in human lipoproteins, it has received much attention as a suppressor of LDL lipid oxidation and as an epidemiological marker for ischaemic heart disease. However, a careful examination of lipid peroxidation in LDL induced by a steady flux of aqueous peroxyl radicals has demonstrated that, following consumption of endogenous ubiquinol-10, the rate of peroxidation (i) declines as vitamin E is consumed, (ii) is faster in the presence of vitamin E than following its complete consumption, (iii) is substantially accelerated by enrichment of the vitamin in LDL, either in vitro or by diet, and (iv) is virtually independent of the applied radical flux. We propose that perodixation is propagated within lipoprotein particles by reaction of the vitamin E radical (i.e. alpha-tocopheroxyl radical) with polyunsaturated fatty acid moieties in the lipid. This lipid peroxidation mechanism, which can readily be rationalized by the known chemistry of the alpha-tocopheroxyl radical and by the radical-isolating properties of fine emulsions such as LDL, explains how reagents which reduce the alpha-tocopheroxyl radical (i.e. vitamin C and ubiquinol-10) strongly inhibit lipid peroxidation in vitamin E-containing LDL.

Inverse deuterium kinetic isotope effect for peroxidation in human low‐density lipoprotein (LDL): a simple test for tocopherol‐mediated peroxidation of LDL lipids

“…Previous studies from this laboratory [12,15] (J. Neuzil, S.R. Thomas and R.S., unpublished) have demonstrated that the extent to which the pro-oxidant activity of ~-TOH in ascorbateand ubiquinol-10-free LDL is seen depends largely on the rate of peroxidation initiation (Ri) rather than the nature of the ~-TOH and Chl8:2-OOH (squares) were determined as described [21].…”

When and why a water-soluble antioxidant becomes pro-oxidant during copper-induced low-density lipoprotein oxidation: a study using uric acid

“…Furthermore, since α-tocopherol is an efficient Cu(II) reductant [14,30] and during this reaction it is rapidly consumed [34], the shift of the copper redox equilibrium toward Cu(I) would spare endogenous α-tocopherol and would make LDL more resistant to an oxidative attack. Additionally, it can be proposed that uric acid might act in synergism with α-tocopherol by reducing tocopheroxyl radical back to the parent compound.…”

“…In a number of very elegant studies Stocker and co-workers [14][15][16] have demonstrated that the antioxidant α-tocopherol may behave, under appropriate conditions, as pro-oxidant, thus paradoxically stimulating LDL oxidation promoted by a constant radical flow originating from the thermal decomposition of the azo-compound 2,2h-azobis-(2-amidino propane) hydrochloride (AAPH) or by low concentrations of copper. The pro-oxidant activity of α-tocopherol is mediated through the one-electron oxidation catalysed by peroxyl radicals or by the reductive activation of Cu(II) to Cu(I) with the concomitant formation of the α-tocopheroxyl radical which, in turn, may abstract a hydrogen atom from a polyunsaturated fatty acid in LDL, thus initiating a radical chain ultimately leading to extensive lipid peroxidation.…”

Mechanism of the antioxidant to pro-oxidant switch in the behavior of dehydroascorbate during LDL oxidation by copper(II) ions

“…Due to the epidemiological evidence indicating an inverse relationship between dietary fruit and vegetable intake and the incidence of cardiovascular disease [20,21], numerous studies have been undertaken to show that micronutrients provided by such diets, including α-tocopherol [22,23], ascorbic acid [24][25][26][27] and various flavonoids [28][29][30][31], can protect LDL from oxidative modification [32]. Under certain circumstances, however, they have been shown to display prooxidant activity.…”

“…Under certain circumstances, however, they have been shown to display prooxidant activity. Indeed, it has been suggested the α-tocopheroxyl radical, generated by the oxidation of α-tocopherol within LDL, is the species responsible for the initiation of lipid peroxidation in the particle [22,33,34].…”