Requirement for, Promotion, or Inhibition by α-Tocopherol of Radical-Induced Initiation of Plasma Lipoprotein Lipid Peroxidation

α-Tocopherol (α-TOH), generally regarded as the most important lipid-soluble, chain-breaking antioxidant in human plasma, can also be a pro-oxidant in isolated low-density lipoprotein (LDL) (Bowry V. W.; Stocker R. J. Am. Chem. Soc. 115:6029–6044; 1993). Here we examined whether this pro-oxidant activity of α-TOH is of more general relevance. We compared the oxidizability of lipid hydroperoxide-free, in vivo or in vitro α-TOH–depleted LDL and high-density lipoprotein (HDL), as well as plasma reconstituted with α-TOH–depleted lipoproteins, with that of the corresponding native and α-TOH–supplemented samples, using water- and lipid-soluble peroxyl radicals (ROO·), hydroxyl radicals (·OH), Cu2+, the transition metal-containing Hamʹs F-10 medium, soybean 15-lipoxygenase, and horseradish peroxidase as oxidants. Lipoprotein and plasma oxidizability was assessed by the loss of cholesteryl esters and α-TOH and the accumulation of hydroperoxides of cholesteryl esters and phospholipids. Compared to native LDL, HDL, and plasma, the in vivo and in vitro α-TOH–depleted counterparts were highly resistant to peroxidation initiation by all oxidants when used at mild radical flux conditions. Wherever tested, the oxidizability of isolated LDL decreased proportionally with decreasing α-TOH content. Initiation of LDL lipid oxidation by lipoxygenase and Cu2+ (even up to Cu2+:LDL ratio of 20:1) had an absolute requirement for α-TOH. Oxidation of reconstituted plasma with ROO· showed that in the absence of the vitamin, plasma lipids were largely resistant to oxidation, whereas bilirubin and urate oxidized more rapidly. Replenishing the in vitro depleted LDL with α-TOH, but not with α-tocopherol acetate, fully restored its original content of vitamin E and its oxidizability. Similarly, dietary supplementation with α-TOH restored the vitamin content and oxidizability of the in vivo α-TOH–depleted lipoproteins and plasma obtained from a patient with familial isolated vitamin E deficiency. Under high fluxes of ROO· and ·OH, the activity of α-TOH in LDL switched from pro- to anti-oxidant, with the switching point for ·OH observed at a lower radical flux than that for ROO·. Together, our results show that α-TOH generally makes lipoproteins more reactive towards radical oxidants; this can result in a pro-oxidant activity depending on the specific oxidation conditions. Copyright © 1996 Elsevier Science Inc.