Effect of a-tocopherol

The poor results with the two phenols were unexpected in view of their effectiveness as antioxidants in emulsions. R, Stadnick and A, Govil investigated the effect of a-tocopherol in a system identical to that used in the present study except for the absence of the oil phase (14), They found that after incubation for 90 hours, the recovery of nitrite in the presence of a-tocopherol was half that observed in its absence. 

Yeum, K.J. et al., The effect of a-tocopherol on the oxidative cleavage of P-carotene,... 

Tomwall, M.E. et al., Effect of a-tocopherol and P-carotene snpplementation on coronary heart disease during the 6-year post-trial foUow-up in the ATBC stndy, Eur. Heart]., 25, 1171, 2004. 

The potency of a chain-breaking antioxidant, which scavenges peroxyl radicals, will decrease as the concentration of lipid peroxides in the LDL particle increases (Scheme 2.2). This is illustrated in the experiment shown in Fig. 2.3 in which the antioxidant potency of a peroxyl radical scavenger (BHT) decreases as a function of added exogenous hpid hydroperoxide. If the endogenous lipid peroxide content of LDL were to vary between individuals, this could explain the observed diferences in the effectiveness of a-tocopherol in suppressing lipid peroxidation promoted by copper. 

Stohs, S.J., Hassan, M.Q. and Murray, W.J. (1984). Effects of a-tocopherol and retinol acetate on TCDD-mediated changes in lipid peroxidation, glutathione peroxidase activity and survival. Xenobiotica 14, 533-537. 

As mentioned previously, in the AMD retina iron metabolism is compromised (He et al., 2007 Wong et al., 2007). Thus, it is of interest to determine the effects of potential antioxidants in the presence of iron. In an in vitro study of ARPE-19 cells, addition of a lipophilic iron complex led to about a ninefold increase in the photosensitized yield of 7a,(3-cholesterol hydroperoxides (Wrona et al., 2004). In the presence of the iron, ascorbate exerted pro-oxidant effects, while the effects of a-tocopherol, zeaxanthin, or their combination were still protective (Wrona et al., 2004). Thus, it appears that the effects of potential antioxidants are strongly dependent on the sources of oxidative damage. The same antioxidant may be protective under certain conditions and exert deleterious effects when the conditions are changed. Therefore a detailed understanding of the sources of the oxidative damage is required in order to design an adequate antioxidant mixture. 

Belkner et al. [32] demonstrated that 15-LOX oxidized preferably LDL cholesterol esters. Even in the presence of free linoleic acid, cholesteryl linoleate continued to be a major LOX substrate. It was also found that the depletion of LDL from a-tocopherol has not prevented the LDL oxidation. This is of a special interest in connection with the role of a-tocopherol in LDL oxidation. As the majority of cholesteryl esters is normally buried in the core of a lipoprotein particle and cannot be directly oxidized by LOX, it has been suggested that LDL oxidation might be initiated by a-tocopheryl radical formed during the oxidation of a-tocopherol [33,34]. Correspondingly, it was concluded that the oxidation of LDL by soybean and recombinant human 15-LOXs may occur by two pathways (a) LDL-free fatty acids are oxidized enzymatically with the formation of a-tocopheryl radical, and (b) the a-tocopheryl-mediated oxidation of cholesteryl esters occurs via a nonenzymatic way. Pro and con proofs related to the prooxidant role of a-tocopherol were considered in Chapter 25 in connection with the study of nonenzymatic lipid oxidation and in Chapter 29 dedicated to antioxidants. It should be stressed that comparison of the possible effects of a-tocopherol and nitric oxide on LDL oxidation does not support importance of a-tocopherol prooxidant activity. It should be mentioned that the above data describing the activity of cholesteryl esters in LDL oxidation are in contradiction with some earlier results. Thus in 1988, Sparrow et al. [35] suggested that the 15-LOX-catalyzed oxidation of LDL is accelerated in the presence of phospholipase A2, i.e., the hydrolysis of cholesterol esters is an important step in LDL oxidation. 

The mechanism of prooxidant effect of a-tocopherol in aqueous lipid dispersions such as LDLs has been studied [22], This so-called tocopherol-mediated peroxidation is considered in detail in Chapter 25, however, in this chapter we should like to return once more to the question of possible prooxidant activity of vitamin E. The antioxidant effect of a-tocopherol on lipid peroxidation including LDL oxidation is well established in both in vitro and in vivo systems (see, for example, Refs. [3,4] and many other references throughout this book). However, Ingold et al. [22] suggested that despite its undoubted high antioxidant efficiency in homogenous solution a-tocopherol can become a chain transfer agent in aqueous LDL... 

Frankel, E.N. and Gardner, H.W. 1989. Effect of a-tocopherol on the volatile thermal decomposition products of methyl linoleate hydroperoxides. Lipids 24 603-608. 

Takenaka, Y., Miki, M., Yasuda, H., and Mino, M. 1991. The effect of a-tocopherol as an antioxidant on the oxidation of membrane protein thiols induced by free radicals generated in different sites. Arch. Biochem. Biophys. 285 344. 

Jialal I, Fuller CJ, Huet BA. The effect of a-tocopherol supplementation on LDL oxidation. Arteriosc Thromb Vase Biol 1995 15 190-198. 

An X-ray diffraction study on the effect of a-tocopherol on the phase behavior of dimyristoylphosphatidylethanolamine led to the following conclusions ... 

St. Laurent, A M., Hidiroglou, M., Snoddon, M., Nicholson, J.W.G. 1990. Effect of a-tocopherol supplementation to dairy cows on milk and plasma a-tocopherol concentrations and on spontaneous oxidized flavor in milk. Can. J. Anim. Sci. 70, 561-570. 

Fukuzawa, K., Chida, H., Akira,T., and Tsukatani, H. (1981), Autooxidative effect of a-tocopherol incorporation into lecithin hposomes on ascorbic acid Fe++-induced lipid peroxidation, Arch. Biochem. Biophys., 206,173-180. 

Most of these effects of vitamin E deficiency can be attributed to membrane damage. In deficiency, there is an accumulation of lysophosphatidylcholine in membranes, which is cytolytic. The accumulation of lysophosphatidylcholine is a result of increased activity of phospholipase A. It is not clear whether a-tocopherol inhibits phospholipase A whether there is increased phospholipase activity because of increased peroxidation of polyunsaturated fatty acids in phospholipids, and hence an attempt at membrane Upid repair or whether the physicochemical effects of a-tocopherol on membrane organization and fluidity prevent the cytolytic actions of lysophosphatidylcholine (Douglas et al., 1986 Erin et al., 1986). 

Kotegawa, M., Sugiyama M., Shoji, T., Haramaki N., Orgura, R. (1993). Effect of a-tocopherol on high energy phosphate metabolite levels in rat heart hy P-NMR using a Langendorff perfusion technique. J. Mol. Cell Cardiol. 25 1067-74. 

Punz, A., Nanobashvili, N., Feugl, A. et al. (1998). Effect of a-tocopherol pretreatment on high energy metabolites in rabbit skeletal muscle after ischemia-reperfusion. Clin. Nutr. 17 85-7. 

Paradoxically, chlorophyll was found to synergize the antioxidant effect of a-tocopherol in the dark (121), but chlorophyll degradation was found to contribute... 

In the sections below, a discussion of the effect of a-tocopherol at cellular level will be carried out, particularly focusing on the non-antioxidant properties shown by the molecule (Tables 1 and 2). 

Table 2. Effects of a-tocopherol and their supposed molecular mechanisms ...

In 1991 inhibition of PKC activity was found to be at the basis of the vascular smooth muscle cell growth arrest induced by a-tocopherol [16,17]. A number of reports have subsequently confirmed the involvement of PKC in the effect of a-tocopherol on different cell types, including monocytes, macrophages, neutrophils, fibroblasts and mesangial cells [8,18-20]. a-Tocopherol, but not P-tocopherol, was found to inhibit thrombin-induced PKC activation and endothelin secretion in endothelial cells [21]. a-Tocopherol, and not P-tocopherol or trolox, inhibits the activity of PKC fi-om monocytes, followed by inhibition of phosphorylation and translocation of the cytosolic factor p47(phox) and by an impaired assembly of the NADPH-oxidase and of superoxide production [22]. a-Tocopherol has the important biological effect of inhibiting the release of the proinflammatory cytokine, IL-lp, via inhibition of the 5-lipoxygenase pathway [23]. 

Inhibition of PKC by a-tocopherol in vascular smooth muscle cells is observed to occur at concentrations of a-tocopherol close to those measured in healthy adults [24]. P-Tocopherol per se is not very effective but prevents the inhibitory effect of a-tocopherol. The mechanism involved is not related to the radical scavenging properties of these two molecules, which are essentially equal [25]. In vitro studies with recombinant PKC have shown that inhibition by a-tocopherol is not caused by tocopherol-protein interaction, a-Tocopherol does not inhibit PKC expression as well. Inhibition of PKC activity by a-tocopherol occurs at a cellular level by producing dephosphorylation of the enzyme, whereby P-tocopherol is much less potent [26]. Dephosphorylation of PKC occurs via protein phosphatase PP2A, which is activated by the treatment with a-tocopherol [26-28]. 

The following questions remain open. In some cases differential effects of a-tocopherol and P-tocopherol have been found, pointing to a non-antioxidant mechanism at the basis of gene regulation [31,36]. In other cases, however, only a-tocopherol has been tested leaving the mechanism of a-tocopherol action unclarified. Furthermore, the... 

Ottino, P. Duncan, J.R. Effect of a-tocopherol succinate on free radical and lipid peroxidation levels in BL6 melanoma cells. Free Radical Biol. Med. 1997, 22, 1145-1151. 

---