Review ArticleVitamin E, antioxidant and nothing more
Introduction
Vitamin E was discovered in 1922 by Evans and Bishop as a necessary dietary factor for reproduction in rats [1]. Subsequent studies showed that the presence of rancid fat in the experimental diets fed to rats and chickens was the causative agent of various pathologies in these animals and that these abnormalities could be “cured” by wheat germ oil concentrates that later were demonstrated to contain tocopherols [2], [3], [4], [5], [6], [7], [8], work that has been reviewed by Wolf [9].
Given that most other vitamins have a cofactor function, are ligands for nuclear receptors, or have some unique molecular role, the search for a more specific vitamin E function has continued since its discovery. We propose the hypothesis that all of the observations concerning the in vivo mechanism of action of α-tocopherol result from its role as a lipid-soluble antioxidant. Why are the proofs of this hypothesis so scarce after more than 80 years research on vitamin E? If oxidized α-tocopherol accumulated, or even was excreted in detectable amounts, its role as an antioxidant could be readily demonstrated. Instead, the tocopheroxyl radical is formed during the antioxidant action, but then is reduced by other antioxidants and thus the ephemeral oxidation product of α-tocopherol does not remain to be measured. Although this concept of antioxidant interactions has been discussed and demonstrated in vitro [10], it is only recently that evidence has been obtained in humans for its existence [11]. Moreover, a combination deficiency of vitamin E and either selenium [12] or vitamin C [13] results in death to guinea pigs within days of the initiation of the second deficiency. These results highlight the importance of the multiple low molecular weight antioxidant systems necessary for vitamin E’s function.
The purpose of this review then is to describe the evidence for α-tocopherol’s in vivo function and to make the claim that α-tocopherol’s vitamin function, if not only function, is that of a peroxyl radical scavenger. The importance of this function is to maintain the integrity of long-chain polyunsaturated fatty acids in the membranes of cells and thus maintain their bioactivity. That is to say that these bioactive lipids are important signaling molecules and that changes in their amounts, or in their loss due to oxidation, or their oxidation products are the key cellular events that are responded to by cells. This hypothesis is supported by studies in plants where the genes for vitamin E synthesis have been knocked out. Sattler et al. [14] show that nonenzymatic lipid peroxidation products in the seedlings from these plants up-regulated genes, and they proposed that increased tocopherol levels in response to environmental stresses may limit nonenzymatic lipid peroxidation and thereby prevent the inappropriate induction of stress responses.
Section snippets
Regulation of α-tocopherol concentrations
Of the four tocopherols and four tocotrienols (designated as α-, β-, γ-, and δ-) found in food, only α-tocopherol meets human vitamin E requirements [15]. Despite the fact that all of these vitamin Es have similar antioxidant functions (rate constants for H-atom donation within an order of magnitude (Table 1)), non-α-tocopherols are poorly recognized by the hepatic α-tocopherol transfer protein (α-TTP) [16]. Moreover, defects in the human α-TTP [17] lead to severe vitamin E deficiency [18]. The
Vitamin E antioxidant activities
The curiosity is that all of the naturally occurring vitamin E forms, as well as those of synthetic all-rac-α-tocopherol, have relatively similar antioxidant activities, so why does the body prefer α-tocopherol as its form of vitamin E? Vitamin E’s antioxidant function, as a peroxyl radical scavenger that terminates chain reactions, is well-known and well-described by various chemists [44], [45], [46], [47], [48], [49], [50], [51], [52], [53], [54].
There are important differences between the
Human vitamin E deficiency
Human vitamin E deficiency symptoms began to be reported in the 1960s [69] in various case studies of patients with lipoprotein abnormalities and subsequently in fat malabsorption syndromes, but because these patients had malabsorption of other nutrients, especially long-chain fatty acids, it was not clear the extent to which various symptoms could be attributed to lack of vitamin E. In the early 1980s [70] case studies and various reports of unique humans with vitamin E deficiency symptoms
Cell proliferation and apoptosis: Protein kinase C
Cell proliferation and differentiation, along with apoptosis, are important cellular regulatory mechanisms that must be closely controlled. Protein kinase C (PKC) is a key signaling molecule involved in this regulation of growth and differentiation. The PKC family encompasses 12 different isozymes that transduce various signals as a result of receptor activation [83]. PKC is expressed in a variety of cells [84] and reportedly is inhibited by α-tocopherol [85], perhaps by activation of protein
Lipoxygenase and cyclooxygenase, prostaglandins, and arachidonic acid
Prostaglandins I2 (PGI2; prostacyclin) and E2 (PGE2) are cyclooxygenase (COX)-derived prostanoids that counteract and/or inhibit the secretion of vasoconstrictors such as thromboxane A2 (TXA2) [99]. Arachidonic acid, a long-chain polyunsaturated fatty acid, is a precursor of all of these molecules and vitamin E plays a key role in arachidonic acid availability by apparently regulating cytosolic phospholipase A2 (cPLA2) activity. In fact, Wu et al. [99] demonstrated that vitamin E increased PGE2
Cytokines and inflammation
The release of arachidonic acid from membranes and its cellular availability appear to be critical for the inflammatory responses of macrophages. Moller and Lauridsen [106] showed that dietary fish oil supplemented at a level of 5% of the diet, but not supplemental vitamin E, decreased the inflammatory responses of alveolar macrophages isolated from weaned pigs. Production of TNF-α, IL (interleukin)-8, LTB-4, and PGE2 was decreased with fish oil feeding, a difference likely caused by the
Nuclear receptors
The nuclear receptor superfamily of ligand-dependent transcription factors functions to regulate a diverse number of genes involved in reproduction, development, metabolism, and immune responses [113]. The ligands for about half of these nuclear receptors have not been identified, so are called “orphan” nuclear receptors. Specific members of the nuclear receptor superfamily bind fat-soluble vitamins A and D; thus, it is not unreasonable to expect that α-tocopherol might also function to control
Oxidative stress in humans
Does vitamin E act as an antioxidant in humans? In general, there are numerous studies showing that vitamin E supplements can decrease measures of lipid peroxidation in subjects with oxidative stress, examples include decreasing urinary F2-isoprostanes in hypercholesterolemic subjects [127] and in diabetics [128]. However, normal subjects not under oxidative stress showed no effect of vitamin E supplements on markers of oxidative damage [129]. We believe that the level of antioxidant protection
Conclusion
The thrust of this review is to propose the idea that the various signaling pathways that have been described by others to be under α-tocopherol regulation, appear rather to be dependent on the oxidative stress of the cell or tissue under question. Moreover, it seems unlikely that these pathways are specifically under the control of α-tocopherol given that various antioxidants and oxidative stressors can manipulate their responses. For example, regulation of the expression of the lipoprotein
Acknowledgments
M.G.T. has received support from NIH DK 067930. J.K.A. has received support from Discovery and Equipment Grants from the Natural Sciences and Engineering Research Council (NSERC) of Canada; NIH ES012249; Research Corporation, Cottrell College Science Award; and a Premier’s Research Excellence Award from the Province of Ontario.
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