Vitamin E, antioxidant and nothing more

Abstract

All of the naturally occurring vitamin E forms, as well as those of synthetic all-rac-α-tocopherol, have relatively similar antioxidant properties, so why does the body prefer α-tocopherol as its unique form of vitamin E? 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 potent lipid-soluble antioxidant. 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 major 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, are the key cellular events that are responded to by cells. 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 other than α-tocopherol and various oxidative stressors can manipulate their responses. Thus, virtually all of the variation and scope of vitamin E’s biological activity can be seen and understood in the light of protection of polyunsaturated fatty acids and the membrane qualities (fluidity, phase separation, and lipid domains) that polyunsaturated fatty acids bring about.

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.