Vitamin E is indispensible for reproduction in female rats. In humans, vitamin E deficiency primarily causes neurologic dysfunctions, but the underlying molecular mechanisms are unclear. Because of its antioxidative properties, vitamin E is believed to help prevent diseases associated with oxidative stress, such as cardiovascular disease, cancer, chronic inflammation, and neurologic disorders. However, recent clinical trials undertaken to prove this hypothesis failed to verify a consistent benefit. Given these findings, a group of European scientists met to analyze the most recent knowledge of vitamin E function and metabolism. An overview of their discussions is presented in this article, which includes considerations of the mechanisms of absorption, distribution, and metabolism of different forms of vitamin E, including the alpha-tocopherol transfer protein and alpha-tocopherol-associated proteins; the mechanism of tocopherol side-chain degradation and its putative interaction with drug metabolism; the usefulness of tocopherol metabolites as biomarkers; and the novel mechanisms of the antiatherosclerotic and anticarcinogenic properties of vitamin E, which involve modulation of cellular signaling, transcriptional regulation, and induction of apoptosis. Clinical trials were analyzed on the basis of the selection of subjects, the stage of disease, and the mode of intake, dosage, and chemical form of vitamin E. In addition, the scarce knowledge on the role of vitamin E in reproduction was summarized. In conclusion, the scientists agreed that the functions of vitamin E were underestimated if one considered only its antioxidative properties. Future research on this essential vitamin should focus on what makes it essential for humans, why the body apparently utilizes alpha-tocopherol preferentially, and what functions other forms of vitamin E have.

Molecules in biological systems often can perform more than one function. In particular, many molecules have the ability to chemically scavenge free radicals and thus act in the test tube as antioxidant, but their main biological function is by acting as hormones, ligands for transcription factors, modulators of enzymatic activities or as structural components. In fact, oxidation of these molecules may impair their biological function, and cellular defense systems exist which protect these molecules from oxidation. Vitamin E is present in plants in 8 different forms with more or less equal antioxidant potential (alpha-, beta-, gamma-, delta-tocopherol/tocotrienols); nevertheless, in higher organisms only alpha-tocopherol is preferentially retained suggesting a specific mechanism for the uptake for this analogue. In the last 20 years, the route of tocopherol from the diet into the body has been clarified and the proteins involved in the uptake and selective retention of alpha-tocopherol discovered. Precise cellular functions of alpha-tocopherol that are independent of its antioxidant/radical scavenging ability have been characterized in recent years. At the posttranslational level, alpha-tocopherol inhibits protein kinase C, 5-lipoxygenase and phospholipase A2 and activates protein phosphatase 2A and diacylglycerol kinase. Some genes (e. g. scavenger receptors, alpha-TTP, alpha-tropomyosin, matrix metalloproteinase-19 and collagenase) are modulated by alpha-tocopherol at the transcriptional level. alpha-Tocopherol also inhibits cell proliferation, platelet aggregation and monocyte adhesion. These effects are unrelated to the antioxidant activity of vitamin E, and possibly reflect specific interactions of alpha-tocopherol with enzymes, structural proteins, lipids and transcription factors. Recently, several novel tocopherol binding proteins have been cloned, that may mediate the non-antioxidant signaling and cellular functions of vitamin E and its correct intracellular distribution. In the present review, it is suggested that the non-antioxidant activities of tocopherols represent the main biological reason for the selective retention of alpha-tocopherol in the body, or vice versa, for the metabolic conversion and consequent elimination of the other tocopherols.

This study indicates that CD36 is expressed in cultured human SMCs. In these cells, CD36 transports oxLDL into the cytosol. alpha-Tocopherol inhibits oxLDL uptake by a mechanism involving downregulation of CD36 mRNA and protein expression. Therefore, the beneficial effect of alpha-tocopherol against atherosclerosis can be explained, at least in part, by its effect of lowering the uptake of oxidized lipoproteins, with consequent reduction of foam cell formation.

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Since the discovery of vitamin E in 1922, its deficiency has been associated with various disorders, particularly atherosclerosis, ischemic heart disease, and the development of different types of cancer. A neurological syndrome associated with vitamin E deficiency resembling Friedreich ataxia has also been described. Whereas epidemiological studies have indicated the role of vitamin E in preventing the progression of atherosclerosis and cancer, intervention trials have produced contradictory results, indicating strong protection in some cases and no significant effect in others. Although it is commonly believed that phenolic compounds like vitamin E exert only a protective role against free radical damage, antioxidant molecules can exert other biological functions. For instance, the antioxidant activity of 17-beta-estradiol is not related to its role in determining secondary sexual characters, and the antioxidant capacity of all-trans-retinal is distinguished from its role in rhodopsin and vision. Thus, it is not unusual that alpha-tocopherol (the most active form of vitamin E) has properties independent of its antioxidant/radical scavenging ability. The Roman god Janus, shown in ancient coins as having two faces in one body, inspired the designation of 'Janus molecules' for these substances. The new biochemical face of vitamin E was first described in 1991, with an inhibitory effect on cell proliferation and protein kinase C activity. After a decade, this nonantioxidant role of vitamin E is well established, as confirmed by authoritative studies of signal transduction and gene regulation. More recently, a tocopherol binding protein with possible receptor function has been discovered. Despite such important developments in understanding the molecular mechanism and the targets of vitamin E, its new Janus face is not fully elucidated. Greater knowledge of the molecular events related to vitamin E will help in selecting the parameters for clinical intervention studies such as population type, dose response effects, and possible synergism with other compounds.

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Vitamin E deficiency increases expression of the CD36 scavenger receptor, suggesting specific molecular mechanisms and signaling pathways modulated by ␣-tocopherol. We show here that ␣-tocopherol down-regulated CD36 expression (mRNA and protein) in oxidized low density lipoprotein (oxLDL)-stimulated THP-1 monocytes, but not in unstimulated cells. Furthermore, ␣-tocopherol treatment of monocytes led to reduction of fluorescent oxLDL-3,3-dioctadecyloxacarbocyanine perchlorate binding and uptake. Protein kinase C (PKC) appears not to be involved because neither activation of PKC by phorbol 12-myristate 13-acetate nor inhibition by PKC412 was affected by ␣-tocopherol. However, ␣-tocopherol could partially prevent CD36 induction after stimulation with a specific agonist of peroxisome proliferator-activated receptor-␥ (PPAR␥; troglitazone), indicating that this pathway is susceptible to ␣-tocopherol action. Phosphorylation of protein kinase B (PKB) at Ser 473 was increased by oxLDL, and ␣-tocopherol could prevent this event. Expression of PKB stimulated the CD36 promoter as well as a PPAR␥ element-driven reporter gene, whereas an inactive PKB mutant had no effect. Moreover, coexpression of PPAR␥ and PKB led to additive induction of CD36 expression. Altogether, our results support the existence of PKB/PPAR␥ signaling pathways that mediate CD36 expression in response to oxLDL. The activation of CD36 expression by PKB suggests that both lipid biosynthesis and fatty acid uptake are stimulated by PKB.In many cell types, oxidized low density lipoproteins (oxLDL) 2 modulate cellular processes such as apoptosis, adhesion, migration, gene expression, and the induction of signal transduction cascades (1). Exposure of monocytes to oxLDL may alter gene expression and signaling, making them more susceptible to the following pro-atherogenic stimuli. The migration of monocytes into the intima and the conversion of monocytes/macrophages into foam cells represent initial steps in atherosclerosis. Current strategies to prevent atherosclerosis are aimed either at lowering the cholesterol load of lipoproteins or at reducing oxidative stress.Vitamin E is a redox-active natural compound that can act, depending on the conditions, as a pro-or antioxidant on low density lipoproteins (LDL) in vitro and in vivo (2-5). The major form of vitamin E in human plasma is ␣-tocopherol, and reduced plasma levels of ␣-tocopherol, such as in vitamin E-deficient mice, increase the incidence of atherosclerosis (6). Animal and cell culture studies strongly suggest that vitamin E can prevent atherosclerosis; however, the anti-atherogenic effects in clinical trials are still controversial (7-10). ␣-Tocopherol in lipoproteins (mainly LDL) and also in the subendothelial space has been assumed to play a central role in reducing atherosclerosis by preventing lipid peroxidation and consequent lesion development. Nevertheless, since many compounds exist that can interfere with the oxidation of LDL without being equally effective, alternative modes of action have bee...