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Vitamin E is a term used to refer to eight molecules, which are divided into two categories: tocopherols and tocotrienols. Each category is further divided up into alpha (α), beta (β), gamma (γ), and delta (δ) vitamers. The vitamer α-tocopherol is considered to be the ‘main’ vitamer, but the gammas (γ-tocopherol and γ-tocotrienol) are also popular research topics, due to their presence in the diet. Collectively, these compounds are called vitamin E. Vitamin E supplements almost always contain α-tocopherol.
The majority of vitamin E’s benefits come from avoiding a deficiency, but there are several instances where supplementation can offer additional benefits. Supplementing α-tocopherol is able to improve T-cell mediated immune function, which boosts the immune system.
Vitamin E also seems to be able to enhance the body’s antibody response to vaccinations. Vitamin E supplementation is particularly important for the elderly, since a deficiency is associated with a higher risk of bone fractures. Supplementing additional vitamin E, however, will not provide additional benefits to bone health. Vitamin E may also be able to protect against age-related cognitive decline, but further research is needed before supplementation can be recommended specifically for Alzheimer’s and Parkinson’s treatment.
Vitamin E was one of the first two antioxidant compounds to be sold as dietary supplements, the second being Vitamin C. It is sometimes used as the ‘reference’ antioxidant compound when fat soluble compounds are being researched. Vitamin E may function as a signaling molecule within cells and for phosphate groups.
Since the majority of vitamin E’s benefits are associated with low doses slightly above the Recommended Daily Allowance (RDA), vitamin E supplementation is not always necessary. Dietary changes can singlehandedly prevent a vitamin E deficiency and eliminate the need for supplementation. Sesame seeds in particular contain a lot of tocotrienols, as well as Sesamin, which improves the retention of vitamin E. Vitamin E is safe to supplement, but it should not be mixed with coumarin-based anticoagulants like warfarin.
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Maintaining adequate levels of vitamin E in the body can be achieved through very low daily doses of 15mg (22.4 IU) or less. This dose of vitamin E can be acquired through the diet, making supplementation unnecessary in many cases. An elderly person supplementing vitamin E to improve immunity should take a 50-200mg dose.
Vitamin E supplements should contain α-tocopherol. Avocados, olives, vegetable oils and almonds are all high in vitamin E.
Vitamin E's antioxidant properties are improved when taken with unsaturated dietary fat. The minimum intake of vitamin E is 1 IU per gram of saturated fat. The ideal range is between 2-4 IU per gram of saturated fat.
Vitamin E can be quantified by weight (mg) or bioactivity (International Units, or IU). This is due to all forms of vitamin E not sharing the same bioactivity.
Out of all forms of vitamin E, the liver tends to target α-tocopherol most for incorporation into lipoproteins. This is also the specific isomer commonly used in studies to reverse deficiency symptoms and has the highest bioavailability.
Alpha-Tocopherol is used as a signalling molecule and is able to inhibit smooth muscle cell proliferation, decrease Protein kinase C (PKC, an enzyme family that plays a role in signal transduction) activity in cells, increase phosphoprotein phosphatase 2A activity, and regulate the the α-tropomyosin gene. The inhibition of PKC may be secondary to reducing levels of diacylglycerol (a PKC activator) leaked from the membrane and requires vitamin E to be a constituent of the membrane, which indicates a more chronic inhibition rather than acute.
Vitamin E can also regulate the expression of some pro-thrombotic and atherogenic factors and may be secondary to upregulation of Phospholipase A2 and CycloOxygenase enzymes. These effects may explain why vitamin E has been shown to dose-dependently increase prostacyclin levels in vivo.
Vitamin E requirements tend focus on a plasma concentration range of 12-46µM, resulting in the recommended dietary intake being (according to the NIH) 15mg of natural α-tocopherol or 22.4 international units (IU) for persons over the age of 14 regardless of sex. While the recommendations appear to be based exclusively on α-tocopherol equivalents, there are differences between natural sources providing RRR-α-tocopherol (where 15mg is recommended, as 1mg is equivalent to 1.67IU) and synthetic all-rac α-tocopherol (where 10mg is recommended, as 1mg is equivalent to 2.22IU).
The daily recommended intake of vitamin E, as α-tocopherol, is slightly above 20 international units (IU). While synthetic vitamin E appears to have a lower overall requirement, the difference is controlled for when measuring vitamin E in international units
Overt deficiencies are rare, and are usually due to genetic defects in the transport proteins responsible for Vitamin E) or complete malabsorption secondary to alcoholism or intestinal diseases such as Crohn's or cystic fibrosis (without enzyme therapy).
True vitamin E deficiencies in an otherwise healthy population are rare if not unheard of, with almost all cases of vitamin E deficiency being noted in disease states where fatty acid absorption from the intestines is significantly impaired (e.g. Crohn's)
The tolerable upper limit (TUL) for vitamin E intake is 800mg (1,200 IU) for persons between the ages of 14-18 and 1,000mg (1,500 IU) for adults, with no changes in adult females due to pregnancy or lactation.
Vitamin E is found in nature in 8 different forms. The tocopherols (where alpha(α), beta(β), gamma(γ) and delta(δ) variants exist) and the tocotrienols (same alpha(α), beta(β), gamma(γ) and delta(δ) variants). All forms are biologically active, although α-tocopherol is commonly seen as the most bioactive form and the true 'essential vitamin' as it has preference for a particular transporation protein known as tocopherol transfer protein (TTP) which brings orally supplement Vitamin E in the liver to other tissues in the body.
Tocotrienols can be transported in the blood, since their elevation in the blood following oral administration is present (and faster than tocopherols at an equal dose) and they can be detected in serum platelets and adipose tissue following oral ingestion. There also appears to be less efflux from tissues with tocotrienols (suggesting a greater reliance for loading and chronic effects), but it is still possible for the benefits associated with tocotrienols seen in vitro to be overstated due to transportation issues.
'Vitamin E' refers to vitamers (isomers of a vitamin) that share structural and functional similarities, and while only the form known as α-tocopherol is an essential vitamin all of the vitamers have biological functions. There are also some differences in transportation of these vitamers to tissues, although they all seem to be able to influence peripheral tissue beyond the liver.
The terms 'natural' and 'synthetic' vitamin E appear to be legitimate terms, as Vitamin E that occurs in food tends to be an RRR configuration (RRR-α-tocopherol usually used as the abbreviation) whereas synthetic Vitamin E commonly used in supplements exists as eight isomers of α-tocopherol abbreviated as all-rac-α-tocopherol due to having multiple chiral centers.
Synthetic α-tocopherol tends to have 50% of the affinity for the tocopherol transport protein (TTP) as does natural and when comparing bodily retention of α-tocopherol it seems that when natural and synthetic are both ingested (150mg each) that the synthetic is more readily eliminated via nonoxidative metabolism; due to these reasons, it is thought that natural vitamin E is more readily available to the body.
Natural vitamin E food sources (not so much dietary supplements of pure α-tocopherol) may also contain tocotrienols in its mixture, whereas synthetic Vitamin E does not contain tocotrienols and is limited to the essential α-tocopherol vitamer; this is more of a concern to food intake which is mixed vitamers, since a supplement standardized for α-tocopherol will not containg tocotrienols regardless of whether it is natural or synthetic.
There does appear to be a difference between 'natural' and 'synthetic' Vitamin E even when it is pure α-tocopherol, as the synthetic form is a mixture of four isomers whereas the natural form consists of α-tocopherol (RRR-α-tocopherol) rather than the mixture. Depending on the source, natural vitamin E sources may also include other vitamers and tocotrienols whereas the synthetic version does not.
γ-tocopherol is the other majorly researched tocopherol (most research is conducted on α-tocopherol with less on beta and delta) in part due to it being the highest dietary source in the american diet via flour and vegetable oil products. It does have the ability to exert vitamin-like properties in the deficient animal, although as it is approximately 7-13% the potency of α-tocopherol the increased content in the diet is only hypothesized to account for up to 20% of vitamin E-like activity in the human diet.
γ-tocopherol is known to have its concentrations in serum decline when α-tocopherol by itself is supplemented (1,200IU all-rac α-tocopherol over eight weeks reducing serum γ-tocopherol to 30-50% of baseline) and the two have somewhat of an inverse relationship in serum where elevating α-tocopherol concentrations are correlated with lower γ-tocopherol concentrations. This antagonistic relationship has also been noted with β-tocopherol, being reduced with supplemental α-tocopherol at 1,200IU.
γ-Tocopherol has been shown to exert a 'trapping' effect on nucleophilic mutagens (mutation causing agents) and aids in the chemoprotective properties of the anti-oxidant system Glutathione.
It appears to have its efficacy in chemoprotection reduced when paired with alpha-tocopherol.
Of the tocopherols, γ-tocopherol is investigated to a large degree both independently and in the context of α-tocopherol supplements.
Tocotrienols are named as such since they possess 3 double bonds in their isoprenoid side chains whereas tocopherols only possess two.
Tocotrienols can be seen as more potent than tocopherols in vitro in regards to their anti-oxidant properties directly and vicariously through selenoproteins, at inducing apoptosis and protecting against some forms of cancer, and at neuroprotection. In vivo, tocotrienols appear to be more potent than tocopherols for prevention of certain cancers, for antioxidation as well as anti-inflammation, and better protection of bone health.
Vitamin E has been known to inhibit PKC activation in immune cells such as macrophages, blood platelets, and other cells within tissue such as aortic cells. Secondary to suppressing PKC in macrophages (resulting in less PGE2 secretion) this may also influence T-cell function.
Vitamin E appears to have a suppressive role on diacylglycerol (DAG) concentrations within a cell, having been implicated in suppressing increases in DAG and promoting its clearance by reducing its release from the membrane (where DAG is stored) and increasing the activity of DAG kinase respectively. Since DAG positively influences PKC activity, its reduced activity is thought to underlie the suppressive effects of vitamin E on PKC.
Vitamin E appears to be a PKC inhibitor, secondary to reducing the DAG-induced increases in PKC activity. This appears to extend to numerous cell lines, and appears to be relevant to oral consumption of vitamin E supplements (implicated in the benefits of vitamin E and immunology in the elderly)
When in the intestines, all vitamin E isomers are almost exclusively taken up via chylomicrons and esters (ie. vitamin E acetate) are hydrolyzed either in the intestines or stomach acid prior to absorption. Vitamin E does not appear to be reesterified after absorption and studies in serum and cerebrospinal fluid confirm the lack of esterified vitamin E (unlike vitamin A or cholesterol, which are reesterified after absorption).
Absorption appears to be increased in the presence of medium chain triglycerides as more vitamin E appears in lymphatic tissue, When comparing the absorption rates and processes of α-tocopherol against γ-tocopherol in rat studes, there do not appear to be any significant differences at the intestinal level.
Similar to most fat-soluble nutrients as well as dietary long chain fatty acids, vitamin E isomers are absorbed from the intestines into lymph tissue via chylomicrons which then distribute vitamin E to circulation
Lymphatic transportation in the intestines plays a vital role in absorption of lipophilic drugs and nutrients. The absorption of such drugs into lymphatic transport can be enhanced with the addition of bile acids and some surfactants such as Cremaphor EL or Tween 80 particularly in the presence of chylomicrons which are required for transportation via lymph. A variant of Vitamin E known as Vitamin E-TPGS (polyethylene glycol 1000 succinate), beyond its emulsifying properties, appears to enhance the bioavailability of a variety of water insoluble drugs such as paclitaxel. This is thought to be related to its surfactant properties and inducing secretion of chylomicrons at concentrations of 0.1-0.5%.
Water soluble vitamin E (Vitamin E-TPGS) appears to have the ability to enhance the absorption of fat-soluble drugs when coingested, thought to be due to enhancing secretion of chylomicrons (which are required to transport fat-soluble drugs)
Vitamin E succinate appears to yield free vitamin E following topical application in the mouse, with conversion rates being noted to be approximately 6% after 24 hours of absorption. This conversion rate is similar to what has been noted in the mouse with Vitamin E acetate (5-6%).
Vitamin E in the forms of acetate and succinate both appear to be absorbed through the skin (better absorption with an appropriate vehicle) and, despite being limited, can convert into free form Vitamin E
Oral ingestion of pure α-tocopherol supplements is known to dose-dependently reduce circulating concentrations of γ-tocopherol, with a 36-42% increase in basal α-tocopherol being met with a 28-61% reduction in γ-tocopherol. This reduction in γ-tocopherol also seems to extend to red blood cells when they experience an increase in α-tocopherol, and has been repeatedly noted either inherently or when combined with Fish Oil supplementation. Supplementation of γ-tocopherol in isolation (100mg) conversely does not reduce circulating α-tocopherol concentrations.
It is thought that the reduction in serum γ-tocopherol comes secondary to α-tocopherol inducing secretion of vLDL particles rich in α-tocopherol, as there does not appear to be competitive inhibition in the absorption of the two molecules from the intestines.
Phospholipid transfer protein (PLTP) is a plasma protein appears to have a role in distributing vitamin E from lipoproteins towards tissue, as a deficiency of this protein results in accumulation of α-tocopherol in lipoproteins at the cost of the vascular wall and reduces vitamin E donation to the brain as well where it is expressed at high levels.
PLTP plays a role in donating vitamin E from lipoproteins (its initial transportation around the body) towards body tissue
Oral consumption of mixed tocotrienols from rice brain (90% γ-tocotrienol) have been noted to increase skin concentrations of tocotrienols in mice when dosed orally at 1mg/kg over the course of one week, increasing baseline concentration of γ-tocotrienol from 0.4+/-0.1nM/g to 27.9+/-1.4nM/g; this increase did not negatively influence α-tocopherol concentrations in the skin.
At least in mice, oral supplementation of low doses of tocotrienols appears to greatly increase the concentration of tocotrienols found in the skin
Vitamin E isomers can be detected in cerebrospinal fluid (CSF) where concentrations of vitamin E as α-tocopherol in CSF have been reported to be in the range of 30.1+/-11.6nM (persons with ALS), 42.1+/-17nM (otherwise healthy controls), and 56.7+/-28.4nM (Alzheimer's) while in studies comparing CSF concentrations to serum there appears to be a significant correlation between the two which is not affected by age nor cholesterol levels in serum; CSF concentrations of α-tocopherol appear to be 580-fold lower than serum (42.1nM in CSF relative to 21.7µM) and γ-tocopherol which also shares a correlation between CSF and serum is more than 1000-fold lower in CSF (5.9nM relative to 6.29µM in serum). The known serum relationship between these two isomers (acute doses of α-tocopherol reducing γ-tocopherol concentrations) may also apply to CSF concentrations.
Vitamin E isomers are detected in human cerebrospinal fluid, and despite their concentrations being lower than that found in serum they seem to correlate with serum. Correlations between the isomers themselves seen in serum may also extend to cerebrospinal fluid
Vitamin E (tocopherols) appear to be metabolized by the CYP3A enzyme, and a function of this enzyme known as ω-hydroxylation has been dubbed tocopherol-ω-hydroxylase; this function metabolizes tocopherols into their metabolites known as carboxyethyl-hydroxychromans (CEHCs). This particular function of the enzyme is a molecular target of the lignan Sesamin, which acts to inhibit the metabolism and increase endogenous tocopherol concentrations. This process also applies to tocotrienols (forming CEHC metabolites in accordance with their isomer) and is known as nonoxidative metabolism. These metabolites ultimately appear in the urine as glucuronides or sulfated metabolites (indicative of Phase II metabolism after the initial CYP3A mediated step).
In accordance with nonoxidative metabolism, when CEHC is reduced in the urine despite vitamin E intake being held constant or supplement it is thought to be representative of increased oxidation in the body (directing vitamin E to oxidative metabolism rather than nonoxidative). CEHC metabolism of -tocopherol doesn't occur to a significant degree when persons are not supplement and are below the range of 30-40μM, and the reduced dose-dependent responses of tocopherols in plasma as a result of supplementation are thought to be due to increased nonoxidative metabolism.
Vitamin E vitamers appear to be metabolized by a CYP3A mediated function into carboxyethyl-hydroxychroman derivatives (CEHCs), and this metabolism occurs to both tocopherols and tocotrienols. This metabolism is nonoxidative, and when CEHCs increase or decrease in the urine (if vitamin E intake is held constant) it is thought to reflect either no additional antioxidant effects or increased oxidation respectively
Tocotrienols (α and γ) also appear to be metabolized and excreted in the urine as carboxyethyl-hydroxychroman (CEHC) derivatives similar to the tocopherols, with 1-2% of the oral dose of α-tocotrienol (125-500mg) and 4-6% of the oral dose of γ-tocotrienol (125-500mg) being detected in the urine one day after supplementation. The elimintation pattern of γ-CEHC from tocotrienol ingestion is approximately 10% after 9 hours of ingestion which is similar to that from gamma-tocopherol.
A small amount of the CEHC derivatives from vitamin E are eliminated in the urine
Exposure to lead is known to cause prooxidative stress in the organism and although α-tocopherol seems unaffected increasing lead concentration has been assocaited with reduced γ-tocopherol levels in serum.
Vitamin E has been shown to have protective effects against lead in rat models on neurological, testicular, and liver damage while supplementation of 400IU Vitamin E (α-tocopherol) paired with 1,000mg Vitamin C supplementation to lead exposed workers with elevated concentrations of lead in the blood appears to be able to reduce the lead-induced oxidative changes in serum and red blood cells, but this protective effect was without any changes in bodily lead levels.
The increased oxidative stress seen alongside higher than normal blood concentrations of lead (from occupational exposure) appears to be reduce with antioxidant therapy; noted elsewhere with N-Acetylcysteine by itself while vitamin E and C combination therapy also appeared beneficial. This benefit does not appear to be due to reducing lead accumulation in the body
Vitamin E (α-tocotrienol) appear to be able to inhibit glutamate-induced phospholipase A2 (PLA2; the protein which releases eicosanoids) activation resulting in less arachidonic acid release, and may also reduce the activation of 5-LOX in response to neuronal injury which would bioactivate said arachidonic acid. This occurs at a concentration of 250nM resulting in neuroprotection, (4 to 10-fold lower than plasma levels of α-tocotrienol from oral supplementation of 250mg) and is due to less phosphorylation of Ser505 (on PLA2) from glutamate.
This neuroprotection is not seen with α-tocopherol, the major vitamin E isomer, indicating a benefit due to the tocotrienol sidechain which is classically seen as a more potent antioxidant.
α-tocotrienol has been noted to reduce glutamate induced release of eicosanoids (the signalling molecules in a cell produced from Fish Oil and Arachidonic acid) and neuroprotection from concentrations of glutamate seen as toxic to the cell, secondary to inhibiting the enzyme mediating the release of the fatty acids from the membrane. This may occur at a concentration low enough to be influenced by supplementation
A diet deficient in vitamin E over the course of twelve weeks has not resulted in significantly altered synthesis or release of serotonin in rats, although there may be mild alterations in the intracellular/extracellular ratio within 15-21 days with both the prefrontal cortex and hippocampus being implicated, these changes seem to be normalized after twelve weeks.
There do not appear to be any long-term abnormalities in serotonin metabolism associated with vitamin E deficiency
Despite it's anti-clotting mechanisms, vitamin E supplementation (at 50mg) does not appear to protect the body significantly from strokes in normal populations but could potentially be of use in those with significantly high blood pressure. Those without high blood pressure may experience a greater risk for hemorrhagic stroke when exceeding the RDA with supplementation.
The pro-hemorrhagic effects may be more chronic than acute though, as even 800IU of vitamin E does not affect blood clotting factors for short durations (14 days).
Inducing vitamin E deficiency in the rat (via ablating α-tocopherol transport protein or via a deficient diet) can caused anxiety symptoms, and other instances where genes are ablated which result in significantly less α-tocopherol in the brain also result in anxiety symptoms. This increase in anxiety is seen alongside elevated corticosterone concentrations in serum both at rest and after anxiety testing relative to control.
A large study of 600 IU Vitamin E supplementation (one dose every other day) in otherwise healthy women over the age of 65 spanning an average of 5.6 years failed to find any benefit of Vitamin E supplementation relative to placebo in improving cognitive parameters including verbal memory, categorical fluency, and general cognition relative to placebo.
One study in diabetics (type I and II) given high dose α-tocopherol supplementation at 1,600 IU for the course of one year failed to find any significant changes in left ventricular function relative to placebo.
In otherwise healthy men given supplemental α-tocopherol, the rise in plasma α-tocopherol and subsequent decrease in plasma γ-tocopherol was reflected in red blood cells which experienced similar changes; both required four weeks of constant supplementation to reach peak concentrations.
Low density lipoproteins (LDL) are a form of cholesterol susceptable to oxidation (as up to half the fatty acids are polyunsaturated which are more susceptable to oxidation), which triggers changes in the LDL structure that make it more conducive to form plaque in arteries; the oxidation of LDL shows a pathological role in cardiovascular disease pertaining to atherosclerosis, and supplements which reduce the oxidation of LDL (such as Olive leaf extract) are thought to be highly protective. Due to the oxidized portions being fatty acids and vitamin E reducing lipid peroxidation, it is thought that vitamin E (and other chain breaking fat soluble antioxidants) play a particularly protective role. Vitamin E is also inherently present in LDL particules as the predominant antioxidant.
Oral supplementation of high dose vitamin E as α-tocopherol (1,000 IU) has been noted to increase the -tocopherol content of LDL particules in type I diabetics by 127%.
Homocysteine is an independent biomarker for cardiovascular disease risk particular to atherosclerosis, and due to a preliminary study in arthritic rats where supplemental vitamin E reduced homocysteine and the mechanism of homocysteine being oxidative the potential protective effects of vitamin E have been investigated further.
Human evidence assessing homocysteine concentrations in hyperlipidemic smokers have not found relations with dietary vitamin E intake nor does supplementation of vitamin E to otherwise healthy athletes influence homocysteine concentrations.
Despite preliminary evidence in rodents, supplementation of vitamin E does not appear to significantly reduce homocysteine concentrations
There appears to be a correlation based on epidemiological research between sufficient vitamin E intakes and a reduced risk of heart disease, thought to be related to either reduced LDL oxidation (and thus atherogenic formation) or from an increase in prostacyclin concentrations (antiatherosclerotic as well as vasorelaxants).
The augmentation index (thought to reflect arterial stiffness) appears to be improved in otherwise healthy males given 160mg of mixed tocotrienols daily for two months by 5.3%, although lower (80mg) and higher (320mg) doses were not effective on this parameter.
When looking at diabetics, high dose vitamin E as α-tocpherol (1,600 IU) has failed to improve blood flow after eight weeks of supplementation relative to placebo and has been implicated in worsening blood flow mildly when continued at this dose for one year.
A study in otherwise healthy young males given tocotrienol supplementation at one of three doses (80, 160, or 320mg) daily for two months noted that the two higher doses were associated with mild reductions in aortic systolic blood pressure of around 5%.
Unlike red and white blood cells which experienced a peak concentration and subsequent plateau of vitamin E concentrations after four weeks of supplementation, platelets appears to require a full twelve weeks to reach maximal concentrations.
Vitamin E has been noted to inhibit platelet aggregation in vitro, leading to both its investigation into protecting against thrombosis (clots leading to heart attacks) but also concerns for excessive bleeding when overdosed or paired with other anticoagulants.
The decrease in platelet aggregation may occur independent of any changes in lipid peroxidation in serum, with the actions within platelets being related to Nitric Oxide (NO) release (NO inherently inhibits platelet aggregation) due in part to suppressing superoxide release. Although superoxide (a radical) can sequester NO leading to less NO activity and thus platelet aggregation, the suppression of superoxide from vitamin E does not appear to be related to its antioxidant actions as it appears that α-tocopherol inhibits PKC in platelets as PKC-dependent phosphorylation of the enzyme which makes NO (eNOS) reduces its activity and vitamin E attenuates this process at 500-1,000µM.
Vitamin E (α-tocopherol) is able to inhibit PKC in platelets, which then leads to less platelet aggregation and is a mechanism not related to the antioxidant properties of vitamin E
Intravenous infusions of vitamin E have been known to induce bleeding due to a lack of coagulation and this phenomena appears to be more pronounced in those with lower Vitamin K activity such as those on Warfarin therapy.
Studies which simply use oral vitamin E supplements (as α-tocopherol) daily have failed to notice any changes in bleeding times when using 600 IU for a month and up to 800IU (727mg) for four months.
A large scale study (Women's Health) assessing an average of 10.2 years usage of 600IU vitamin E every other day noted that, relative to placebo, the risk of venous thromboembolism was reduced significantly by 27%; this was particularly pronounced in the subjects who reported such an event previously (experiencing a 44% reductoin) with more minor protective effects (18%) in those without prior events.
In regards to diabetic complications vitamin E (α-tocopherol) has been noted to suppress the increase in DAG release induced by high glucose in vitro in a variety of cell lines including smooth muscle, aortic tissue, and in retinal tissue.
The release of DAG into a cell and the subsequent activation of PKC plays a pathological role in cardiovascular complications seen in diabetes, and due to the inhibition by vitamin E it is thought to be able to exert protective effects against diabetic complications (even if an inherent therapeutic effect of vitamin E on diabetes does not appear to exist).
Although oxidative stress is associated with the development of impaired pancreatic β-cell function and overall pathogenesis of type II diabetes (as well as, in rats, diabetes being able to be triggered via oxidative stressors) one large scale study (n=38,716) using 600 IU α-tocopherol every other day for ten years in otherwise healthy women failed to show a protective effect of vitamin E supplementation relative to placebo on the development of type II diabetes. Serum α-tocopherol have at times, but not always, been associated with protective effects from the development of type II diabetes.
When looking at supplemenation of vitamin E by otherwise healthy persons in order to reduce the risk of developing diabetes, there does not appear to be a significant protective effect associated with supplementation relative to placebo
Supplementation of 1,200 IU α-tocopherol daily for four weeks in type II diabetics prior to an oral glucose tolerance test noted that while DNA damage was not per se affected by supplementation that the increase seen after a glucose test (expected in type II diabetics) was exacerbated (13.6%) relative to placebo. The lack of changes without glucose test has been noted previously in type II diabetics with 400 IU over four weeks.
Elsewhere, supplementation of 500mg vitamin E (as either α-tocopherol or mixed tocopherols) appeared to mildly reduce oxidation as assessed by serum F2-Isoprostane levels although red blood cell antioxidants were unaffected.
1,800 IU of α-tocopherol daily for a year in diabetics noted that, relative to placebo, vitamin E appeared to worsen blood pressure and blood flow (flow mediated vasodilation) mildly at six months with a rather large increase in systolic blood pressure seen after one year in vitamin E (12.1mmHg) relative to placebo (2.1mmHg); this study also failed to find benefits on other parameters such as HbA1c and cholesterol with vitamin E. This particular study pooled type I and type I diabetics together, which may have differing responses to antioxidant therapy from Vitamin C and E favoring type I with other studies on vitamin E in type II diabetics failing to find protective effects (1,600 IU for eight weeks).
IL-6 is normally produced during exercise from contracting skeletal muscle where it is released into serum where it is thought to positively influence muscle protein synthesis, and due to exercise causing oxidative stress within muscle tissue which has been noted to promote the formation of IL-6 via oxidative stress it is thought that the antioxidant activities of vitamin E per se are reducing IL-6 formation. IL-6 has been noted to be suppressed by other antioxidants as well, such as vitamin C with carotenoids and N-Acetylcysteine.
Oral supplementation of antioxidants (400IU α-tocopherol with 500mg Vitamin C) for one month prior to resistance training which was sufficient to prevent an increase in lipid peroxidation from exercise was also able to ablate the exercise-induced increase in IL-6 concentrations and IL-1ra. The actual mRNA transcription rates for IL-6 in skeletal muscle and its accumulation within the tissue are unaffected by antioxidant therapy.
Oxidative stress appears to be involved in the production and release of interleukin six (IL-6) from skeletal muscle into the blood during exercise, and antioxidants can attenuate or abolish the release of IL-6. Vitamin E has been shown to be capable of suppressing IL-6 release from muscle into serum when paired with vitamin C
Vitamin E deficiency within skeletal muscle results in the typical mitochondrial dysfunction and increased lipid peroxidation as in other cells, although relative to liver cells they appear to be more susceptable. These results suggest a mechanism for the observed myopathies that occur in instances of vitamin E deficiency which appear to fully deplete vitamin E content of skeletal muscle and may promote said muscle tissue to greater damage from exercise.
Vitamin E is present in skeletal muscle, where a deficiency of vitamin E results in skeletal myopathies associated with damage and prooxidative changes to the mitochondria
Supplementation of 800IU (α-tocopherol) to elite athletes for two months prior to an Ironman race failed to improve performance relative to placebo therapy and in elite cyclists given supplementation for five months there has been no apparent benefit to aerobic performance. These two studies in elite athletes differ in their observations on lipid peroxidation despite similar inefficacy on performance, as one study noted a reduction in MDA concentrations whereas the other noted no significant changes immediately after exercise yet an increase in lipid hydroperoxides 90 minutes afterwards.
The progression of osteoporosis and age-related bone loss is one known to be associated with oxidative stress, leading some researchers to investigate the role of vitamin E in bone metabolism.
It has been noted that an oral intake of 600mg/kg vitamin E (as α-tocopherol) has stimulated bone loss in rodents secondary to increasing activity of osteoclasts, which is approximately 30-fold the recommended dose for rodents; this interference may be related to such high doses interfering with the activity of Vitamin D, which has been noted with high doses in broiler chicks.
Conversely, beneficial effects on bone structural have been noted in otherwise healthy male rats at an oral intake of 60mg daily (with more efficacy seen with γ-tocotrienol than α-tocopherol) as well as in ovarectomized rats subject to bone fracture where α-tocopherol showed anabolic properties on bone tissue at this same dose.
In rodent studies (rats and mice), supplementation of low doses of vitamin E appears to confer anabolic properties to bone tissue whereas superloading vitamin E to high levels appears to be able to stimulate bone tissue losses
In assessing dietary and serum α-tocopherol in older subjects over the course of five years it was noted that compared to the highest quintile of α-tocopherol status that the lower four quintiles had a greater risk of overall fractures (Hazard ratio of 1.84, 95% confidence interval of 1.18-2.88) with large increases in fracture rats at those with a daily intake below 5mg; supplementation of vitamin E as α-tocopherol appeared protective (HR 0.78; 95% CI of 0.65-0.93), and it appeared that vitamin E intake positively correlated with lean mass and bone mineral density (BMD). It was noted by the authors that intakes above 10mg did not appear to cause dose dependent resistance to fractures, and that a near-exponential increase in fractures at intakes below 5mg may have explained much of the protective effect.
Other correlational studies have noted lower vitamin E levels in the serum of hip fracture patients relative to control at the time of hip fracture and higher vitamin E levels in serum (both α-tocopherol and γ-tocopherol) to be correlated with better functioning after hip fracture Despite a positive correlation being noted previously between BMD and vitamin E intake, it was in a study with an average intake of 5mg daily whereas another study with an average intake of 39mg daily failed to find such an association.
When looking at epidemiological research (surveys and correlations), it seems that a better vitamin E status and vitamin E supplementation are both protective factors against fractures in the elderly. This may be potentially explained by a large increase in fracture risk when vitamin E intake drops below 5mg daily (7.5 IU, 33% of the recommended daily intake) and dose dependent protective effects do not appear to exist
It has been noted that the increase seen in PMBC proliferation (induced ex vivo) following ingestion of 200mg vitamin E as α-tocopherol in elderly persons is lessened when ingested alongside 2.5g of EPA+DHA (Fish Oil) supplementation.
α-tocopherol has been noted to decrease IFN-γ concentrations at the 50-100mg dosage range after six months supplementation in otherwise healthy older persons.
When tested in vitro, vitamin E (α-tocopherol) has been noted to increase proliferation and IL-2 secretion from a variety of immune cells including splenocytes, purified T-cells, and naive T-cells yet not memory T-cells.
Supplementation of 50mg and 100mg of α-tocopherol daily for six months in otherwise healthy older adults has been noted to increase circulating IL-4 concentrations with at trend towards decreasing IL-2. As IL-2 tends to be an inflammatory (Th2) cytokine and IL-4 an antiinflammatory (Th1), this change may be seen as proinflammatory although due to shifts towards Th1 during aging associated with a compromised immune system during the aging process it is thought to also be immunosupportive, and in accordance with this hypothesis it has been noted that the dampening effects of Fish Oil on the immunoenhancement of vitamin E (seen with DTH reactivity) was seen alongside no IL-2 secretion from lymphocytes in persons given both supplements when tested ex vivo. This increase in IL-4 is not observed in otherwise healthy youth given supplementation at 200mg (as either pure α-tocopherol or mixed tocotrienols) except perhaps in the context of vaccine augmentation.
Vitamin E has been noted to reduce PGE2 secretion from macrophages isolated from aged mice, the increase of PGE2 from macrophages of old mice being a factor underlying reduced T-cell mediated immunity (PGE2 suppresses IL-2 production) seen during the aging process (as macrophages can influence T-cell function secondary to secreting prostaglandins).
Supplementation of vitamin E as either α-tocopherol or mixed (mostly α-tocopherol and γ-tocopherol) at 500mg for eight weeks appears to be sufficient to alter the vitamin E status of neutrophils, with the changes paralleling those found in serum (a decrease in γ-tocopherol seen with supplementation of α-tocopherol only, increase in both seen with mixed tocopherols).
Supplementation of various doses of vitamin E (60, 200, and 800 IU) for four months in otherwise healthy aged adults has failed to significantly modify the response of neutrophils in vitro against Candida albicans.
One study has noted that supplementation of γ-tocopherol (315mg) alongside α-tocopherol (75mg) for eight weeks, but not 500mg of α-tocopherol alone, was able to reduce serum levels of leukotriene B4 by 17% relative to baseline; leukotriene B4 being a neutrophil-derived Arachidonic acid based eicosanoid involved in atherosclerosis. This has been noted previously in rats and although both vitamers seem effective in vitro in suppressing leukotriene B4 secretion γ-tocopherol seems more potent (effective at 25μM compared to 50μM with α-tocopherol).
When comparing aged mice fed either normal (30ppm) or high doses (500ppm; thought to be approximate to 500mg in a human) Vitamin E as either α-tocopherol or γ-tocopherol for four weeks and stimulating their T-cells ex vivo (with anti-CD3/CD28), supplementation showed influence on T-cell function in a dose-dependent manner with differences depending on the form used. Notable genes influenced included the CD40 ligand (10-fold induction), leukemia inhibitory factor (3.3-fold induction), and Slamf1 (4.4-fold induction) with high dose α-tocopherol whereas SLC25A30 (also known as UCP6, induced 10.4-fold) and polovirus receptor related 2 (10.8-fold) were most heavily affected by γ-tocopherol (low dose relative to α-tocopherol); many other genes were influenced to lesser degrees.
Vitamin E is known to stimulate T-cell proliferation in vitro, and the actions may differ depending on the particular vitamer used
Age is known to be associated a reduction in immune responsiveness with particular regard to T-cell functions of which include delayed responses to mitogens, antibody responses to immunization with antigens, and reductions delayed-type hypersensitivity (DTH) and IL-2 production.
When tested in otherwise healthy elderly persons, 50mg and 100mg of α-tocopherol for six months, immune responsiveness (as assessed by DTH reactivity) has been noted to be increased with more drastic increases in subjects with low baseline DTH reactivity. Other studies have noted this benefit occurring with α-tocopherol supplementation on this parameter in otherwise healthy elderly persons with 200mg, and due to 50mg working in only those with low baseline DTH reactivity it is thought that the doses requires for a response inversely relate to initial susceptability.
It has also been noted that coingestion of Fish Oil supplementation (5g; of which conferred 2.5g EPA+DHA) alongside vitamin E lessened the immunoenhancing properties of vitamin E (100, 200, and 400mg), this study noted that despite the α-tocopherol in serum being similar among the three tests doses (in the range of a 36-42% increase over placebo) the expected dose-dependent reduction of γ-tocopherol still occurred (28% at 100mg up to 61% at 400mg). Limited studies assessing T-cell function in non-elderly adults (20-50yrs) given supplemental vitamin E have not found any significant influence.
At least in the elderly which may have compromised immune function related to impaired T-cell function, supplemental vitamin E at low doses appears to stimulate these immune functions and are thought to be supportive
RBL-2H3 mast cells incubated with α-tocopherol (100µM) as well as β-tocopherol yet not α-tocopherol phosphate (a biologically relevant form of α-tocopherol) nor Trolox (water soluble variant of vitamin E) appear to have higher basal and stimulated degranulation, while tocotrienols from rice bran (mostly γ-tocotrienol) have been noted to have suppressive effects on degranulation in these same mast cells up to 50µM, althoguh all tocotrienols appear to have suppressive effects. This has been interpreted in having both the 6-OH position of the backbone and the sidechain both being relevant to the actions of select tocopherols
α-tocopherol has been noted to be involved in promoting mRNA involved in vesicular transport in mice (three months feeding)MID:17654050 although the mast cell proteins do not appear to be induced in vitro from α-tocopherol at the concentration it causaes degranulation over the course of 24 hours.
When looking at in vitro studies, it appears that the main vitamer (α-tocopherol) may stimulate mast cell degranulation (a pro-allergenic effect) whereas the tocotrienols may have the opposite effect and suppress degranulation
Mice fed rice bran tocotrienols at 1mg/kg daily (mostly γ-tocotrienol) for one week appears to confer anti-allergic effects against skin sensitization by reducing symptoms 50% relative to control; due to a reduction serum histamine this was thought to reflect the suppression of degranulation at the level of the mast cell as the IgE (released from T-cells to induce degranulation) was not affected by supplementation.
It has been noted in epidemiological research that higher vitamin E intake is associated with less risk of asthma and in asthmatics there are reduced activity of antioxidant system in the lung including those related to vitamin E.
Supplementation of 500mg vitamin E (α-tocopherol) for six weeks in nonsmoking asthmatics on corticosteroids noted that supplementation, relative to placebo, was associated with a mild improvment in responsiveness to methacholine yet no influence on other measured parameters (FEV1, FVC, morning peak flow, and bronchodilator use) or subjective symptoms.
Studies on vitamin E and immunity have at times noted reductions in infectious diseases in the elderly, and when elderly persons are given minor micronutrient supplementation (and influenza vaccination) but then an additional 200 IU vitamin E (α-tocopherol) or placebo supplementation over the course of one year is associated with a reduced occurrence of upper respiratory tract infections (URTIs) reducing a 64% occurrence to 50% with particular regard to the common cold (comprised 84% of URTIs).
Vitamin E is thought to have a role as an immune adjuvant with vitamin E administration to animals subject to immunization increasing the immune response to tetanus vaccinations and influenza vaccines; vitamin E administration is associated with greater IFNγ concentrations in serum in these contexts which is thought to underlie the benefits as IFNγ (secreted from T-cells and natural killer cells in response to infection exerting antiviral properties) although increased IL-4 secretion and suppressed IL-6 have also been noted in humans supplementing vitamin E with vaccines.
Vitamin E (multiple vitamers) appear to be able to increase the immune response to vaccinations and ultiamtely the production of antibodies to the vaccine, serving an adjuvant role
A study assessing vitamin E status of otherwise healthy older adults found that serum vitamin E in non-deficient persons (without supplemental intervention) was not associated with the serological response to vaccination for influenza.
Interventions with supplemental vitamin E have found an increased response to vaccination against hepatitis B associated with supplementation of 200mg vitamin E (α-tocopherol) before vaccination, with a 6-fold increase in antibody titre which outperformed both 60mg and 800mg of vitamin E (each reaching 3-fold). Increases in the response to tetanus have been noted in young and otherwise healthy adults subject to vaccination paired with 400mg (70% tocotrienols, which based on animal evidence may be more effective than α-tocopherol).
Although baseline vitamin E levels do not appear to be correlated with antibody production to vaccines, studies using moderate supplemental dosages of vitamin E (200-400mg range) show an adjuvant role when compared to placebo. Unlike the interactions with T-cells, this particular role of vitamin E may work in persons of all ages and not just the elderly
Vitamin E dietary deficiency in the rat has been noted to increase corticosterone concentrations both at rest and after anxiety testing relative to sufficient controls, with most significance seen in adult rats after testing where corticosterone concentrations were near doubled. It has also been noted in bovine that vitamin E administration in the diet (as well as Selenium) was able to reduce cortisol concentrations although when tested in vitro in bovine adrenal cells vitamin E (in combination with Vitamin C) failed to influence cortisol secretion either inherently or in the presence of ACTH stimulation.
Limited human evidence has seen vitamin E (400IU as α-tocopherol) used alongside Vitamin C (1,000mg) in the context of physical exercise, where the combined supplementation for four weeks appeared to attenuate the 170% increase in post-exercise cortisol down to 120%. Such an effect has been noted with vitamin C supplementation in isolation, and studies using only α-tocopherol have failed to find any effect of supplementation on cortisol.
Vitamin E has been implicated in a few instances where bovine experienced reductions in cortisol, and a deficiency of vitamin E appears to increase cortisol. Despite these interactions, studies on vitamin E supplementation in humans have not shown any benefit relative to placebo
Supplemental vitamin E at 300mg daily in uremic patients (tend to have elevated prolactin concentrations due to reduced clearance) has been noted to reduce circulating prolactin (50.8ng/mL down to 15.4ng/mL) without apparent influence on free testosterone. There are currently no studies investigating healthy controls and the influence of vitamin E supplementation.
At least one study has noted reductions in prolactin in uremic patients, although there is no evidence in healthy persons at this moment in time
Supplementation of 800mg vitamin E (α-tocopherol) daily for a month in otherwise healthy elderly persons has failed to significantly modify circulating T3, T4 (free or total) or the uptake ratio of T3 relative to placebo, this time period of four weeks also being the one where a slight decrease in thyroid hormones has been noted in young males and females not on contraceptives where T3 (26.3-31%) and T4 (12.3-14.6%) where reduced by 800mg α-tocopherol. Studies over longer periods of time (12 weeks to a year) using dosages in the 600-900mg range have failed to find alterations in thyroid function.
Vitamin E has the ability to act as a chain-breaking anti-lipid peroxidation agent, specifically in lipoproteins where it is incorporated by the liver. 'Chain-breaking' refers to being able to interrupt a series of oxidative events caused initially by oxidants. Vitamin E appears to be the central chain-breaker, as it still retains this ability even during deficiency states.
Supplemental vitamin E (as alpha-tocopherol) can alleviate mitochondrial dysfunction that is secondary to vitamin E losses.
In humans, supplementation of 400-800 IU of vitamin E in those with artherosclerotic buildup (artery plaque) was associated with a greatly reduced chance of a cardiac event from occurring. Doses of 300IU can improve markers of lipid peroxidaiton in humans. These events may be secondary to decreases in prothrombrotic factors.
Vitamin E (α-tocopherol) is known to, in vitro, reverse from reducing lipid peroxidation to exacerbating it when concentrations of vitamin E are increased which has been noted numerously in LDL particles leading to a possible explanation for at times null effects in atherosclerosis.
This prooxidative effects seems to be mediated by α-tocopherol sequestering free radicals to a degree where itself turns prooxidative, which would then normally be reduced by co-antioxidants (such as Vitamin C); in the event a co-antioxidant cannot act on the newly formed α-tocopherol radical, the radical then in turns accelerates the lipid peroxidation it initially suppressed.
Nitrosylation (oxidation involving nitrogen) is known to be mediated in large by peroxynitrate (ONOO-), the product of the superoxide radical (O2-) pairing with Nitric Oxide (NO). The peroxynitrate radical tends to target lipophilic substrate more than hydrophilic and its production is accelerated in the cell membrane; although it can react with γ-tocopherol (forming 5-nitro-γ-tocopherol or NGT, thought to also extend to δ-tocopherol) it cannot act similarly against α-tocopherol or less importantly β-tocopherol which instead simply reduce nitrogen radicals and when incubated alongside L-Tyrosine (usually a molecular target of nitrosylation) it seems that γ-tocopherol is preferred as a target for peroxynitrate. γ-tocopherol loses its antioxidative metabolism in this reaction (does not form CEHC as a metabolite).
In some diseases there are elevated serum or urinary concentrations of NGT such as cognitive decline and coronary artery disease, and beyond an elevation in the plasma of persons with Alzheimer's it also appears to be higher in the brain tissue itself specifically in areas where there is histopathological damage.
While all vitamers appear to have general antioxidant properties against nitrogen based radicals, γ-tocopherol has a unique role where it can sequester peroxynitrate which is more effective in reducing the oxidative effects of peroxynitrate. The metabolite, NGT, is elevated in certain disease states which suggests that this process is important in the pathology and implicates γ-tocopherol (and possibly γ-tocotrienol) in unique protective roles
When 800IU α-tocopherol is given for two months prior to an Ironman marathon, while supplementation appeared to be ineffective in modifying lipid hydroperoxides in serum before or immediately after the race there was a large spike (indicative or more lipid peroxidation) seen after 90 minutes relative to placebo alongside an increase in F2-isoprostanes (oxidative product made from lipid peroxidation).
Supplementation of 1,200 IU α-tocopherol daily for four weeks in type II diabetics prior to an oral glucose tolerance test noted that while DNA damage was not per se affected by supplementation that the increase seen after a glucose test was exacerbated (13.6%) relative to placebo. Such an increase in DNA damage has not been noted with 400 IU (no oral glucose tolerance test) in type II diabetics.
Non-alcoholic fatty liver disease (NAFLD) is a disease state associated with oxidative stress and characterized by an increase in triglyceride and fatty acid accumulation in liver tissue leading to scarring, and is known to be associated with less circulating antioxidants in serum (of which include α-tocopherol) and higher oxidative byproducts. Vitamin E is thought to play a therapeutic role due to its antioxidant properties.
Nonalcoholic fatty liver (NAFLD or NASH) is a condition associated with elevated oxidative stress in the blood and liver, which is thought to be pathological. Due to vitamin E being an antioxidant, it has been investigated for its role in reducing symptoms of NAFLD/NASH
Pilot studies on the topic of vitamin E and NAFLD have noted benefits to serum biochemical markers such as TGF-β and the liver enzyme ALT, at times being noted even if fibrotic and steatohepatitis scores in the liver are not significantly changed; at least two studies have noted benefits to fibrotic scores, although one was a retrospective study of vitamin E at 300mg for periods longer than two years whereas the other also used Vitamin C alongside vitamin E at 1,000mg and 1,000IU respectively, and as one pilot study has noted benefit to fibrosis in persons with steatohepatitis (inflammation) but not those in NAFLD without inflammation it is thought that benefits of vitamin E to firbosis are related to baseline inflammation in the liver.
The currently msot well conducted trial using 800IU vitamin E (α-tocopherol) as a daily supplement for 96 weeks in persons with non-alcoholic fatty liver disease (NAFLD) appears to be associated with a greater rate of improvements on histology and serum liver enzymes relative to placebo, with 43% of subjects seeing benefit relative to 19% in placebo with the benefits of vitamin E being additive to weight loss (which is inherently therapeutic) but the reduction in serum ALT seen with supplementation being attenuated when vitamin E is ceased for 24 weeks.
Supplementation of high dose vitamin E in persons with NAFLD appears to be more effective than placebo at reducing elevated serum enzymes and some other factors indicative of liver damage, although evidence is mixed on whether vitamin E actually reduces fat buildup in the liver and the subsequent fibrotic score (may only occur in persons with evidence of inflammatory damage to the liver, and not as a per se benefit)
Vitamin E has, at times, been either noted to have lower circulating levels in the plasma of smokers or no significant differences relative to nonsmokers; an increased clearance from the blood does seem apparent though, thoughts to be due to vitamin E being depleted when exposed to cigarette smoke. This depletion rate seems to be lesser when Vitamin C levels in serum are higher, and supplementation of vitamin C (500mg twice daily) can attenuate the rate of α-tocopherol depletion from plasma from being 68% faster than controls by a quarter while also reducing the increased γ-tocopherol clearance by 45% (although γ-tocopherol does not tend to be depleted abnormally in smokers relative to nonsmokers, if not elevated).
It has also been noted that the increased clearance of both α-tocopherol and γ-tocopherol from plasma is not due to oxidative metabolism, since α-CEHC and γ-CEHC clearance (respectively) is not increased. This may be due to nitrogen radicals in cigarette smoke forming 5-nitro-γ-tocopherol (NGT) when reacting with γ-tocopherol as this process cannot occur with α-tocopherol; an increase in urinary NGT has been confirmed with smoke exposure. In regards to α-tocopherol, it seems related to increased oxidative metabolism.
Due to the increased rate of clearance, smokers are thought to have higher requirements for α-tocopherol, although the degree of which is uncertain.
Cigarette smoking appears to increase the rate of α-tocopherol elimination from the blood, a reaction that appears to be slowed when other antioxidants are also supplemented (likely as sacrifical antioxidants, indirectly preserving α-tocopherol content). This likely means an increased requirement for vitamin E or other antioxidants in smokers, although the degree of increase is not currently known
The pathological changes that occur with cataract formation are known to be oxidative, where in vitro application of antioxidants exert a protective effect. Of the three variants of cataract formation (nuclear, corticol, and posterior subcapsular cataracts), different oxidative stressors may influence pathology (e.g. smoking and H2O2 on promoting nuclear cataracts and corticosteroids promoting posterior subcapsular cataract formation). Due to the benefits seen in mixed antioxidant supplementation including vitamin E on cataract formation, as well as general protective correlations with dietary vitamin E and cataract formation, the role of supplemental vitamin E in isolation has been tested.
Supplementation of vitamin E (as 500 IU α-tocopherol) to older persons with either early or no signs of cataract formation over the course of four years noted that the cumulative instances of forming cataract in the vitamin E group (4.5%) was not significantly different than placebo (4.8%) with no further differences in assessing posterior subcapsular cataract or nuclear cataract formation rates. Incidences of early or late cataract formation also did not differ between groups.
Previous studies have found benefits with both mixed nutrient supplementation as well as the same dose of Zinc (in isolation) on cataract formation and trials assessing solely the combination of Vitamin E and Vitamin C have failed to find a protective effect suggesting efficacy lays either with zinc or some efficacy seen with β-carotene (routinely included in these formulations) in smokers exclusively.
Although mixed antioxidant supplements appear to have protective effects against cataract formation, this may be due to nutrients such as Zinc which have shown benefits in isolation. When used by itself, Vitamin E has failed to show any protective effects on either the risk of developing cataracts or their continued formation
The administration of vitamin E (intravenous at 100mg/kg) in rabbits has been noted to improve the levels of antioxidative biomarkers (glutathione, MDA) relative to control, and when coadministered alongside testosterone it was able to prevent a decline in these biomarkers seen with testosterone alone.
One study that assigned aspirin (100mg) to be taken every other day for ten years and then assigned on the alternating days either vitamin E (600 IU) or placebo found that vitamin E was not associated with any protective effects on cancer mortality (breast, lung, and colon).
One cohort study in china using a sample of 132,837 persons found that during follow-up that 267 persons (0.2%) developed cancer of the liver, and in comparing dietary information from the base sample against the cohort that developed liver cancer intake of Vitamin E was inversely related to cancer occurrence with a hazard ratio of 0.52 (almost half the risk) and a CI of 0.3-0.9.
When looking at epidemiolgoical evidence looking at associations between α-tocopherol in serum and prostate cancer risk, α-tocopherol has either been implicated in a minor protective role or the association has failed to reach statistical significance (indicating no significant protective effect).
In assessing the data from the ATBC trial (vitamin E and β-carotene on lung cancer in smokers) where there were protective correlations with both α-tocopherol and γ-tocopherol in serum it was noted that supplementation of 50mg α-tocopherol was associated with a 32% reduction in prostate cancer risk and 41% reduction in prostate cancer mortality (smokers); conversely, the β-carotene also used in this study was assocaited with slight increases in prostate cancer risk and mortality. When following up this study 20 years after its initiation (1985-1988), it was noted that while dietary vitamin E was not related to prostate cancer that the highest quintile of serum γ-tocopherol was associated with a protective effect against advanced prostate cancer (RR of 0.50; 95% CI of 0.30-0.84) similar to baseline α-tocopherol (RR of 0.56; 95% CI of 0.36-0.85) and appeared to be slightly more protective with supplementation of 50mg α-tocopherol relative to placebo; there did not appear to be a protective effect of α-tocopherol which manifested during the initial trial period, instead manifesting the six years postintervention.
It has also been noted that among smokers, who have higher instances of prostate cancer associated with smoking, that the risk is further enhanced in those with low α-tocopherol concentrations in serum including instances of advanced prostate cancer.
It appears that higher vitamin E status at baseline or supplementation (before prostate cancer is diagnosed) is associated with less instances of advanced prostate cancer and reductions in prostate cancer related mortality in smokers. Studies investigating the association of vitamin E and prostate cancer per se (not limited to advanced cases) seem to be on the fence about a minor protective effect or none at all
A meta-analysis assessing 19 clinical trials using vitamin E supplementation for over one year in length (9 of which assessed vitamin E in isolation rather than in conjunction with other micronutrients) in the range of 19.5-2,000IU (median value of 400IU) noted that, relative to placebo treatment, there was no overall increase in mortality seen with vitamin E supplementation. This was thought to be due to differences in studies using doses of vitamin E below 400IU (which showed a nonsignificant protective effect against mortality) and doses above 400IU used in 11 trials which had a relative risk of 1.04 (95% CI of 1.01-1.07). Although when the use of concomitant multinutrient formulations alongside vitamin E was controlled for, the risk was slightly increased from 34 persons (per 10,000) to 63. The authors noted a limitation of this study was a lack of evidence in otherwise healthy aged adults, as two of the studies using vitamin E above 400IU (studying cataract formation) assessed healthy cohorts whereas the other nine were in diseased cohorts, and studies in healthy adults using less than 400IU were all confounded with other nutrients).
It was also noted that after initially controlling for dosage there wasn't a statistically significant reduction in mortality seen in the low dose vitamin E group (as the 0.98 relative risk ratio had a nonsignificant 95% CI of 0.96-1.01), but in secondary analyses there was a minor protective effect with low doses reaching 33 fewer deaths per 10,000 persons compared to placebo; a clinical relevance paralleling the 34/10,000 increase seen with high dose vitamin E supplements (prior to controlling for other nutrients).
A small but significant increase in all-cause mortality has been noted in at least one meta-analysis when Vitamin E was used at doses above 400IU. The meta-analysis was focused mostly on unhealthy persons (usually those at high risk for cardiovascular disease) and on α-tocopherol specifically. It is unclear if low doses of vitamin E confer a protective effect, but it cannot be ruled out. Whether these results apply to healthy cohorts is not known.
Because smokers are particularly at risk for increased mortality, the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) study was performed to assess the effects of vitamin E (and beta-carotene) supplementation in male smokers. Although initial analysis of the data from this study failed to show an effect of vitamin E on overall mortality, smoking is known to increase clearance of vitamin E from the plasma, which is normalized by supplementation with vitamin C. Moreover, vitamin E interacts with vitamin C in vitro as well as in vivo.
This prompted a Swiss group in 2009 to re-examine the data from the ATBC study. After accounting for age and vitamin C intake, it was found that vitamin E increased mortality in individuals with a median vitamin C intake above 90mg/day aged 50-62 years by 19% (95% CI: 5, 35). In contrast, vitamin E decreased mortality in subjects aged 66-69 years by 41% (95% CI: -56, -21), and had no effect on participants in the study with a vitamin C intake below the median 90mg/day. Although it is difficult to extrapolate the results of this study in male smokers to the general, healthy population, this work suggests that the effects of vitamin E on all-cause mortality may be population-specific, and possibly influenced by the intake of other nutrients.
The effects of vitamin E supplementation on all-cause mortality may be population-specific, and influenced by the intake of other nutrients, particularly vitamin C.
The different layers of the skin (stratum corneum, epidermis, dermis, subcutis) have various antioxidant defenses to protect against exposure to environmental stressors such as ozone or UV radiation, which are known to cause oxidative changes to lipids, proteins, and DNA.
Vitamin E as α-tocopherol is the predominant vitamer in human skin, present at concentrations approximately 10-fold higher relative to γ-tocopherol. The concentrations of α-tocopherol in these tissues under normal conditions have been noted to be 31+/-3.8nM per gram of tissue (epidermis), 16.2nM/g (dermis), 33+/-4nM/g (stratum corneum), and highest (76.5+/-1.5nM/g) in sebum whereas the concentrations of γ-tocopherol have been reported to be 3.3+/-1nM/g, 1.8+/-0.2nM/g, 4.8+/-0.8nM/g, and 8.7+/-1.8nM/g respectively.
Vitamin E is one of the first oxidative biomarkers to be depleted in response to environmental stressors in these cells. Moreover, depletion can occur below the point where skin would normally redden from such stressors (known as the minimal erythema dose or MED). Vitamin E can become depleted by over 50% in the stratum corneum, although this skin layer sees a more drastic reduction than others due to low concentrations of other co-antioxidants such as Vitamin C. Vitamin E depletion may be induced directly by absorption of UVB rays or indirectly, by free radicals produced by UVA rays. Ozone, an oxidant thought to only affect the outermost skin layers and not diffuse further, is also scavenged by vitamin E.
Both α-tocopherol and γ-tocopherol (forms of vitamin E) are present in the skin, buffering oxidative damage from the environment. Vitamin E is the predominant antioxidant in the outermost layer of the skin (stratum corneum), whereas the antioxidant potential of vitamin E is shared with that of vitamin C in lower layers of the skin.
Vitamin E may prevent signs of aging in skin, as the addition of vitamin E in vitro can restore the synthesis of collagen and prevent the accumulation of glycosaminoglycans (GAGs) due to damage caused to fibroblasts by reactive oxygen species (ROS). Such a preservation of collagen synthesis has also been noted with antioxidant enzymes such as catalase, suggesting a general oxidative role rather than one unique to vitamin E.
In both normal and diabetic rats, α-tocopherol at 200mg/kg oral intake was associated with less lipid peroxidation in serum and increased antioxidant enzymes in red blood cells. A later study using the same dose noted that vitamin E derived from palm oil (70% tocotrienols and 30% tocopherols) was of a greater potency than pure α-tocopherol; this being thought to be due to greater protective effects of tocotrienols in cells (neurons) and in sequestering free radicals in the cell membrane.
In humans, topical vitamin E (320 IU α-tocopherol per gram) applied to surgical scars over twelve weeks where one portion of the large scar was used as control failed to note any differences with vitamin E therapy relative to control therapy. It was noted that vitamin E application to scars was associated with the development of pruritis or redness, resulting in patients dropping out of the study. Reactions to topical vitamin E have also been noted elsewhere with burn scars, where up to 16.4% of subjects reported irritation while no benefits with vitamin E therapy were found. However, one study specifically assessing hypertrophic (raised) scarring and keloids (raised scars growing beyond the original boundries of the wound), did find that the addition of vitamin E to reference therapy (silicon sheets) showed additional benefits.
In regards to skin aging, vitamin E may prevent oxidative damage to the skin based on test tube studies. While rat studies have shown systemic antioxidant benefits of vitamin E, the only human studies are with topical application and they mostly show no significant benefit to healing or scar appearance and in fact may promote possible irritation and reddening.
Hair loss (alopecia) is a condition associated with increased oxidative stress in the blood (even if vitamin E concentrations are similar to controls), and in part due to tocotrienols being more effective at reducing lipid peroxidation they have been tested at 100mg oral intake over eight months in persons with various forms of alopecia; mixed tocotrienol supplementation appeared to cause a 34% increase in hair count in the balding areas relative to 0.1% seen in placebo with only one nonresponder in the tocotrienol group and no significant influence on hair weight.
One study has noted a beneficial influence of tocotrienols on hair regrowth in balding persons (both sexes, androgenic hair loss not specified nor ruled out), it is uncertain if this information applies to other vitamers of vitamin E (such as α-tocopherol) and the study has not been replicated
Alzheimer's disease (AD) is in part characterized by oxidative damage in the brain. Vitamine E (α-tocopherol) could therefore hypothetically be a therapeutic agent for Alzheimer's disease (AD) since, in vitro, it can reduce lipid peroxidative damage in brain cells and cell death associated with β-amyloid protein toxicity.
The antioxidant properties of Vitamin E could theoretically be protective of neurons during Alzheimer's disease, as AD is a disease state characterized by high oxidative damage in the brain.
A study involving supplementation of 2,000 IU Vitamin E (as α-tocopherol) either in isolation or with the glutaminergic antagonist memantine in people with mild to moderate AD already taking an acetylcholinesterase inhibitor noted that, over the course of five years of supplementation, the Vitamin E group experienced less cognitive decline as assessed by the ADCS-ADL rating scale representing a 19% slowing of disease progression per year relative to placebo. This change outperformed memantine in isolation, which had statistically nonsignificant benefits, and combination therapy provided no further benefits. This study reflects previous research where 2,000 IU of α-tocopherol in persons with moderate to severe AD benefitted when vitamin E was given either alongside selegiline (acetylcholinesterase inhibitor) or in isolation.
It has been noted that the above studies are on patients with mild to severe AD, whereas studies of Vitamin E in older individuals without AD but with mild cognitive impairment have not had promising results. Moreover, vitamin E supplementation failed to demonstrate cognitive benefits in otherwise normal, healthy people. In persons with cognitive decline who then went on to develop Alzheimer's disease during the course of the study, Vitamin E (2,000 IU) exerted no protective effect or risk reduction relative to placebo.
Very high dose vitamin E supplements appear to be attenuate disease progression in mild to severe Alzheimer's disease, although the effects of lower doses in this cohort have not been tested and Vitamin E does not appear to benefit people with mild symptoms or cognitive decline not due to AD.
A meta-analysis of observational studies published between 1996 and 2005 revealed that supplementation with vitamin E may have a protective effect against Parkinson’s disease. Moreover, it has been noted that vitamin E increases in specific brain regions in patients with Parkinson’s disease, a possible compensatory mechanism following oxidative damage. This further suggests bolstering vitamin E levels with supplementation may help to limit oxidative damage associated with Parkinson’s. When investigated in vitro, vitamin E attenuates oxidative damage of striatal dopaminergic neurons, a phenomenon associated with the pathology of Parkinson's. Vitamin E deficiency does not appear to increase susceptibility of this brain region to oxidative stress in a mouse-model, however.
In a rotenone-induced Parkinson's model in rats (rotenone being a toxin which causes Parkinson's-like symptoms), intramuscular administration of vitamin E (α-tocopherol, 100IU/kg bodyweight) attenuated pathological reductions in dopamine and increases in lipid peroxidation.
In contrast, the DATATOP study in humans which investigated the effects of selegiline, vitamin E (2,000 IU daily as α-tocopherol), or their combination failed to find any protective effects with vitamin E supplementation relative to placebo.
While very high-dose vitamin E seems to have some benefit in rodent models of Parkinson's disease, the lone human study on vitamin E and Parkinson's using a superloading protocol (same dose as studies in Alzheimer's disease) failed to find any protective effects. This suggests there may be no benefits to vitamin E supplementation for Parkinson's disease.
Vitamin E (as α-tocopherol) has been noted to reduce the toxicity of cerebrospinal fluid (CSF) from people with ALS against healthy neurons in culture, although the concentration used (250µM) was significantly higher than normally present in CSF (30-32.5nM). This is not a property unique to vitamin E, however, as protective effects have also been noted with other antioxidants in vitro.
Concentrations of vitamin E (as α-tocopherol) in the cerebrospinal fluid (CSF) of people with sporadic ALS has been noted in one study to be approximately 31% of those found in healthy controls, while α-tocopherol quinone was reduced by 75%. In contrast, a larger study of those with sporadic ALS failed to find such a reduction in α-tocopherol (α-tocopherol quinone was not measured) or any relationship between CSF α-tocopherol levels and disease duration or age of onset. Moreover, α-tocopherol levels in serum do not appear to be significantly influenced in people with sporadic ALS.
Tocopherol quinone is an oxidative byproduct of tocopherol, so an increased ratio of tocopherol quinone to tocopherol is an indicator of increased oxidative stress. Tocopherol dihydroquinone, a metabolite of tocopherol quinone, is a known antioxidant, however. Despite α-tocopherol serum concentrations under normal conditions being somewhat maintained in the 20-30µM range, concentrations of tocopherol quinone are normally quite variable (in the range of 15-980nM), even in healthy controls. Thus, the relevance of the lone study that associated low tocopherol quinone concentrations with ALS is uncertain.
Vitamin E concentrations (as α-tocopherol) have been measured in the blood and cerebrospinal fluid of those with ALS relative to healthy controls, but there does not appear to be any significant difference between groups.
In assessing serum α-tocopherol concentrations in a secondary data analysis from the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study, it was noted that males with serum vitamin E levels above the median value had a relative risk of 0.56 in developing ALS when compared to the males below the median value, although this trend was found by pooling the serum levels of all patients, whether or not they supplemented α-tocopherol. This study failed to find a protective effect of α-tocopherol supplementation for ALS, however, although this could be due to the insufficient statistical power of the study. One other study examining dietary and supplemental vitamin E intake and risk of developing ALS noted a protective effect in the highest quartile of dietary vitamin E intake relative to the lowest. Although this failed to reach overall statistical significance, long-term supplementation with vitamin E did show a statistically significant protective effect for ALS that increased with time.
Limited evidence suggests that high serum α-tocopherol levels may be correlated with lower risks of developing ALS. Studies examining α-tocopherol supplementation to date have had mixed results, however, suggesting at most that long-term (but not short term) α-tocopherol intake may protect against ALS. Further research is needed to confirm this finding.
Polyunsaturated fatty acids (PUFAs) are fatty acids with more than one double bond. Since double bonds may be oxidized, the more double bonds there are in a fatty acid, the more susceptable it is to lipid peroxidation; PUFAs are the most susceptable, those with a lone double bond (MonoUnsaturated Fatty Acids or MUFAs) being less so, and saturated fatty acids being mostly immune to oxidation under standard conditions.
It has been noted that while an increase in lipid peroxidation (which occurs from oral ingestion of high doses of PUFA which are then integrated into organ tissue) from feeding rats PUFAs is not as high as expected, this difference is not completely accounted for by vitamin E levels in rats given adequate vitamin E intake in the short term,  although a vitamin E-deficient diet clearly does lead to increased peroxidation and damage.  It is thought by some, however, that increasing dietary PUFAs may increase the requirement of vitamin E. The increased need of vitamin E is known to correlate with the degree of fatty acid unsaturation, with more highly-saturated PUFAs reducing vitamin E stores more.
An adequate oral intake of vitamin E in humans has been estimated to be 0.6mg (approximately 1 IU) of α-tocopherol per gram of linoleic acid and may be higher for fatty acids with more than two double bonds (most dietary PUFAs).
Adequate vitamin E intake is necessary to prevent unsaturated fatty acids from becoming oxidized. Highly unsaturated fatty acids are more susceptable to oxidation than less unsaturated (or more saturated) ones. Preventing fatty acid oxidation reduces bodily vitamin E stores, so increasing dietary intake of unsaturated fatty acids should come alongside an increase in vitamin E intake (with the overall intake of vitamin E being thought to be at least 1 international unit per gram of unsaturated fatty acid).
Sesamin is a lignan from sesame seeds, and is an inhibitor of the process of Tocopherol-ω-hydroxylation (via CYP4F2 enzymes). This process metabolizes the vitamin E vitamers, and works more readily on the gamma vitamers (γ-tocopherol and γ-tocotrienol). Thus inhibiting it with sesamin has caused either inherent increases in plasma γ-tocopherol and γ-tocotrienol concentrations or augmentation of diet- or supplement-induced increases in plasma and tissue levels in rats. This has been confirmed in human men given sesame oil in food which contained 94mg sesamin (and 42mg of the related lignan sesaminol), which halved the excretion of γ-tocopherol metabolites in the urine over the course of 72 hours.
Sesamin inhibits the metabolism of vitamin E vitamers (via inhibiting tocopherol-ω-hydroxylation), and since this process works fastest on the gamma vitamers (γ-tocopherol and γ-tocotrienol) oral ingestion of sesamin will cause an increase in or augment the increase of plasma and tissue γ-tocopherol and γ-tocotrienol.
Procyanidin molecules from Grape Seed Extract have been noted to protect membrane stability in erythrocytes (red blood cells) from radiation-induced oxidation. A concentration of 0.1-10µM of procyanidins have shown synergistic actions with the α-tocopherol content of red blood cells.
At least in vitro, vitamin E appears to be synergistic with procyanidins from grape seed extract in exerting antioxidant effects on cell membranes.
In the process of protecting unsaturated lipids from oxidation, vitamin E forms hydroperoxides as byproducts which are readily reduced by the selenoprotein phospholipid hydroperoxide glutathione peroxidase. In this manner, both vitamin E and Selenium can act together to alleviate oxidative stress in certain tissues.
One study has noted that administration of supplemental vitamin E (1,200mg α-tocopherol) prior to an exercise test reversed the expected reduction in serum CoQ10 from exercise-induced oxidation (39%) into a mild increase (8.5%).
They also show synergy in anti-clotting of the blood, which could be cardioprotective or pro-hemorhhagic depending on dose.
Vitamin K is a vitamin most well known for its involvement in coagulating blood, and works via a series of proteins known as 'vitamin K dependent proteins' which are bioactivated in concert with bodily vitamin K stores.
Vitamin E by itself does not necessarily increase clotting time in otherwise healthy adults either over short (up to 800 IU) or long term (up to 800 IU) supplementation, but it has been noted to significantly augment coumarin-based anticoagulants such as warfarin (which are vitamin K antagonists).
The role of vitamin K and its activity in these effects of vitamin E are uncertain, as while one study failed to note any adverse effects of vitamin E supplementation (900 IU α-tocopherol) on a biomarker of vitamin K status known as PIVKA-II another study using a more precise measuring device and 1,000 IU over 12 weeks found a modest increase (indicative of reduced vitamin K status) despite the other indicators of vitamin K status (carboxylated osteocalcin and plasma phylloquinone) being unaffected.
Vitamin E is known to augment the action of a class of vitamin K antagonists (the coumarin-based anticoagulants like warfarin). The current evidence is unclear, however, as to whether vitamin E plahys a direct or practically significant role in vitamin K status or activity.
Lycopene is a carotenoid that is inherently present in LDL particles alongside vitamin E (as both α-tocopherol and γ-tocopherol) and alongside other carotenoids as both groups (carotenoids and tocols) are fat soluble, requiring that they be transported around the body via lipoproteins.
It has been noted that lycopene and vitamin E have synergistically inhibit LDL oxidation in vitro.
When other factor are controlled for, high dosages of Vitamin E supplements (exceeding 400 IU daily) are associated with increase mortality from all causes, however these results have been contested by other analyses and counter points given in response to those. Some researchers have suggested that while indiscriminate vitamin E supplementation is not warranted based on the current evidence, the possibility that some subgroups may benefit from it remains an open one.
Tocotrienols could theoretically be a safer alternative than vitamin E in helping stop the spread of cancerous cells, since they possess higher bioactivity (thus needing a lower dose to exert the same effect) and accumulate in tissues and tumors rather than in the blood; these purported benefits are mostly hypothetical at this point in time, however, and more research is needed to confirm them.
Topical application of vitamin E (as α-tocopherol) has, at times, been noted to cause more reddening (erythema) and irritation when applied to scars than do control gels not containing vitamin E. Other reports suggest instances of contact urticaria, eczematous dermatitis, and erythema multiform-like reactions when vitamin E is applied to broken skin (such as after chemical peel or dermabrasion). It has been hypothesized that oxidized vitamin E derivates could act as haptens or irritants in these instances.
When vitamin E is applied topically to an area of the skin which is abrased or scarred, it appears to be associated with more frequent instances of erythema (reddening) and irritation than do control gels. For this reason, topical application of vitamin E for the purposes of healing scars is not generally recommended.
(Common misspellings for Vitamin E include tokopherol, tokoferol, tokotrinol, tokotrienol, tocoferol, tocotrinol, vitmin)
(Common phrases used by users for this page include vitamin e reviews, side effects of vitamin e, rrr-alfa-tokoferol, notes on general points on vitamin e, examine.com vitamin c, antioxidant activity gamma and alfa tokoferol)