The Role of Vitamin E in Human Health and Some Diseases

Saliha Rizvi, *Syed T. Raza, Faizal Ahmed, Absar Ahmad, Shania Abbas, Farzana Mahdi

فيتامين هـ ودوره في الصحة والمرض عند البشر

�صالحة ريزفي، �سيد ت�سليم ر�ضا، في�صل �أحمد، �أب�صار �أحمد، �شانية عبا�س، فرزانة مهدي

abstract: Vitamin E is the major lipid-soluble component in the cell antioxidant defence system and is

exclusively obtained from the diet. It has numerous important roles within the body because of its antioxidant

activity. Oxidation has been linked to numerous possible conditions and diseases, including cancer, ageing,

arthritis and cataracts; vitamin E has been shown to be effective against these. Platelet hyperaggregation, which

can lead to atherosclerosis, may also be prevented by vitamin E; additionally, it also helps to reduce the production

of prostaglandins such as thromboxane, which cause platelet clumping. The current literature review discusses

the functions and roles of vitamin E in human health and some diseases as well as the consequences of vitamin E

deficiency. The main focus of the review is on the tocopherol class of the vitamers.

Keywords: Vitamin E; Health; Tocopherols; Antioxidants.

الملخ�ص: يعد فيتامين هـ المكون الرئي�سي الذائب في الدهن في الجهاز الدفاعي الم�ضاد للأك�سدة. يتح�صل الب�شر على هذا الفيتامين ب�صورة كاملة من

الغذاء. للفيتامين وظائف مهمة عديدة في داخل الج�سم لكونه م�ضادا للأك�سدة. ترتبط الأك�سدة بعدد من الحالت والأمرا�ض مثل ال�شرطان والهرم والتهابات

المفا�صل وال�ساد (كاتراكت)، و لفيتامين هـ فعالية �ضد جميع هذه الأمرا�ض والحالت. يمنع تناول فيتامين هـ التجلط المفرط لل�صفائح الدموية، والذي

قد ي�ؤدي �إلى الت�صلب الع�صيدي، ويقوم �أي�ضا الفيتامين بتقليل انتاج البرو�ستاغلدين مثل الثرومبوك�سين والذي ي�سبب تكد�س ال�صفائح الدموية. يناق�ش

هذا المقال ال�ستعرا�ضي وظائف و�أدوار فيتامين هـ في حالتي ال�صحة والمر�ض، والنتائج المترتبة على نق�ص الفيتامين. يركز المقال عن هذا الفيتامين

على التوكوفيرول

مفتاح الكلمات: فيتامين هـ؛ ال�صحة؛ التوكوفيرول؛ م�ضادات الأك�سدة.

Vitamin E is the collective term given

to a group of fat-soluble compounds first

discovered in 1922 by Evans and Bishop;

these compounds have distinct antioxidant activities

essential for health.1 Vitamin E is present in fat-

containing foods2 and, as the fat-soluble property of the

vitamin allows it to be stored within the fatty tissues of

animals and humans, it does not have to be consumed

every day. The vitamin E group (i.e. chroman-6-ols),

collectively termed tocochromanols (divided into

tocopherols and tocotrienols), includes all of the tocol

and tocotrienol derivatives which qualitatively exhibit

the biological activity of d-alpha-tocopherol.

There are eight naturally occurring forms of

vitamin E; namely, the alpha, beta, gamma and delta

classes of tocopherol and tocotrienol, which are

synthesised by plants from homogentisic acid. Alpha-

and gamma-tocopherols are the two major forms of

the vitamin, with the relative proportions of these

depending on the source. The richest dietary sources

of vitamin E are edible vegetable oils as they contain

all the different homologues in varying proportions

[Table 1]. Among the tocopherols, the alpha- and

gamma-tocopherols are found in the serum and the

red blood cells, with alpha-tocopherol present in the

highest concentration.3 Beta- and delta-tocopherols

are found in the plasma in minute concentrations only.

The preferential distribution of alpha-tocopherol in

humans over the other forms of tocopherol stems from

the faster metabolism of the other forms and from

the alpha-tocopherol transfer protein (alpha-TTP). It

is due to the binding affinity of alpha-tocopherol with

alpha-TTP that most of the absorbed beta-, gamma-

and delta-tocopherols are secreted into the bile and

excreted in the faeces, while alpha-tocopherol is largely

excreted in the urine. The alpha-tocopherol form also

accumulates in the non-hepatic tissues, particularly

at sites where free radical production is greatest,

such as in the membranes of the mitochondria and

endoplasmic reticulum in the heart and lungs.

This review mainly focuses on the current

developments in vitamin E research in the context

Department of Biochemistry, ERA’S Lucknow Medical College India, Lucknow, India

*Corresponding Author e-mail: tasleem24@gmail.comThe Role of Vitamin E in Human Health and Some Diseases

Table 1: Vitamin E content in vegetable oils

Oil Alpha-

tocopherol

G-

tocopherol

D-

tocopherol

A-

tocotrienol

in mg of tocopherol per 100 g

Coconut 0.5 0 0.6 0.5

11.2 60.2 1.8 0

Maize

(corn)

Palm 25.6 31.6 7.0 14.3

Olive 5.1 Trace

0 0

amounts

Peanut 13.0 21.4 2.1 0

Soybean 10.1 59.3 26.4 0

Wheatgerm 133.0 26.0 27.1 2.6

Sunflower 48.7 5.1 0.8 0

Source: Slover HT. Tocopherols in foods and fats.4

of their importance to human health and disease

prevention. The data obtained from a survey of clinical

trials or systematic reviews have been included here

due to the difficulty of proving the efficacy of vitamin

E supplementation, and in order to describe the

evidence-based results.

Chemistry of Vitamin E

Table 2: Selected dietary sources of vitamin E (alpha-

tocopherol)

Food and recommended

Alpha-

intake

tocopherol

content

in mg per

serving

Percent

daily

value

Wheat germ oil, 1 tablespoon 20.3 100

Sunflower seeds, dry roasted,

1 ounce

7.4 37

Almonds, dry roasted, 1

ounce

6.8 34

Sunflower oil, 1 tablespoon 5.6 28

Safflower oil, 1 tablespoon 4.6 25

Hazelnuts, dry roasted, 1

ounce

4.3 22

Peanut butter, 2 tablespoons 2.9 15

Peanuts, dry roasted, 1 ounce 2.2 11

Corn oil, 1 tablespoon 1.9 10

Spinach, boiled, ½ cup 1.9 10

Broccoli, chopped, boiled,

½ cup

1.2 6

Soybean oil, 1 tablespoon 1.1 6

Kiwifruit, 1 medium 1.1 6

Mango, sliced, ½ cup 0.7 4

Tomato, raw, 1 medium 0.7 4

Spinach, raw, 1 cup 0.6 3

Adapted from: United States Department of Agriculture (USDA),

Agricultural Research Service. USDA National Nutrient Database for

Standard Reference, Release 25.8

Sources and Recommended

Intakes

The term ‘tocopherol’ signifies the methyl-substituted

derivatives of tocol and is not synonymous with the

term ‘vitamin E’. Natural tocochromanols comprise

two homologous series: tocopherols with a saturated

side chain and tocotrienols with an unsaturated side

chain. Tocopherols and tocotrienols have the same

basic chemical structure, which is characterised by a

long isoprenoid side chain attached at the 2 position of

a 6-chromanol ring, as shown in Figure 1.

Tocotrienols differ from tocopherols in that they

possess a farnesyl rather than a saturated isoprenoid

C16 side chain. Natural tocopherols occur in the

RRR-configuration while the synthetic form contains

eight different stereoisomers and is called all-rac-

alpha-tocopherol. Tocotrienols possess only the

chiral stereocenter at C-2 and naturally occurring

tocotrienols exclusively possess the 2R,3’E,7’E

configuration.5 The receptors and enzymes in the

body are highly stereoselective and interact exclusively

with one of the enantiomers of a chiral molecule in a

process called chiral recognition. As a result, only one

enantiomer has the desired effect on the body, while

the others may have either no effect or an adverse

effect.6 Vitamin E isoforms are not interconvertible

inside the human body.7

Vitamin E is found in various foods and oils. Nuts,

seeds and vegetable oils contain high amounts of

alpha-tocopherol, and significant amounts are also

available in green leafy vegetables and fortified cereals.

Some of the richest sources of vitamin E, along with

their tocopherol content and percent daily values, are

shown in Tables 1 and 2.

No specific recommendations regarding the intake

of vitamin E have been made officially, and the optimal

supplementation dosage of mixed tocopherols is still

undetermined. When obtained from food sources

alone, vitamin E has no documented evidence of

toxicity. However, evidence of pro-oxidant damage

has been found to be associated with supplements, but

usually only at very high doses (for example at >1,000

mg/day).9 The recommended dietary allowances

(RDAs) for vitamin E (alpha-tocopherol) are shown in

Table 3.

e158 | SQU Medical Journal, May 2014, Volume 14, Issue 2Saliha Rizvi, Syed T. Raza, Faizal Ahmed, Absar Ahmad, Shania Abbas and Farzana Mahdi

Figure 1: The structures of a tocopherol and tocotrienol.

Adapted from: Colombo ML. An update on vitamin E, tocopherol and tocotrienol: Perspectives.10

Interactions with Dietary

Factors

vitamin E supplements in humans were also seen to

increase the under-carboxylation of prothrombin,13

suggesting that vitamin E decreases the vitamin K

status in humans.

Vitamin E is heavily dependent on vitamin C, vitamin

B3, selenium and glutathione. A diet high in vitamin E

cannot have an optimal effect unless it is also rich in

foods that provide these other nutrients. It was found

that a cooperative interaction between vitamin C and

vitamin E is quite probable, while one between vitamin

C and beta-carotene is improbable and one may exist

between vitamin E and beta-carotene.10 Interactions

were also found between thiols, tocopherols and other

compounds which enhance the effectiveness of the

cellular antioxidant defence systems.11

In 2007, reports from the Women’s Health Study

(WHS) demonstrated that vitamin E supplements

decrease the risk of mortality from thromboembolism

and that alpha-tocopherol decreases the tendency

for clotting in normal healthy women.12 In addition,

Functions of Vitamin E

Table 3: Recommended dietary allowances for vitamin

E (alpha-tocopherol)

Age RDA in mg (IU)

Males Females

0–6 months* 4 (6) 4 (6)

7–12 months* 5 (7.5) 5 (7.5)

1–3 years 6 (9) 6 (9)

4–8 years 7 (10.4) 7 (10.4)

9–13 years 11 (16.4) 11 (16.4)

>14 years

15 (22.4) 15 (22.4)

In pregnancy

15 (22.4)

If lactating

19 (28.4)

RDA = recommended dietary allowances; IU = international units.

*Adequate intake.

Source: Institute of Medicine. Food and Nutrition Board. Dietary

Reference Intakes: Vitamin C, Vitamin E, Selenium, and Carotenoids.63

prevention of oxidative stress

Vitamin E is a potent chain-breaking antioxidant that

inhibits the production of reactive oxygen species

molecules when fat undergoes oxidation and during the

propagation of free radical reactions.14 It is primarily

located in the cell and organelle membranes where it

can exert its maximum protective effect, even when

its concentration ratio may be only one molecule for

every 2,000 phospholipid molecules. It acts as the first

line of defence against lipid peroxidation, protecting

the cell membranes from free radical attack [Figure

2]. Studies have shown that a mixture of tocopherols

has a stronger inhibitory effect on lipid peroxidation

induced in human erythrocytes compared to alpha-

tocopherol alone.15 Due to its peroxyl radical-

scavenging activity, it also protects the polyunsaturated

fatty acids present in membrane phospholipids and

in plasma lipoproteins.16 The tocopheroxyl radicals

formed can either: (1) oxidise other lipids; (2) undergo

further oxidation producing tocopheryl quinones; (3)

form non-reactive tocopherol dimers by reacting with

another tocopheroxyl radical, or (4) be reduced by

other antioxidants to tocopherol.

It has been found that alpha-tocopherol mainly

inhibits the production of new free radicals, while

gamma-tocopherol traps and neutralises the existing

free radicals. Oxidation has been linked to numerous

possible conditions/diseases including: cancer, ageing,

arthritis and cataracts. Thus, vitamin E might help

prevent or delay the chronic diseases associated with

review | e159The Role of Vitamin E in Human Health and Some Diseases

Figure 2: The mechanism of vitamin E (alpha-tocopherol)-mediated low-density lipoprotein lipid peroxidation.

Adapted from: Rathore GS, Suthar M, Pareek A, Gupta RN. Nutritional antioxidants: A battle for better health.17

reactive oxygen species molecules.

protection of the cell

membranes

Vitamin E increases the orderliness of the membrane

lipid packaging, thus allowing for a tighter packing

of the membrane and, in turn, greater stability to

the cell. In 2011, Howard et al. showed that vitamin

E is necessary for maintaining proper skeletal muscle

homeostasis and that the supplementation of cultured

myocytes with alpha-tocopherol promotes plasma

membrane repair.18 This occurs because the membrane

phospholipids are prominent targets of oxidants and

vitamin E efficiently prevents lipid peroxidation.

Conversely, in the absence of alpha-tocopherol

supplementation, the exposure of the cultured cells

to an oxidant challenge strikingly inhibits the repair.

Comparative measurements reveal that in order to

promote the repair, an antioxidant must associate

with the membranes, as alpha-tocopherol does, or

be capable of alpha-tocopherol regeneration. Thus,

vitamin E promotes membrane repair by preventing the

formation of oxidised phospholipids that theoretically

might interfere with the membrane fusion events.

regulation of platelet

aggregation and protein kinase

c activation

An increase in the concentration of alpha-tocopherol

in the endothelial cells has been found to inhibit platelet

aggregation and to release prostacyclin from the

endothelium. This effect was thought to occur because

of the downregulation of the intracellular cell adhesion

molecule (ICAM-1) and the vascular cell adhesion

molecule (VCAM-1), thereby decreasing the adhesion

of blood cell components to the endothelium. Also, due

to their upregulation by vitamin E in the arachidonic

acid cascade, the increase in the expression of cytosolic

phospholipase A2,19 and cyclooxygenase-1,20 increases

the release of prostacyclin, which is a potent vasodilator

and inhibitor of platelet aggregation in humans.21 A

few other studies suggest that tocopherols appear to

inhibit platelet aggregation through the inhibition of

protein kinase C (PKC)22 and the increased action of

nitric oxide synthase.23

The natural RRR-configuration form of alpha-

tocopherol has been shown to be twice as potent as

the other all-racemic (synthetic) alpha-tocopherols

in inhibiting PKC activity.24 This occurs because of

the attenuating effect of alpha-tocopherol on the

generation of membrane-derived diacylglycerol (a lipid

which facilitates PKC translocation and thus increases

its activity); additionally, alpha-tocopherol increases

the activity of protein phosphatase type 2A, which

inhibits PKC autophosphorylation and, consequently,

its activity. Mixed tocopherols are more effective than

alpha-tocopherol in inhibiting platelet aggregation.

Adenosine diphosphate-induced platelet aggregation

decreased significantly in healthy people who were

given gamma-tocopherol-enriched vitamin E (100 mg

of gamma-tocopherol, 40 mg of delta-tocopherol and

20 mg of alpha-tocopherol per day), but not in those

receiving pure alpha-tocopherol alone (100 mg per

day) or in the controls.25

Vitamin E in Disease

Prevention

Vitamin E has been found to be very effective in

e160 | SQU Medical Journal, May 2014, Volume 14, Issue 2Saliha Rizvi, Syed T. Raza, Faizal Ahmed, Absar Ahmad, Shania Abbas and Farzana Mahdi

the prevention and reversal of various disease

complications due to its function as an antioxidant,

its role in anti-inflammatory processes, its inhibition

of platelet aggregation and its immune-enhancing

activity.

cardiovascular diseases

Cardiovascular complications basically arise because

of the oxidation of low-density lipoproteins present in

the body and the consequent inflammation.26 Gamma-

tocopherol is found to improve cardiovascular

functions by increasing the activity of nitric oxide

synthase, which produces vessel-relaxing nitric

oxide.27 It does this by trapping the reactive nitrogen

species (peroxynitriten) molecules and thus enhancing

the endothelial function. Researchers have found that

the supplementation of 100 mg per day of gamma-

tocopherol in humans leads to a reduction in several

risk factors for arterial clotting, such as platelet

aggregation and cholesterol.28 In another study, mixed

tocopherols were found to have a stronger inhibitory

effect on lipid peroxidation and the inhibition

of human platelet aggregation than individual

tocopherols alone,25 suggesting a synergistic platelet-

inhibitory effect. Apart from tocopherols, tocotrienols

were also found to inhibit cholesterol biosynthesis by

suppressing 3-hydroxy-3-methylglutaryl-CoA (HMG-

CoA) reductase, resulting in less cholesterol being

manufactured by the liver cells.29 Contradictory to this,

most of the recent large interventional clinical trials

have not shown cardiovascular benefits from vitamin

E supplementation and report that the use of vitamin

E was associated with a significantly increased risk of

a haemorrhagic stroke in the participants.30 Thus, it

was suggested that understanding the potential uses of

vitamin E in preventing coronary heart disease might

require longer studies with younger participants.

cancer

Vitamin E also possesses anti-cancer properties. This

is possibly because of the various functions of vitamin

E which include: the stimulation of the wild-type p53

tumor suppressor gene; the downregulation of mutant

p53 proteins; the activation of heat shock proteins, and

an anti-angiogenic effect mediated by the blockage of

transforming growth factor alpha.31 Alpha-, gamma-

and delta-tocopherols have emerged as vitamin E

molecules with functions clearly distinct from each

other in anti-cancer activity as well. Alpha-tocopherol

was found to inhibit the production of PKC and

collagenase,32 which facilitate cancer cell growth. In

this context gamma-tocopherol was found to be more

effective than alpha-tocopherol in its growth inhibitory

effect on human prostate cancer cell lines, whereas

delta-tocopherol has shown growth inhibitory activity

against mouse mammary cancer cell lines.33

Gamma-tocopherol inhibits the growth of cancer

cells in cultures through a number of mechanisms.

It traps free radicals, including the reactive nitrogen

species molecules that cause mutations in the

deoxyribonucleic acid strands and malignant

transformations in the cells.34 It also downregulates

the control molecules known as cyclins, stopping the

cancerous cell cycle in the middle and thus preventing

their proliferation.35 Gamma-tocopherol has also been

found to be superior to alpha-tocopherol in: inducing

apoptosis; triggering a number of cell-death-inducing

pathways;36 stimulating peroxisome proliferator-

activated receptor gamma activity, especially in colon

cancer cells,37 and in reducing the formation of new

blood vessels in tumours, thus depriving them of

the nutrients they need to thrive.38 In this context,

tocotrienols were also found to have antiproliferative

and apoptotic activities on normal and cancerous

cells in humans, which could be due to the induction

of apoptosis by a mitochondria-mediated pathway,

or due to the suppression of cyclin D which would

therefore arrest the cell cycle.39 They also inhibit

vascularisation and suppress 3-hydroxy-3-methyl

coenzyme A (HMG-CoA) reductase activity, thus

preventing malignant proliferation.

Jiang et al. showed that, of the various forms

of vitamin E, gamma-tocopherol, particularly in

combination with delta-tocopherol, induced apoptosis

in androgen-sensitive prostate cancer cells within

three days of treatment, while alpha-tocopherol alone

did not have the same effect.40 The gamma and delta

E fractions appear to induce apoptosis by interrupting

the synthesis of sphingolipid in the membranes of

human prostate cancer cells.40 The fractions do this by

inducing the release of cytochrome c, the activation

of caspase-9 and caspase-3, the cleavage of poly-

adenosine diphosphate (ADP)-ribose polymerase

(PARP) and the involvement of caspase-independent

pathways. Recently, Chen reported that, of the

tocopherols tested, the gamma form was the most

potent anti-cancer form of the vitamin. They also

found a novel anti-cancer mechanism of vitamin E:

gamma-tocopherol, they created a new agent which

was found to be 20-fold more effective. They did so by

removing a string of chemical groups dangling from

the head group of gamma-tocopherol which enhanced

its anti-cancer effect. Chen et al. said that gamma-

tocopherol was more effective than other tocopherols

because of its chemical structure which is more

effective in attaching and thus shutting off the Akt

enzyme.38 These findings suggest that an agent based

on the chemical structure of one form of vitamin E

review | e161The Role of Vitamin E in Human Health and Some Diseases

could help to prevent and treat numerous types of

cancer—particularly those associated with a mutation

in the PTEN gene, a fairly common cancer-related

genetic defect that keeps protein kinase B (Akt) active.

Chen studied both alpha and gamma forms of the

vitamin E molecule; both inhibited the Akt enzyme in

very targeted ways, but the gamma structure emerged

as the more powerful form of the vitamin. In effect,

the vitamin halted Akt activation by attracting Akt

and the PHLPP1 protein to the same region of a cell

where the vitamin was absorbed in the fat-rich cell

membrane. The PHLPP1 tumour suppressor protein

then launched a chemical reaction that inactivated

Akt, rendering it unable to keep cancer cells alive.

Apart from these findings, the role of vitamin

E in cancer prevention remains controversial. The

reports from the Cancer Institute of New Jersey

show that gamma- and delta-tocopherols can prevent

colon, lung, breast and prostate cancers, while alpha-

tocopherol had no such effect. In addition, human

trials and surveys aiming to study the association

between vitamin E intake and cancer have found

that vitamin E is not beneficial in most cases. Both

the Heart Outcomes Prevention Evaluation—The

Ongoing Outcomes (HOPE-TOO) trial and the WHS

study evaluated whether vitamin E supplements might

protect people from cancer and found no significant

reduction in the risk of developing cancer in individuals

taking daily doses of 400 IU or 600 IU of vitamin E.41,42

cataracts

Cataracts are one of the commonest causes of significant

vision loss in older people. They basically occur due

to the accumulation of proteins damaged by free

radicals. Several observational studies have revealed a

potential relationship between vitamin E supplements

and the risk of cataract formation. Leske et al. found

that lens clarity was superior in participants who took

vitamin E supplements and those with higher blood

levels of the vitamin.43 In another study, a long-term

supplementation of vitamin E was associated with the

slower progression of age-related lens opacification.44

However, in the randomised Age-Related Eye Disease

Study (AREDS), vitamin E had no apparent effect on

cataract development/progression over an average

of 6.3 years.45 Overall, the available evidence is

insufficient to conclude that vitamin E supplements,

taken alone or in combination with other antioxidants,

can reduce the risk of cataract formation.

alzheimer’s disease

Alzheimer’s disease (AD) occurs as a result of protein

oxidation and lipid peroxidation via a free radical

mechanism, where the beta amyloid protein induces

cytotoxicity through a mechanism involving oxidative

stress and hydrogen peroxide, leading to neuronal

cell death and, finally, AD. Vitamin E can block the

production of hydrogen peroxide and the resulting

cytotoxicity. It reduces beta amyloid-induced cell death

in rat hippocampal cell cultures46 and PC12 cells47 and

attenuates the excitatory amino acid-induced toxicity

in neuroblastoma cells.48 The Alzheimer’s Disease

Cooperative Study in 1997 showed that vitamin E may

slow disease progression in patients with moderately

severe AD. High doses of vitamin E delayed the loss

of the patient’s ability to carry out daily activities

and their consequent placement in residential care

for several months.49 In another study, it was found

that subjects with AD had reduced concentrations

of plasma antioxidant micronutrients, suggesting

that inadequate antioxidant activity is a factor in this

disease. High plasma levels of vitamin E are associated

with a reduced risk of AD in older patients and this

neuroprotective effect is related to the combination

of different forms of vitamin E rather than to alpha-

tocopherol alone.50 A study published in 2009 examined

the effects of taking 2,000 IU of vitamin E with and

without an AD drug on 847 people. It concluded that

vitamin E plus a cholinesterase inhibitor may be more

beneficial than taking either agent alone.51

At the biomarker level, Mangialasche et al.

demonstrated that plasma levels of tocopherols and

tocotrienols together with automated magnetic

resonance imaging (MRI) measures can help to

differentiate patients with AD and mild cognitive

impairment (MCI) from the control subjects, and

prospectively predict the MCI conversion into AD.49

This therefore suggests the potential role of nutritional

biomarkers detected in plasma-tocopherols and

tocotrienols as indirect indicators of AD pathology.52

However, researchers have recommended that

patients should not take vitamin E to treat AD without

the supervision of a physician, as in high doses it can

interact negatively with other medications, including

those prescribed to lower cholesterol.

human immunodeficiency virus

and acquired immunodeficiency

syndrome

Vitamin E is an important anti-inflammatory

agent that is often found to be deficient in human

immunodeficiency virus (HIV)-positive individuals;

however, it is not known whether vitamin E

supplementation is beneficial either at every or any

stage of HIV infection. At a dose of 400 IU, vitamin

E was shown to restore delayed skin hypersensitivity

reactions and interleukin-2 production, and at high

doses it was shown to stimulate T helper cell (CD4

e162 | SQU Medical Journal, May 2014, Volume 14, Issue 2Saliha Rizvi, Syed T. Raza, Faizal Ahmed, Absar Ahmad, Shania Abbas and Farzana Mahdi

T-cell) proliferation.53 In 1997, Tang et al. studied the

association between serum vitamin A and E levels with

HIV-1 disease progression. In this study, it was found

that men with serum vitamin E levels above 23.5 µm/L

had a significantly reduced risk of disease progression.

A strong correlation was noted in this cohort between

the intake of supplements containing vitamin E at the

point of entry into the study and high blood levels of

vitamin E.54

A study on murine acquired immunodeficiency

syndrome (AIDS) using a 15-fold increase in dietary

vitamin E showed the normalisation of immune

parameters that are altered in HIV/AIDS.55 Apart

from this, an increase in dietary vitamin E has also

been shown to protect against the side-effects of

azidothymidine, such as bone marrow toxicity.56 Related

studies on bone marrow cultures from stage IV AIDS

patients using d-alpha-tocopherol supplementation

revealed similar results.57 Nevertheless, it has also been

reported that higher vitamin E levels pre-infection

were found to be associated with increased mortality.

Thus, further research is needed to elucidate the role

vitamin E plays in the pathogenesis of HIV-1.58

immunity

It has now been proven that vitamin E stimulates the

body’s defences, enhances humoral and cell immune

responses and increases phagocytic functions. It has

a pronounced effect in infectious diseases where

immune phagocytosis is involved, but is less effective

in the case of cell-mediated immune defences. Its

supplementation significantly enhances both cell-

mediated and humoral immune functions in humans,

especially in the elderly. A daily intake of 200 mg of

vitamin E improved the antibody response to various

vaccines in healthy subjects who showed no adverse

side-effects to vitamin E supplementation.59 Vitamin

E also enhanced resistance to viral diseases in elderly

subjects, where higher plasma vitamin E levels

correlated with a reduced number of infections over

a three-year period.60 A recent study by Kutty et al.

showed that a daily supplementation of vitamin E can

enhance the immune response to a specific antigen.61

Besides the above mentioned diseases, vitamin E

has also been found to play a beneficial role in other

diseases, such as photodermatitis, menstrual pain/

dysmenorrhoea, pre-eclampsia and tardive dyskinesia,

when taken along with vitamin C.62

Vitamin E Deficiency

Vitamin E deficiency is quite rare in humans. It

happens almost exclusively in people with an inherited

or acquired condition that impairs their ability to

absorb the vitamin (for instance, cystic fibrosis, short

bowel syndrome or bile duct obstruction) and in those

who cannot absorb dietary fat or have rare disorders

of fat metabolism. Recent reports have shown that the

alpha-TTP regulates the secretion of alpha-tocopherol

from the liver cells and that missense mutations of

some arginine residues at the surface of the alpha-

TTP can cause severe vitamin E deficiency in

humans.63 The wild-type alpha-TTP was found to bind

phosphatidylinositol phosphates (PIPs), whereas the

arginine mutants did not—where the PIPs in the target

membrane promoted the inter-membrane transfer

of alpha-tocopherol by alpha-TTP. The resulting

symptoms of vitamin E deficiency include muscle

weakness, vision problems, immune system changes,

numbness, difficulty in walking and tremors as well as

a poor sense of balance. Apart from these symptoms,

deficiency can also lead to neuromuscular problems

such as spinocerebellar ataxia and myopathies,24

dysarthria, an absence of deep tendon reflexes, the

loss of both vibratory sensations and positive Babinski

reflexes.24 Vitamin E deficiency can also cause anaemia

due to the oxidative damage to the red blood cells,24

retinopathy64–67 and the impairment of the immune

response.59–61 If untreated, vitamin E deficiency may

result in blindness, heart disease, permanent nerve

damage and impaired thinking. Some reports also

suggest that vitamin E deficiency can even result in

male infertility.24

Conclusion

Vitamin E was first used as a supplement in Canada by

the physicians Shute and Shute; based on the positive

results it achieved, they began using it regularly in their

practices. Since then, well-designed experimental and

clinical studies have progressed steadily and increased

our knowledge of vitamin E. The antioxidative

properties of vitamin E have been found to play a

vital role in the battle against various diseases such as

atherosclerosis, oxidative stress, cancer, cataract and

AD, among others.

This review focussed on the important functions

of vitamin E in some diseases; in addition to these, this

vitamin has been found to be effective against asthma,

allergies and diabetes, among others. Discussion

of the dietary sources, RDA and the interaction of

vitamin E supplements with other dietary factors, has

demonstrated the need for and significance of vitamin

E in the human context. Thus, raising public awareness

of the role of dietary antioxidants in maintaining better

health would benefit a number of lives.

review | e163The Role of Vitamin E in Human Health and Some Diseases

Apart from the enormous benefits reported, there

has always been debate about the exact function of

vitamin E and its role in various diseases. There are

many conflicting reports of positive and negative

results on the same biological activities in the

literature. The primary hindrance in determining

the roles of vitamin E in human health is the lack

of validated biomarkers for vitamin E intake and

status, which would help to relate intakes to possible

clinical outcomes. In conclusion, although the data

surrounding vitamin E is contradictory, the current

literature appears to support the view that the benefits

outweigh the side-effects.

References

1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. Niki E, Traber MG. A history of vitamin E. Ann Nutr Metab

2012; 61:207–12.

Zingg JM. Vitamin E: An overview of major research directions.

Mol Aspects Med 2007; 28:400–422.

Chow CK. Distribution of tocopherols in human plasma and

red blood cells. Am J Clin Nutr. 1975; 28:756–60.

Drotleff AM, Ternes W. Determination of RS,E/Z-tocotrienols

by HPLC. J Chomatogr A 2001; 909:215–23.

Zingg JM. Molecular and cellular activities of vitamin E

analogues. Mini Rev Med Chem 2007; 7:543–58.

Ball GFM. Vitamins in Foods: Analysis, bioavailability, and

stability. Boca Raton, Florida: CRC Press, 2006, pp. 119–36.

Brown KM, Morrice PC, Duthie GG. Erythrocyte vitamin E

and plasma ascorbate concentrations in relation to erythrocyte

peroxidation in smokers and non-smokers: Dose response to

vitamin E supplementation. Am J Clin Nutr 1997; 65:496–502.

Niki E, Noguchi N, Tsuchihashi H, Gotoh N. Interaction among

vitamin C, vitamin E, and beta-carotene. Am J Clin Nutr 1995;

62:1322S–26S.

Di Mascio P, Murphy ME, Sies H. Antioxidant defense systems:

The role of carotenoids, tocopherols, and thiols. Am J Clin Nutr

1991; 53:194S–200S.

Glynn RJ, Ridker PM, Goldhaber SZ, Zee RY, Buring JE. Effects

of random allocation to vitamin E supplementation on the

occurrence of venous thromboembolism: Report from the

Women’s Health Study. Circulation 2007; 116:1497–503.

Booth SL, Golly I, Sacheck JM, Roubenoff R, Dallal GE, Hamada

K, et al. Effect of vitamin E supplementation on vitamin K

status in adults with normal coagulation status. Am J Clin Nutr

2004; 80:143–8.

Burton GW, Ingold KU. Autoxidation of biological molecules:

1. The antioxidant activity of vitamin E and related chain-

breaking phenolic antioxidants in vitro. J Am Chem Soc 1981;

103:6472–7.

Liu M, Wallin R, Wallmon A, Saldeen T. Mixed tocopherols

have a stronger inhibitory effect on lipid peroxidation than

alpha-tocopherol alone. J Cardiovasc Pharmacol 2002; 39:714–

21.

Burton GW, Joyce A, Ingold KU. Is vitamin E the only lipid-

soluble, chain-breaking antioxidant in human blood plasma

and erythrocyte membranes? Arch Biochem Biophys 1983;

221:281–90.

Howard AC, Anna K. McNeil AK, McNeil PL. Promotion of

plasma membrane repair by vitamin E. Nat Commun 2011;

20:597.

16. Tran K, Wong JT, Lee E, Chan AC, Choy PC. Vitamin E

potentiates arachidonate release and phospholipase A2 activity

in rat heart myoblastic cells. Biochem J 1996; 319:385–91.

17. Chan AC, Wagner M, Kennedy C, Mroske C, Proulx P,

Laneuville O, et al. Vitamin E up-regulates phospholipase A2,

arachidonic acid release and cyclooxygenasin endothelial cells.

Aktuel Ernährungsmed 1998; 23:1–8.

18. Szczeklik A, Gryglewski RJ, Domagala B, Dworski R,

Basista M. Dietary supplementation with vitamin E in

hyperlipoproteinemias: Effects on plasma lipid peroxides,

antioxidant activity, prostacyclin generation and platelet

aggregability. Thromb Haemost 1985; 54:425–30.

19. Freedman JE, Farhat JH, Loscalzo J, Keaney JF Jr. Alpha-

tocopherol inhibits aggregation of human platelets by a protein

kinase C-dependent mechanism. Circulation 1996; 94:2434–40.

20. Li D, Saldeen T, Romeo F, Mehta JL. Different isoforms of

tocopherols enhance nitric oxide synthase phosphorylation

and inhibit human platelet aggregation and lipid peroxidation:

Implications in therapy with vitamin E. J Cardiovasc Pharmacol

Ther 2001; 6:155–61.

21. Brigelius-Flohé R, Traber MG. Vitamin E: Function and

metabolism. FASEB J 1999; 13:1145–55.

22. Liu M, Wallmon A, Olsson-Mortlock C, Wallin R, Saldeen

T. Mixed tocopherols inhibit platelet aggregation in humans:

Potential mechanisms. Am J Clin Nutr 2003; 77:700–6.

23. Steinberg D, Parthasarathy S, Carew TE, Khoo JC, Witztum JL.

Beyond cholesterol: Modifications of low-density lipoprotein

that increase its artherogenicity. N Engl J Med 1989; 320:915–

24.

24. Li D, Saldeen T, Romeo F, Mehta JL. Relative effects of alpha-

and gamma-tocopherol on low-density lipoprotein oxidation

and superoxide dismutase and nitric oxide synthase activity and

protein expression in rats. J Cardiovasc Pharmacol Ther 1999;

4:219–26.

25. Singh I, Turner AH, Sinclair AJ, Li D, Hawley JA. Effects of

gamma-tocopherol supplementation on thrombotic risk

factors. Asia Pac J Clin Nutr 2007; 16:422–8.

26. McAnally JA, Gupta J, Sodhani, S, Bravo L, Mo H. Tocotrienols

potentiate lovastatin-mediated growth suppression in vitro and

in vivo. Exp Biol Med (Maywood) 2007; 232:523–31.

27. Sesso HD, Buring JE, Christen WG, Kurth T, Belanger C,

MacFadyen J, et al. Vitamins E and C in the prevention of

cardiovascular disease in men: The Physicians’ Health Study II

randomized controlled trial. JAMA 2008; 300:2123–33.

28. Shklar G, Oh SK. Experimental basis for cancer prevention by

vitamin E. Cancer Invest 2000; 18:214–22.

29. Ricciarelli R, Maroni P, Ozer N, Zingg JM, Azzi A. Age-

dependent increase of collagenase expression can be reduced

by alpha-tocopherol via protein kinase C inhibition. Free Radic

Biol Med 1999; 27:729–37.

30. McIntyre BS, Briski KP, Gapor A, Sylvester PW. Antiproliferative

and apoptotic effects of tocopherols and tocotrienols on

preneoplastic and neoplastic mouse mammary epithelial cells.

Proc Soc Exp Biol Med 2000; 224:292–301.

31. Christen S, Woodall AA, Shigenaga MK, Southwell-Keely PT,

Duncan MW, Ames BN. Gamma-tocopherol traps mutagenic

electrophiles such as NO(X) and complements alpha-

tocopherol: Physiological implications. Proc Natl Acad Sci U S

A 1997; 94:3217–22.

32. Gysin R, Azzi A, Visarius T. Gamma-tocopherol inhibits

human cancer cell cycle progression and cell proliferation by

down-regulation of cyclins. FASEB J 2002; 16:1952–4.

33. Takahashi S, Takeshita K, Seeni A, Sugiura S, Tang M, Sato SY,

et al. Suppression of prostate cancer in a transgenic rat model

via gamma-tocopherol activation of caspase signaling. Prostate

2009; 69:644–51.

e164 | SQU Medical Journal, May 2014, Volume 14, Issue 2Saliha Rizvi, Syed T. Raza, Faizal Ahmed, Absar Ahmad, Shania Abbas and Farzana Mahdi

34. 35. 36. 37. 38. 39. 40. 41. 42. 43. 44. 45. 46. 47. 48. 49. Stone WL, Krishnan K, Campbell SE, Qui M, Whaley SG, Yang

H. Tocopherols and the treatment of colon cancer. Ann N Y

Acad Sci 2004; 1031:223–33.

Wells SR, Jennings MH, Rome C, Hadjivassiliou V, Papas KA,

Alexander JS. Alpha-, gamma- and delta-tocopherols reduce

inflammatory angiogenesis in human microvascular endothelial

cells. J Nutr Biochem 2010; 21:589–97.

Wada S. Chemoprevention of tocotrienols: The mechanism of

antiproliferative effects. Forum Nutr 2009; 61:204–16.

Jiang Q, Wong J, Fyrst H, Saba JD, Ames BN. Gamma-tocopherol

or combinations of vitamin E forms induce cell death in human

prostate cancer cells by interrupting sphingolipid synthesis.

Proc Natl Acad Sci U S A 2004; 101:17825–30.

Chen CS. Study Shows How Vitamin E Can Help Prevent

Cancer. From: www.researchnews.osu.edu/archive/silenceakt.

htm Accessed: Dec 2013.

Lonn E, Bosch J, Yusuf S, Sheridan P, Pogue J, Arnold JM,

et al. Effects of long-term vitamin E supplementation on

cardiovascular events and cancer: A randomized controlled

trial. JAMA 2005; 293:1338–47.

Lee IM, Cook NR, Gaziano JM, Gordon D, Ridker PM, Manson

JE, et al. Vitamin E in the primary prevention of cardiovascular

disease and cancer: The Women’s Health Study: A randomized

controlled trial. JAMA 2005; 294:56–65.

Jacques PF, Taylor A, Moeller S, Hankinson SE, Rogers G,

Tung W, et al. Long-term nutrient intake and 5-year change in

nuclear lens opacities. Arch Ophthalmol 2005; 123:517–26.

Age-Related Eye Disease Study Research Group. A randomized,

placebo-controlled, clinical trial of high-dose supplementation

with vitamins C and E and beta carotene for age-related

cataract and vision loss: AREDS report no. 9. Arch Opthalmol

2001; 119:1439–52.

Goodman Y, Mattson MP. Secreted forms of beta-amyloid

precursor protein protect hippocampal neurons against

amyloid beta-peptide-induced oxidative injury. Exp Neurol

1994; 128:1–12.

Behl C, Davis J, Cole GM, Schubert D. Vitamin E protects nerve

cells from amyloid beta protein toxicity. Biochem Biophys Res

Commun 1992; 186:944–50.

Murphy TH, Schnaar RL, Coyle JT. Immature cortical neurons

are uniquely sensitive to glutamate toxicity by inhibition of

cystine uptake. FASEB J 1990; 4:1624–33.

Sano M, Ernesto C, Thomas RG, Klauber MR, Schafer K,

Grundman M, et al. A controlled trial of selegiline, alpha-

tocopherol, or both as treatment for Alzheimer’s disease. The

Alzheimer’s Disease Cooperative Study. N Engl J Med 1997;

336:1216–22.

Mangialasche F, Kivipelto M, Mecocci P, Rizzuto D, Palmer K,

Winblad B, et al. High plasma levels of vitamin E forms and

reduced Alzheimer’s disease risk in advanced age. J Alzheimer’s

Dis 2010; 20:1029–37.

Pavlik, VN, Doody RS, Rountree SD, Darby EJ. Vitamin E use

Is associated with improved survival in an Alzheimer’s disease

cohort. Dement Geriatr Cogn Disord 2009; 28:536–40.

Mangialasche F, Westman E, Kivipelto M, Muehlboeck JS,

Cecchetti R, Baglioni M, et al. Classification and prediction

of clinical diagnosis of Alzheimer’s disease based on MRI

and plasma measures of α-/γ-tocotrienols and γ-tocopherol. J

Intern Med 2013; 273:602–21.

50. Meydani M. Vitamin E. Lancet 1995; 345:170–5.

51. Tang AM, Graham NM, Semba RD, Saah AJ. Association

between serum vitamin A and E levels and HIV-1 disease

progression. AIDS 1997; 11:613–20.

52. Wang Y, Huang DS, Watson RR. Vitamin E supplementation

modulates cytokine production by thymocytes during murine

AIDS. Immunol Res 1993; 12:358–66.

53. Ganser A, Greher J, Volkers B, Staszewski A, Hoelzer D.

Azidothymidine in the treatment of ATDS. N Engl J Med 1988;

318:250–1.

54. Geissler RG, Ganser A, Ottmann OG, Gute P, Morawetz A,

Guba P, et al. In vitro improvement of bone marrow-derived

hematopoietic colony formation in HIV-positive patients by

alpha-D-tocopherol and erythropoietin. Eur J Haematol 1994;

53:201–6.

55. Graham SM, Baeten JM, Richardson BA, Bankson DD, Lavreys

L, Ndinya-Achola JO, et al. Higher pre-infection vitamin E

levels are associated with higher mortality in HIV-1-infected

Kenyan women: A prospective study. BMC Infect Dis 2007;

7:63.

56. Meydani SN, Meydani M, Blumberg JB, Leka LS, Siber G,

Loszewski R, et al. Vitamin E supplementation and in vivo

immune response in healthy elderly subjects: A randomized

controlled trial. JAMA 1997; 277:1380–6.

57. Chavance M, Herbeth B, Fournier C, Janot C, Vernhes

G. Vitamin status, immunity and infections in an elderly

population. Eur J Clin Nutr 1989; 43:827–35.

58. Radhakrishnan AK, Mahalingam D, Selvaduray KR, Nesaretnam

K. Supplementation with natural forms of vitamin E augments

antigen-specific TH1-type immune response to tetanus toxoid.

Biomed Res Int 2013; 2013:782067.

59. University of Maryland Medical Center. Vitamin E. From:

www.umm.edu/health/medical/altmed/supplement/vitamin-

e#ixzz2c7gfq93R Accessed: Dec 2013.

60. Kono N, Ohto U, Hiramatsu T, Urabe M, Uchida Y, Satow Y, et

al. Impaired a-TTP-PIPs interaction underlies familial vitamin

E deficiency. Science 2013; 340:1106–10.

61. Office of Dietary Supplements, National Institutes of Health.

Dietary Supplement Fact Sheet: Vitamin E.. From: www.ods.

od.nih.gov/factsheets/vitamine.asp Accessed: Aug 2010.

62. Food and Nutrition Board, Institute of Medicine. Dietary

Reference Intakes for Vitamin C, Vitamin E, Selenium, and

Carotenoids. Washington, DC: National Academy Press, 2000.

63. Kowdley KV, Mason JB, Meydani SN, Cornwall S, Grand

RJ. "Vitamin E deficiency and impaired cellular immunity

related to intestinal fat malabsorption". Gastroenterology.

1992;102(6):2139–42.

64. Slover HT. Tocopherols in foods and fats. Lipids 1971; 6:291–6.

65. United States Department of Agriculture (USDA), Agricultural

Research Service. USDA National Nutrient Database for

Standard Reference, Release 25. From: www.ars.usda.gov/

SP2UserFiles/Place/12354500/Data/SR25/nutrlist/sr25a323.

pdf Accessed: Dec 2013.

66. Colombo ML. An update on vitamin E, tocopherol and

tocotrienol: Perspectives. Molecules 2010; 15:2103–13.

67. Rathore GS, Suthar M, Pareek A, Gupta RN. Nutritional

antioxidants: A battle for better health. J Nat Pharmaceuticals

2011; 2:2–14.