Medicinal Significance and Complications of Vitamin E

*Naresh Podila, Sathish Kumar Konidala, Jithendra Chimakurthy, Srilatha Muddisetti, Suryaprabha Matangi, Natesh Gunturu, Yamarthi Venkateswara Rao and Mithun Rudrapal*

## **Abstract**

Vitamin E is a lipid-soluble substance that is the main component of the body's defense system against free radicals. It performs a range of important functions in the body as a result of its antioxidant action. Cancer, aging, and other diseases and ailments have all been related to oxidation. It has been shown that vitamin E protects against rheumatoid arthritis and cataracts. Additionally, vitamin E can help to prevent the production of prostaglandins like thromboxane, which encourage platelet clustering and hyper aggregation, which can lead to atherosclerosis. The present literature review examines the roles and functions of vitamin E in human health, different disorders, and the consequences of vitamin E deficiency. The tocopherol family of vitamers is the focus of the review's main points. In this review article, the part and actions of vitamin E are talked about, as well as the things that affect how well vitamin E treatment works. When given at the right time and for the right amount of time, Vitamin E should help people with oxidative stress caused by free radicals.

**Keywords:** vitamin E, health, antioxidants, tocopherols, free radicals

## **1. Introduction**

A vitamin that dissolves in fat is vitamin E. Cereals, vegetable oils, meat, chicken, eggs, and fruits are just a few examples of the many meals that contain it. An essential vitamin, vitamin E is needed for the healthy operation of numerous organs in the body. As an antioxidant, it is also. RRR-alpha-tocopherol, a form of vitamin E that naturally occurs in foods, differs from the synthetic Supplemental vitamin E is available as all-rac-alpha tocopherol [1]. When patients have certain hereditary abnormalities or premature infants who were born very low in weight, vitamin E is used to treat vitamin E insufficiency, a condition that is uncommon but can occur. There is other more ailments for which vitamin E is utilized, however many of these other uses lack solid scientific backing. The antioxidant vitamin E has the potential to shield the body's cells from harm. Antioxidants may offer defense against major

illnesses including cancer and heart disease. Additionally essential for the production of vitamin E and red blood cells also aids in the utilization of vitamin K [2].

The liver absorbs vitamin E once it is absorbed in the small intestine and stores it there until it is required. At that time, the liver only secretes alpha-tocopherol again, which the body can identify. Your immune system benefits from vitamin E, which also supports healthy skin, eyes, and brain function. Despite the rarity of vitamin E deficiency, maintaining health and preventing and treating disease depend on achieving daily vitamin E needs. Several circumstances can lead to vitamin E insufficiency. Premature infants with low birth weight are one example. It is also possible among those who have an illness that impairs the body's ability to effectively absorb dietary fat, such as Crohn's disease or cystic fibrosis. Both require supplementation to reduce the risk of complications [3].

Those who struggle to adequately absorb fats may become vitamin E deficient. Serious vitamin E deficiency symptoms include [4].


Continuing deficiencies may also result in issues with the liver and kidneys. Although the majority of Americans do not have severe vitamin E deficiencies, many may have slightly low amounts. Edible vegetable oils are the best sources of vitamin E in the diet because they have the highest concentrations of all the different homologs (**Table 1**) Red blood cells and serum contain alpha- and gamma-tocopherols, with alpha-tocopherol having the highest quantity [5]. Only trace amounts of beta- and delta-tocopherols can be found in plasma. The higher metabolism of the other forms of tocopherol and the α-tocopherol possess protein are the causes of


#### **Table 1.**

*Vegetable oils contain vitamin E.*

#### *Medicinal Significance and Complications of Vitamin E DOI: http://dx.doi.org/10.5772/intechopen.112761*

alpha-preferential tocopherol distribution in humans (alpha-TTP). The reason why alpha-tocopherol is largely removed in the urine while the majority of the absorbed beta-, gamma, and delta-tocopherols are released into the bile and excreted in the feces, is because of the binding affinity of α-tocopherol with alpha-TTP. In nonhepatic tissues, such as the endoplasmic reticulum and mitochondrial membranes of the heart and lungs and other organs with high amounts of free radical production, the alpha-tocopherol form also accumulates [6].

Oxidative stress has been linked to the pathogenesis of a number of diseases, including atherosclerosis, fatty liver disease, cancer, and neurodegenerative disorders [7, 8]. Oxidation of biological molecules such as lipids, proteins, and DNA, mediated by reactive oxygen species (ROS) and free radicals, results in injury to biological membranes, modification of proteins, inactivation of enzymes, and modification of DNA, according to an abundance of experimental evidence. Therefore, the function of antioxidants against oxidative stress in disease prevention and treatment has received considerable attention from both scientists and the general public [9]. If oxidative stress plays a causal role, it is expected that antioxidants will reduce the risk or be beneficial in the prevention and treatment of these diseases.

Several 1980s epidemiological studies suggested the health benefits of antioxidants such as vitamin E and carotenoids. Cancer incidence is negatively associated with the ingestion of fresh fruits and green-yellow vegetables [10]. This is attributable, at least in part, to the numerous phytochemical compounds found in plant foods, the majority of which are powerful antioxidants [11]. The Multinational Monitoring of Trends and Determinants in Cardiovascular Disease (MONICA) study revealed an inverse association between plasma vitamin E concentration and mortality due to ischemic heart disease and malignancy. Several large cohort studies have supported the protective function of antioxidants with overwhelmingly positive findings. Antioxidant-containing dietary supplements are very popular among a sizable fraction of the population, as a result of the heightened enthusiasm.

Large-scale randomized clinical trials and meta-analyses, on the other hand, have shown disappointing and contradictory data about vitamin E's effects. Not only have there been a number of "null" results, but some studies have shown that taking a lot of vitamin E may be bad for you, which has caused a lot of debate [12–14].

This article talks about the roles and effects of vitamin E and uses the scientific data to answer the following questions. Are oxidative harm and diseases caused by free radicals? Does vitamin E stop damage caused by free radicals and diseases that come with it? Why do controlled, randomized human studies of vitamin E give mixed and disappointing results?

#### **1.1 Chemistry of vitamin E**

Vitamin E is not the same thing as tocopherol; rather, Tocopherol refers to tocol derivatives with a methyl substitution. The two homologous sets of natural tocochromanols are Unsaturated tocotrienols and tocopherols with saturated side chains are two types of tocopherols. (**Figure 1**) depicts the fundamental chemical structure of tocopherols and tocotrienols; it has two places on a 6-chromanol ring where a lengthy isoprenoid side chain is connected. In contrast to tocopherols, which have a saturated isoprenoid C16 side chain, tocotrienols have a farnesyl side chain. Natural tocopherols have the RRR-configuration, but all-racalpha-tocopherol, which is the synthesized version, has eight distinct stereoisomers. Natural tocotrienols only have the 2R, 3′E and 7′E structure, and tocotrienols only have the chiral stereo center at C-2 [7]. Chiral

**Figure 1.** *Structure of tocopherol.*

recognition is the process by which the enzymes and body's receptors solely communicate with the enantiomers of the one of chiral compounds. As a consequence, only one of the two enantiomers has the desired effect on the body, while the other two may either have no effect or a negative effect. E- Vitamin cannot be converted to one another within the human [15, 16].

## **1.2 Sources and recommended intakes**

Various foods and oils contain vitamin E. Alpha-tocopherol is present in substantial quantities in vegetable oils, fortified cereals, green leafy vegetables, nuts, seeds.


**Table 2.**

*Food that contain vitamin E found in some foods.*

*Medicinal Significance and Complications of Vitamin E DOI: http://dx.doi.org/10.5772/intechopen.112761*


#### **Table 3.**

*Guidelines for intake of E vitamin.*

(**Tables 1** and **2**) lists the top resources of vitamin E and their tocopherol quantity, and their percentage of daily values. The ideal supplementation number of mixed tocopherols is yet unknown, and no official recommendations has been established addressing the consumption of vitamin E. Vitamin E may not appear to be hazardous when only received from food sources. However, it has been discovered that supplements might cause pro-oxidant damage, but often only at high levels (for instance, >1000 mg/day) [17]. Listed below are the recommended daily amounts (RDAs) for vitamin E (alpha-tocopherol) (**Table 3**).

#### **1.3 Dietary factors interaction**

The breakdown of vitamin E is significantly influenced by selenium, glutathione, vitamin B3, and vitamin C. For a diet high in vitamin E to be successful, it must also contain foods that are high in these other nutrients. Beta-carotene and vitamin E have a potential cooperative connection, but vitamin C and beta-carotene have a very high likelihood of having one [3]. It has been discovered that the interactions between tocopherols, Thiols increase the potency of cellular antioxidant protection mechanisms [18]. Findings in the year of 2007 the study from the Women's Health manifestation that E vitamin and alpha-tocopherol supplementation lower the risk of dying from thromboembolism in healthy normal women [19]. Additionally, it was shown that vitamin E supplementation increased prothrombin's under-carboxylation in humans, which suggests that vitamin E lowers people's levels of vitamin K [20].

### **2. Vitamin E's functions**

#### **2.1 Controlling oxidative stress**

The E Vitamin, a potent antioxidant that disrupts chemical bonds, stops the synthesis of reactive oxygen species molecules when fat is subjected to oxidation and during the spread of free radical reactions [21]. even though the phospholipid concentration level may only be one molecule for every 2000 of it, it is mostly found in the membranes of cells and organelles where it can exert its possessive impact.

To prevent lipid peroxidation, it serves as the first line of defense, shielding the cell membranes from oxidative damage. According to studies, alpha tocopherol alone is not as effective at inhibiting lipid peroxidation in human erythrocytes as a mixture of tocopherols is [22]. The polyunsaturated fatty acids found in membrane phospholipids and plasma lipoproteins are additionally safeguarded through its peroxyl radical scavenging action [23–25]. The resulting tocopheroxyl radicals can then go on to oxidize other lipids, go through extra oxidation to form tocopheryl quinones, combine with another radical to form non-reactive tocopherol dimers, or be reduced by additional antioxidants to tocopherol. It has been discovered that although gammatocopherol captures and neutralizes the free radicals already present, α-tocopherol primarily suppress the generation of anew free radicals. Numerous possible outcomes have been connected to oxidation, including illnesses and disorders, cataracts, cancer, aging, and cancer. As a result, E vitamin might aid in preventing or delaying the Reactive oxygen species molecules have been related to the emergence of chronic illnesses.

#### **2.2 Evidence for in-vivo lipid peroxidation and its link to disease**

Highly susceptible to oxidation are polyunsaturated fatty acids such as linoleic acid and arachidonic acid, as well as their esters. They are oxidized into numerous compounds, some of which are cytotoxic and reactive enough to modify proteins and DNA bases [26]. Enzymes, free radicals, and nonenzymatic, nonradical oxidants oxidize lipids. Frequently, lipoxygenase, cyclooxygenase, and cytochrome P450 induce oxidation in a regulated manner to produce specific physiologically essential products. In contrast, lipid peroxidation, which is oxidation mediated by free radicals, occurs arbitrarily and nonspecifically.

Free radicals attack proteins, DNA, and lipids without discrimination. Therefore, when free radicals are generated in vivo, as a result of high-energy irradiation or ischemia–reperfusion injury, the levels of oxidation products of proteins and DNA, as well as lipid peroxidation, are elevated. In addition, secondary lipid peroxidation products, such as unsaturated aldehydes, readily react with protein thiols, leading to the loss of protein function and cellular homeostasis. Among the lipid peroxidation products, hydroxy octadecadienoic acid (HODE) from linoleic acid and hydroxy eicosatetraenoic acid (HETE) and isoprostanes from arachidonic acid are frequently used as biomarkers of lipid peroxidation in vivo [27]. Vitamin E is a powerful radical-scavenging antioxidant that inhibits lipid peroxidation mediated by free radicals but not enzymatic oxidation by lipoxygenase and cyclooxygenase, as will be discussed in greater detail below. Both enzymatic and free radical oxidation produce HODE and HETE, but their isomer distribution depends on the type of oxidant. To evaluate the effects of vitamin E, it is crucial to understand the mechanisms and oxidants of lipid oxidation. The mechanisms of lipid oxidation have been thoroughly studied and are currently well understood [28, 29]. Trans, trans-forms of HODE and HETE have been shown to be specific products of lipid peroxidation mediated by free radicals.

Numerous studies have demonstrated that the levels of lipid peroxidation products, such as HODE, HETE, and isoprostanes, in biological fluids and tissues of diseased patients are generally, if not always, greater than those of healthy individuals. In addition, clinical research has established a connection between disease states and lipid peroxidation products.

#### *2.2.1 Liver diseases*

The importance of lipid peroxidation mediated by free radicals in liver injury induced by carbon tetrachloride and other halogenated alkanes has been investigated since the 1960s and documented in detail [30]. It was once thought that carbon tetrachloride affects the liver by the action of a simple solvent, but it is now understood that carbon tetrachloride must undergo metabolic activation to trichloromethyl radical by cytochrome P450, primarily by cytochrome P450 2E1, to exert its toxic effect [31]. The trichloromethyl radical reacts rapidly with oxygen to yield the trichloromethyl peroxyl radical, which attacks lipids and induces their peroxidation. Lipid peroxidation mediated by free radicals is involved in alcoholic liver disease caused by chronic alcohol ingestion [32, 33]. Plasma levels of several lipid oxidation products, including oxysterols and isoprostanes, have been shown to be elevated in alcoholic liver disease patients [34, 35].

Nonalcoholic fatty liver disease (NAFLD), a hepatic manifestation of metabolic syndrome, is now the most common liver disorder, affecting a high proportion of the global population. The incidence of NAFLD is increasing due to increases in the prevalence of two major risk factors, obesity, and type 2 diabetes, which are related to lifestyle and diet. The characteristic feature of NAFLD is an excessive accumulation of fat, notably triglyceride, in the liver, and it encompasses a wide spectrum from benign steatosis to nonalcoholic steatohepatitis (NASH), liver cirrhosis, liver failure, and hepatocellular carcinoma [36].

NAFLD and NASH are multifactorial diseases and oxidative stress has been implicated in their pathogenesis. Several human and animal studies have reported an association between NAFLD/NASH disease state and biomarkers of lipid peroxidation [37]. One such study reported that levels of 9- and 13-HODE, major products of linoleic acid peroxidation, were significantly elevated in patients with NASH compared to those with steatosis, and a strong correlation was observed between these oxidation products and liver histopathology such as inflammation, fibrosis, and steatosis [38]. These HODEs were racemic, suggesting them to be produced by free radical oxidation.

Numerous studies have reported a beneficial effect of vitamin E on NAFLD and NASH [39]. In one such study, the effects of vitamin E at a dose of 800 IU/day or placebo for 96 weeks were examined in adults with NASH and without diabetes; there was improvement in the histological features of NASH [40]. Another study reported measurable differences in the metabolic profile of subjects likely to respond to vitamin E treatment for NASH and those who experienced histological improvements following treatment [41]. In a recent retrospective study of the effects of 300 mg/ day vitamin E for 2 or more years in patients with biopsy-proven NASH, vitamin E ameliorated NASH fibrosis, especially in those who showed improved transaminase activities and insulin resistance [42, 43].

## *2.2.2 Atherosclerosis*

Atherosclerosis is a leading cause of cerebral infarction, myocardial infarction, coronary artery disease, and peripheral arterial disease. It is a chronic inflammatory disease characterized by excessive cholesterol deposition in the arterial wall and sluggish progression. It begins in childhood and remains asymptomatic for decades, but it is the primary cause of death in developed nations [44, 45]. It is generally recognized

that oxidative modification of low-density lipoprotein (LDL) is a crucial initial event in the development of atherosclerosis. Incubation of macrophages with oxidized LDL, but not with native LDL, results in accumulation of cholesteryl esters within the cell. Oxidation of low-density lipoprotein increases its pro-atherogenic effect, whereas oxidation of high-density lipoprotein decreases its anti-atherogenic effect [46, 47].

In the 1990s, extensive research was conducted on the oxidative modification of LDL, and its mechanisms and products were elucidated; however, the epitope responsible for recognition by macrophage scavenger receptors has not yet been identified. However, it has been demonstrated that macrophages take up oxidatively modified LDL, which is the first step in the formation of foam cells. LDL oxidation generates diverse byproducts. Cholesteryl esters and phosphatidylcholine (PC) are the predominant lipids in LDL particles of humans. The oxidation of linoleic acid and arachidonic acid esters of cholesterol and PC produces the corresponding hydroperoxides, hydroxides, and degradation products [48]. Plasma levels of lipid peroxidation products are higher in atherosclerotic patients than in healthy individuals. LDL isolated from diabetic patients has higher levels of HODE and HETE than LDL isolated from healthy subjects. In addition, the molecular ratios of HODE and HETE to the primary lipids (linoleates and arachidonates, respectively) are greater in diabetic LDL than in control LDL [49]. In addition, the levels of oxysterols such as 7-b-hydroxycholesterol, 7-ketocholesterol, and cholesterol-5,6-epoxide rise in the order normal artery fatty streak advanced lesion [50]. Moreover, hydroperoxide and hydroxide forms of cholesteryl linoleate are frequently found in human atherosclerotic plaque [51, 52].

The oxidative modification of LDL is mediated by multiple oxidants and distinct mechanisms, it should be noted. LDL is oxidized by both free radicals and nonradical oxidants, including lipoxygenases, cytochrome P450 enzymes, and hypochlorite. Singlet oxygen could also be a factor [53]. Importantly, various oxidants generate distinct oxidation products, necessitating the use of distinct antioxidants. No single antioxidant is capable of preventing all forms of oxidation.

#### **2.3 Safeguarding the cell membranes**

As a result of vitamin E's improved lipid packing orderliness, the membrane can be packed more tightly, which increases cell stability. Vitamin E was demonstrated to be essential for preserving the balance of skeletal muscle by Howard et al. in 2011. and that introducing alpha-tocopherol to cultured myocytes makes it easier to repair plasma membranes. This occurs because phospholipids in the membrane are frequently the target of oxidants, and vitamin E efficiently prevents lipid peroxidation. Contrarily, when cultivated cells are exposed to an oxidant assault without alphatocopherol supplementation, the repair is notably inhibited. Comparative measurements show that an antioxidant needs to join the membranes, like α-tocopherol does, or be able to regenerate α-tocopherol, to promote the repair [54]. As a result, vitamin E aids in membrane repair by reducing the oxidation of phospholipids, which might hypothetically obstruct membrane fusion processes.

#### **2.4 Regulation of protein kinase c activation and platelet aggregation**

It has been discovered that elevating alpha-tocopherol levels in endothelial cells prevents platelet aggregation and causes the endothelium to release prostacyclin. to reduce the components of blood cells' adherence to the endothelium, it was hypothesized that the vascular cell adhesion molecule and the intracellular cell adhesion

*Medicinal Significance and Complications of Vitamin E DOI: http://dx.doi.org/10.5772/intechopen.112761*

molecule (ICAM-1) (VCAM-1) were downregulated. Additionally, vitamin E-induced up regulation of the arachidonic acid cascade enzymes cytosolic phospholipase [55] cyclooxygenase-1 and A2 [56] leads to the generation of prostacyclin, a strong vasodilator that prevents platelet clumping in people [57]. Earlier studies advise that tocopherols may prevent protein kinase C (PKC) [58] and increase the activity of nitric oxide synthase [59] in order tocopherols may inhibit platelet aggregation.

When it comes to lowering PKC activity, alpha-tocopherol in its natural RRR version has been shown to be twice as effective as other all-racemic (synthetic) alpha-tocopherols [60]. This is caused by how alpha-attenuating tocopherols affect the synthesis of diacylglycerol, a lipid that makes PKC more mobile and thus activates it. The activity of protein phosphatase type 2A is also increased by alpha-tocopherol, while PKC autophosphorylation and subsequently its activity is decreased. Compared to mixed tocopherols, alpha-tocopherol is less efficient at preventing platelet aggregation. Gamma-tocopherol-enriched vitamin E (100 mg of gamma-tocopherol, 40 mg of delta-tocopherol, and 20 mg of alpha-tocopherol per day) significantly reduced adenosine diphosphate-induced platelet aggregation in healthy people, but not in those taking pure alpha-tocopherol alone. (100 mg per day) [61].

### **3. Preventing disease with vitamin E**

Due to its role as an antioxidant, its contribution to the reduction of inflammation, due to its immune-stimulating properties and suppression of platelet aggregation, many disease outcomes have been found to be prevented and reversed with the aid of vitamin E.

#### **3.1 Cardiovascular diseases**

Body's low-density lipoproteins are oxidized, which causes inflammation, which in turn leads to cardiovascular issues [62]. Gamma-tocopherol has been shown to enhance functions of cardiovascular by boosting the nitric oxide synthase activity, which generates nitric oxide that relaxes blood vessels [63]. This is accomplished by trapping molecules of peroxynitrite, a reactive nitrogen species, and improving endothelial function. Humans who take 100 milligrams of gamma-tocopherol daily have shown to have fewer arterial clotting risk factors, such as cholesterol, platelet aggregation [64].

Different research revealed that combined tocopherols were more successful than individual tocopherols at preventing lipid peroxidation and human platelet aggregation, indicating a cooperative platelet-inhibitory action. Tocotrienols were also discovered to reduce cholesterol production by inhibiting 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase, in addition to tocopherols, which causes the liver cells to produce less cholesterol [65]. Contrary to what has been reported, the majority of recent large interventional clinical trials suggest that vitamin E use was related to a considerably elevated risk of hemorrhagic stroke in the participants [66]. It was therefore proposed that further extensive research including younger subjects could be necessary to fully comprehend the vitamin E's possibility for preventing coronary heart disease.

#### **3.2 Cancer**

Additionally, vitamin E has anti-cancer qualities. This may be due to vitamin E's several effects, which include activating heat shock proteins, down-regulating mutant p53 proteins, stimulating the p53 tumor suppressor gene, and having an anti-angiogenic action via the inhibition of transforming growth factor alpha [67]. As vitamin E compounds, alpha-, gamma-, and delta-tocopherols have developed, each with specific roles and anti-cancer properties. The development of PKC and collagenase [68], which promotes the proliferation of cancer cells, was found to be inhibited by alpha-tocopherol. Gamma-tocopherol was identified as superior to α-tocopherol in this situation for its capacity to suppress the proliferation of human prostate cancer cell lines, whereas delta-tocopherol has exhibited growth inhibitory efficacy against mouse mammary cancer cell lines [69]. In the culture, gamma-tocopherol suppress the cancer cells growth in a variety of methods.

The reactive nitrogen species of the compounds that modify the DNA strands and provide cells with cancerous changes are among the free radicals that are captured by it [70]. Additionally, it inhibits the activity of the cyclins, which stop the midst of the cancerous cell cycle and block the spread of the cancerous cells [71]. Additionally, it has been discovered that gamma-tocopherol performs better than alpha-tocopherol at inducing apoptosis, encouraging the activity of the peroxisome proliferatorsactivated receptor gamma, especially in colon cancer cells, and triggering several pathways that cause cell death [72, 73], inhibiting the growth of new blood vessels in tumors, and preventing tumors from receiving the supplements they require to grow. Tocotrienols was also found to have apoptotic and antiproliferative effects on both healthy and cancerous human cells in this setting [74]. This could be because apoptosis is induced by a mitochondria-mediated pathway or because cyclin D is suppressed, which would cause the cell cycle to be arrested [39]. Additionally, they impede vascularization and reduce 3-hydroxy-3-methyl coenzyme A (HMG-CoA) reductase activity, which stops the growth of cancer.

#### **3.3 Cataracts**

One of the most common causes of significant vision loss in older individuals is cataracts. They develop as a result of the buildup of proteins that have been harmed by free radicals. There may be a connection between vitamin E supplements and the likelihood of developing cataracts, according to several observational studies. *Leske et al*., discovered that those who took vitamin E supplements and those with greater blood levels of vitamin [40]. Had clearer lenses. a sustained vitamin E treatment was linked in a different study [75] to a slower evolution of age-related lens opacification. Vitamin E, however, did not appear to have any impact on the onset or 6.3 years on average, the randomized Age-Related Eye Disease Study (AREDS) tracked the development of cataracts [76].

#### **3.4 Alzheimer's disease**

Through a mechanism involving oxidative stress and hydrogen peroxide, the beta-amyloid protein causes cytotoxicity, which eventually leads to the death of neuronal cells and AD. This process is what causes Alzheimer's disease (AD), which, through a free radical process, is brought on by protein oxidation and lipid peroxidation. Vitamin E can prevent hydrogen peroxide production and the cytotoxicity it produces. It lessens the cell mortality brought on by beta-amyloid in PC12 cells and rat hippocampus cell cultures [77, 78], as well as the neuroblastoma cell toxicity brought on by excitatory amino acids [79]. Vitamin E may decrease the progression of the disease in those with moderately severe Alzheimer's disease, according to the

cooperative study on Alzheimer's from 1997.High vitamin E doses prevented the patient from losing the capacity to perform daily tasks and postponed their placement for several months in a private facility [80]. Another study revealed that people with AD had lower plasma levels of antioxidant supplements, indicating that the condition may be influenced by insufficient antioxidant activity. The neuroprotective impact of multiple vitamin E forms combined rather than just alpha-tocopherol alone is linked to older patients with high vitamin E plasma levels having a lowering risk of AD [81]. In a 2009 study, the effects of giving 847 individuals with and without taking an AD treatment 2000 IU of E vitamin were examined. It was discovered that combining an E vitamin with a cholinesterase inhibitor may be more advantageous than taking either medication by itself [82].

Using automated magnetic resonance imaging (MRI) measures and plasma levels of tocopherols and tocotrienols, Mangialasche et al. showed that it is possible to distinguish between Alzimers disease patients, people with moderate cognitive impairment, and healthy controls, as well as to predict the progression of with moderate cognitive impairment into Alzimers disease at the biomarker level. This demonstrates that plasma tocopherols and tocotrienols, which are nutritional indicators, may act as a surrogate for AD pathology [83]. However, due to its potential for harmful drug interactions in high doses, particularly those for lowering cholesterol, experts advise against patients taking vitamin E for AD treatment without a doctor's supervision.

#### **3.5 Acute immunodeficiency syndrome and HIV**

Although it is frequently discovered that Human immunodeficiency virus carriers (HIV) are low in E vitamin, unknown is whether E vitamin minerals is advantageous at any point during HIV infection. It has been shown that vitamin E to boost the growth of T helper cells (CD4 T-cells) and to restore delayed cutaneous hypersensitivity reactions at doses of 400 IU and higher [84]. Tang et al. examined the relationship between vitamin E and A levels and the development of HIV-1 illness in 1997. E vitamin levels in men above 24.2 m/l had a noticeably lower chance of illness development, according to this study. High amounts of vitamin E in the blood were shown to be strongly correlated with the consumption of vitamin E supplements at the time of study admission in this cohort [85].

The correction of immunological markers that are disrupted in HIV/AIDS was demonstrated in a study on the mouse acquired immunodeficiency syndrome utilizing a micronutrient intake rose by 15 times [86]. In addition, it has been demonstrated that increasing dietary vitamin E can guard against azidothymidine adverse effects such as bone marrow toxicity [87]. Similar findings were obtained from related research utilizing d-alpha-tocopherol supplementation on bone marrow cells from stage IV acquired immunodeficiency syndrome patients [88]. But it has also been observed that a higher fatality rate was associated with lower pre-infection vitamin E levels. As a result, more investigation is required to clarify the part of role of E vitamin E in the development of human immune deficiency virus-1 [89].

#### **3.6 Immunity**

It is now established that E vitamin boosts phagocytic activity, humoral immunological responses, and cell immunity in addition to stimulating the body's defenses. When immunological phagocytosis is engaged in infectious disorders, it has a noticeable impact, but it has less of an impact on cell-mediated immune defenses. Humans' cell-mediated and humoral immunological functions are markedly improved by its supplementation, especially in the adults. In healthy individuals' daily intake of 200 mg of E vitamin, who did not experience any adverse side effects increased the antibody response to several vaccines [90]. Higher plasma levels of E vitamin were linked with fewer infections throughout a three-year period [91], and additionally, vitamin E increased resilience to viral infections.in aged patients. According to *Kutty et al.* demonstrated that taking vitamin E supplements daily can improve the immunological reaction to a specific antigen [92]. When combined with vitamin CE has been proven to help treat a variety of illnesses, including photo dermatitis, preeclampsia/dysmenorrhea, and tardive dyskinesia, menstrual pain in addition to the conditions already listed [93].

## **3.7 Vitamin E deficiency**


## **3.8 Complications of vitamin E**

## *3.8.1 Safety and adverse effects*

Oral vitamin E use is typically regarded as safe when administered in the proper dosages. Occasionally, taking vitamin E orally can result in:

*Medicinal Significance and Complications of Vitamin E DOI: http://dx.doi.org/10.5772/intechopen.112761*


Higher vitamin E dosages could make side effects more likely. Furthermore, there is a worry that those who consume high amounts of vitamin E but are in bad healthcare more likely to pass away. Numerous illnesses can interact with vitamin E use. For instance, studies indicate that consuming vitamin E orally may raise the risk of prostate cancer. According to additional research, taking vitamin E may make it more likely that a person will pass away if they have a history of severe heart diseases, such as a stroke or heart attack. If any of the following apply to you before using vitamin E:

A lack of vitamin K, retinitis pigmentosa, a condition that damages the retina in the eyes, and bleeding issues.

Diabetes, a prior history of a heart attack or stroke, head and neck malignancy, liver illness, and diabetes.

Your risk of bleeding may go up if you take the supplement. You should stop taking vitamin E two weeks before surgery if you are planning on having it. If you are about to undergo or have recently undergone a technique to unblock arteries and restart your heart's regular blood flow, talk to your doctor about using vitamin E.

Several studies have documented adverse effects of vitamin E supplements in high doses. As stated previously, a meta-analysis of 19 clinical trials involving 135,968 participants indicated that high-dose vitamin E supplements (400 IU) may increase all-cause mortality. In contrast, a recent review article reported that a pooled analysis of 18 randomized controlled trials conducted in individuals who appeared to be healthy found no effect of vitamin E supplementation at doses ranging from 23 to 800 IU/day on all-cause mortality. In addition, meta-analyses of 33 and 57 trials found no correlation between vitamin E supplementation and mortality.

Unknown is the mechanism underlying the increased risk associated with high-dose vitamin E supplementation. The phenomenon may be attributable to the induction of cytochrome P450, an enzyme that speeds up the metabolism of other substances [99]. Vitamin E has eight isoforms, with -tocopherol being the most potent and abundant in humans, despite -tocopherol being ingested in equal amounts. Highdose -tocopherol supplementation accelerates the metabolism of non-tocopherol forms. It has not been established whether or not the different isoforms of vitamin E have specific functions in vivo that could be compromised by -tocopherol supplementation. In certain in vitro systems, −tocopherol has been found to act as a prooxidant. In the absence of reducing agents such as vitamin C, −tocopherol accelerates the oxidation of LDL because the a-tocopheroxyl radical induces LDL oxidation.

Nevertheless, vitamin C absolutely inhibits this pro-oxidant action by decreasing -tocopheroxyl radical levels [100]. Therefore, it is improbable that vitamin E functions as a pro-oxidant in vivo.

#### *3.8.2 Interactions*

Your levels of vitamin E may change if you use certain medications. Several interactions are possible:


### **4. Conclusion**

The doctor's Shute and Shute employed vitamin E as a supplement for the first time in Canada; as a result of the successful outcomes, they started utilizing it frequently in their offices. Since then, carefully planned clinical and experimental investigations have progressively advanced and advanced our understanding of Evitamin. Vitamin E's antioxidant capabilities have been proven to be essential in the fight against a number of illnesses, including cancer, oxidative stress, atherosclerosis cataracts and AD, among others. Additionally, demonstrated to be efficient against diabetes, allergies, asthma, and other illnesses in addition to these. The emphasis of this review was on the vital roles that E-vitamin plays in a number of infections.

A side from the extensive advantages claimed, there has always been disagreement on the precise of E vitamin role and its connection to certain ailments. In the literature, there are several contradictory accounts of both favorable and unfavorable outcomes for the same biological processes. The absence of reliable indicators for monitoring E vitamin consumption and status, which would link intakes to potential clinical outcomes, is the main obstacle to understanding the functions in human health of E vitamin. In conclusion, despite the inconsistent facts surrounding vitamin E, the present body of research seems to be in favor of the idea that the advantages outweigh the drawbacks.

Vitamin E inhibits lipid peroxidation both in vivo and in vitro. These findings suggest that vitamin E may reduce the risk of diseases mediated by free radicals or be beneficial in their prevention and treatment. Numerous epidemiological studies have supported this theory, but the results of clinical intervention studies and

meta-analyses have been controversial; some have reported positive findings, while others have reported null or negative findings.

To attain optimal results, numerous factors must be taken into account. Vitamin E should be beneficial for subjects enduring oxidative stress mediated by free radicals if administered at the appropriate dose, time, and duration.

## **Conflict of interest**

The authors declare no conflict of interest.

## **Author details**

Naresh Podila1 \*, Sathish Kumar Konidala1 , Jithendra Chimakurthy1 , Srilatha Muddisetti2 , Suryaprabha Matangi1 , Natesh Gunturu2 , Yamarthi Venkateswara Rao3 and Mithun Rudrapal1

1 Department Pharmaceutical Sciences, School of Biotechnology and Pharmaceutical Sciences, Vignan's Foundation for Science, Technology and Research, Guntur, A.P., India

2 Vikas College of Pharmaceutical Sciences, Suryapet, Telangana, India

3 Vignan Pharmacy College, Guntur, A.P., India

\*Address all correspondence to: nareshtrcp10@gmail.com

© 2023 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

## **References**

[1] Abner EL, Schmitt FA, Mendiondo MS, Marcum JL, Kryscio RJ. Vitamin E and all-cause mortality: A meta-analysis. Current Aging Science. 2011;**4**(2):158-170

[2] Abraham GE. Nutritional factors in the etiology of the premenstrual tension syndromes. The Journal of Reproductive Medicine. 1983;**28**(7):446-464 View abstract

[3] National Institutes of Health Office of Dietary Supplements. Vitamin E, Niki E, Noguchi N, Tsuchihashi H, Gotoh N. Interaction among vitamin C, vitamin E, and beta-carotene. The American Journal of Clinical Nutrition. 1995;**62**:1322S-1326S

[4] Ames BN. Micronutrient deficiencies: A major cause of DNA damage. Annals of the New York Academy of Sciences. 2000;**889**:87-106

[5] Chow CK. Distribution of tocopherols in human plasma and red blood cells. The American Journal of Clinical Nutrition. 1975;**28**:756-760

[6] Drotleff AM, Ternes W. Determination of RS, E/Z-tocotrienols by HPLC. Journal of Chromatography A. 2001;**909**:215-223

[7] Halliwell B, Gutteridge JM. Free Radicals in Biology and Medicine. 4th. Oxford: Clarendon Press; 2007

[8] Sugamura K, Keaney JF. Jr reactive oxygen species in cardiovascular disease. Free Radical Biology & Medicine. 2011;**51**:978-999

[9] Niki E. Assessment of antioxidant capacity in vitro and in vivo. Free Radical Biology & Medicine. 2010;**49**:503-515

[10] Palmer S. Diet, nutrition, and cancer. Progress in Food & Nutrition Science. 1985;**9**:283-341

[11] Gey KF, Brubacher GB, Stahelin HB. Plasma levels of antioxidant vitamins in relation to ischemic heart disease and cancer. The American Journal of Clinical Nutrition. 1987;**45**(5 Suppl):1368-1377

[12] Bjelakovic G, Nikolova D, Gluud LL, Simonetti RG, Gluud C. Mortality in randomized trials of antioxidant supplements for primary and secondary prevention: Systematic review and meta-analysis. Journal of the American Medical Association. 2007;**297**:842-857

[13] Traber MG, Frei B, Beckman JS. Vitamin E revisited: Do new data validate benefits for chronic disease prevention? Current Opinion in Lipidology. 2008;**19**:30-38

[14] Niki E. Do free radicals play causal role in atherosclerosis? Low density lipoprotein oxidation and vitamin E revisited. Journal of Clinical Biochemistry and Nutrition. 2011;**48**:3-7

[15] Zingg JM. Molecular and cellular activities of vitamin E analogues. Mini Reviews in Medicinal Chemistry. 2007;**7**:543-558

[16] Ball GFM. Vitamins in Foods: Analysis, Bioavailability, and Stability. Boca Raton, Florida: CRC Press; 2006. pp. 119-136

[17] 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. The American Journal of Clinical Nutrition. 1997;**65**:496-502

#### *Medicinal Significance and Complications of Vitamin E DOI: http://dx.doi.org/10.5772/intechopen.112761*

[18] Di Mascio P, Murphy ME, Sies H. Antioxidant defense systems: The role of carotenoids, tocopherols, and thiols. The American Journal of Clinical Nutrition. 1991;**53**:194S-200S

[19] 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**:1497-1503

[20] 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. The American Journal of Clinical Nutrition. 2004;**80**:143-148

[21] Burton GW, Ingold KU. Autoxidation of biological molecules: 1. The antioxidant activity of vitamin E and related chainbreaking phenolic antioxidants in vitro. Journal of the American Chemical Society. 1981;**103**:6472-6477

[22] Liu M, Wallin R, Wallmon A, Saldeen T. Mixed tocopherols have a stronger inhibitory effect on lipid peroxidation than alpha-tocopherol alone. Journal of Cardiovascular Pharmacology. 2002;**39**:714-721

[23] Burton GW, Joyce A, Ingold KU. Is vitamin E the only lipidsoluble, chainbreaking antioxidant in human blood plasma and erythrocyte membranes? Archives of Biochemistry and Biophysics. 1983;**221**:281-290

[24] Howard AC, Anna K, McNeil AK, McNeil PL. Promotion of plasma membrane repair by vitamin E. Nature Communications. 2011;**20**:597

[25] Tran K, Wong JT, Lee E, Chan AC, Choy PC. Vitamin E potentiates arachidonate release and phospholipase A2 activity in rat heart myoblastic cells. The Biochemical Journal. 1996;**319**:385-391

[26] Niki E. Lipid peroxidation: Physiological levels and dual biological effects. Free Radical Biology & Medicine. 2009;**47**:469-484

[27] Niki E. Biomarkers of lipid peroxidation in clinical material. Biochimica et Biophysica Acta. 2014;**1840**:809-817

[28] Yin H, Xu L, Porter NA. Free radical lipid peroxidation: Mechanisms and analysis. Chemical Reviews. 2011;**111**:5944-5972

[29] Cheeseman KH, Albano EF, Tomasi A, Slater TF. Biochemical studies on the metabolic activation of halogenated alkanes. Environmental Health Perspectives. 1985;**64**:85-101

[30] Recknagel RO. Carbon tetrachloride hepatotoxicity. Pharmacological Reviews. 1967;**19**:145-208

[31] Smathers RL, Galligan JJ, Stewart BJ, Petersen DR. Overview of lipid peroxidation products and hepatic protein modification in alcoholic liver disease. Chemico-Biological Interactions. 2011;**192**:107-112

[32] Sid B, Verrax J, Calderon PB. Role of oxidative stress in the pathogenesis of alcohol-induced liver disease. Free Radical Research. 2013;**47**:894-904

[33] Adachi J, Asano M, Ueno Y, Naito T. Identification of 7-hydroperoxycholesterol in human liver by liquid chromatography-mass spectrometry. Alcoholism, Clinical and Experimental Research. 2000;**24** (Suppl. 4):21S-25S

[34] Aleynik SI, Leo MA, Aleynik MK, Lieber CS. Increased circulating products of lipid peroxidation in patients with alcoholic liver disease. Alcoholism, Clinical and Experimental Research. 1998;**22**:192-196

[35] Wierzbicki AS, Oben J. Nonalcoholic fatty liver disease and lipids. Current Opinion in Lipidology. 2012;**23**:345-352

[36] Sumida Y, Niki E, Naito Y, Yoshikawa T. Involvement of free radicals and oxidative stress in NAFLD/NASH. Free Radical Research. 2013;**47**:869-880

[37] Feldstein AE, Lopez R, Tamimi TA, et al. Mass spectrometric profiling of oxidized lipid products in human nonalcoholic fatty liver disease and nonalcoholic steatohepatitis. Journal of Lipid Research. 2010;**51**:3046-3054

[38] Terao K, Niki E. Damage to biological tissues induced by radical initiator 2,2′-azobis(2-amidinopropane) dihydrochloride and its inhibition by chain-breaking antioxidants. Journal of Free Radicals in Biology & Medicine. 1986;**2**:193-201

[39] Morita M, Ishida N, Uchiyama K, et al. Fatty liver induced by free radicals and lipid peroxidation. Free Radical Research. 2012;**46**:758-765

[40] Yoshida Y, Hayakawa M, Cynshi O, Jishage K, Niki E. Acceleration of lipid peroxidation in alpha-tocopherol transfer protein-knockout mice following the consumption of drinking water containing a radical initiator. Journal of Oleo Science. 2008;**57**:577-583

[41] Sanyal AJ, Chalasani N, Kowdley KV, et al. Pioglitazone, vitamin E, or placebo for nonalcoholic steatohepatitis. The New England Journal of Medicine. 2010;**362**:1675-1685

[42] Cheng J, Joyce A, Yates K, Aouizerat B, Sanyal AJ. Metabolomic profiling to identify predictors of response to vitamin E for non-alcoholic steatohepatitis (NASH). PLoS One. 2012;**7**(9):e44106

[43] Sumida Y, Naito Y, Tanaka S, et al. Long-term (>=2 yr) efficacy of vitamin E for non-alcoholic steatohepatitis. Hepatogastroenterology. 2013;**60**:1445-1450

[44] Steinberg D. The LDL modification hypothesis of atherogenesis: An update. Journal of Lipid Research. 2009;**50**(Suppl):S376-S381

[45] Barter PJ, Nicholls S, Rye KA, Anantharamaiah GM, Navab M, Fogelman AM. Antiinflammatory properties of HDL. Circulation Research. 2004;**95**:764-772

[46] Noguchi N, Numano R, Kaneda H, Niki E. Oxidation of lipids in low density lipoprotein particles. Free Radical Research. 1998;**29**:43-52

[47] Colas R, Pruneta-Deloche V, Guichardant M, et al. Increased lipid peroxidation in LDL from type-2 diabetic patients. Lipids. 2010;**45**:723-731

[48] Garcia-Cruset S, Carpenter KL, Guardiola F, Stein BK, Mitchinson MJ. Oxysterol profiles of normal human arteries, fatty streaks and advanced lesions. Free Radical Research. 2001;**35**:31-41

[49] Niu X, Zammit V, Upston JM, Dean RT, Stocker R. Coexistence of oxidized lipids and alpha-tocopherol in all lipoprotein density fractions isolated from advanced human atherosclerotic plaques. Arteriosclerosis, Thrombosis, and Vascular Biology. 1999;**19**:1708-1718

[50] Suarna C, Dean RT, May J, Stocker R. Human atherosclerotic plaque contains both oxidized lipids and relatively

*Medicinal Significance and Complications of Vitamin E DOI: http://dx.doi.org/10.5772/intechopen.112761*

large amounts of alpha-tocopherol and ascorbate. Arteriosclerosis, Thrombosis, and Vascular Biology. 1995;**15**:1616-1624

[51] Kuhn H, Romisch I, Belkner J. The role of lipoxygenase-isoforms in atherogenesis. Molecular Nutrition & Food Research. 2005;**49**:1014-1029

[52] Malle E, Marsche G, Arnhold J, Davies MJ. Modification of low-density lipoprotein by myeloperoxidase-derived oxidants and reagent hypochlorous acid. Biochimica et Biophysica Acta. 2006;**1761**:392-415

[53] Wagner JR, Motchnik PA, Stocker R, Sies H, Ames BN. The oxidation of blood plasma and low density lipoprotein components by chemically generated singlet oxygen. The Journal of Biological Chemistry. 1993;**268**:18502-18506

[54] 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. Thrombosis and Haemostasis. 1985;**54**:425-430

[55] Freedman JE, Farhat JH, Loscalzo J, Keaney JF Jr. Alphatocopherol inhibits aggregation of human platelets by a protein kinase C-dependent mechanism. Circulation. 1996;**94**:2434-2440

[56] 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. Journal of Cardiovascular Pharmacology and Therapeutics. 2001;**6**:155-161

[57] Brigelius-Flohé R, Traber MG. Vitamin E: Function and metabolism. The FASEB Journal. 1999;**13**:1145-1155 [58] Liu M, Wallmon A, Olsson-Mortlock C, Wallin R, Saldeen T. Mixed tocopherols inhibit platelet aggregation in humans: Potential mechanisms. The American Journal of Clinical Nutrition. 2003;**77**:700-706

[59] Steinberg D, Parthasarathy S, Carew TE, Khoo JC, Witztum JL. Beyond cholesterol: Modifications of low-density lipoprotein that increase its artherogenicity. The New England Journal of Medicine. 1989;**320**:915-924

[60] Li D, Saldeen T, Romeo F, Mehta JL. Relative effects of alphaand gammatocopherol on low-density lipoprotein oxidation and superoxide dismutase and nitric oxide synthase activity and protein expression in rats. Journal of Cardiovascular Pharmacology and Therapeutics. 1999;**4**:219-226

[61] Singh I, Turner AH, Sinclair AJ, Li D, Hawley JA. Effects of gamma-tocopherol supplementation on thrombotic risk factors. Asia Pacific Journal of Clinical Nutrition. 2007;**16**:422-428

[62] McAnally JA, Gupta J, Sodhani S, Bravo L, Mo H. Tocotrienols potentiate lovastatin-mediated growth suppression in vitro and in vivo. Experimental Biology and Medicine (Maywood, N.J.). 2007;**232**:523-531

[63] 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**:2123-2133

[64] Shklar G, Oh SK. Experimental basis for cancer prevention by vitamin E. Cancer Investigation. 2000;**18**:214-222

[65] Ricciarelli R, Maroni P, Ozer N, Zingg JM, Azzi A. Agedependent

increase of collagenase expression can be reduced by alpha-tocopherol via protein kinase C inhibition. Free Radical Biology & Medicine. 1999;**27**:729-737

[66] McIntyre BS, Briski KP, Gapor A, Sylvester PW. Antiproliferative and apoptotic effects of tocopherols and tocotrienols on preneoplastic and neoplastic mouse mammary epithelial cells. Proceedings of the Society for Experimental Biology and Medicine. 2000;**224**:292-301

[67] Christen S, Woodall AA, Shigenaga MK, Southwell-Keely PT, Duncan MW, Ames BN. Gammatocopherol traps mutagenic electrophiles such as NO(X) and complements alphatocopherol: Physiological implications. Proceedings of the National Academy of Sciences of the United States of America. 1997;**94**:3217-3222

[68] Gysin R, Azzi A, Visarius T. Gammatocopherol inhibits human cancer cell cycle progression and cell proliferation by down-regulation of cyclins. The FASEB Journal. 2002;**16**:1952-1954

[69] Takahashi S, Takeshita K, Seeni A, Sugiura S, Tang M, Sato SY, et al. Suppression of prostate cancer in a transgenic rat model via gammatocopherol activation of caspase signaling. Prostate. 2009;**69**:644-651

[70] Stone WL, Krishnan K, Campbell SE, Qui M, Whaley SG, Yang H. Tocopherols and the treatment of colon cancer. Annals of the New York Academy of Sciences. 2004;**1031**:223-233

[71] 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. The Journal of Nutritional Biochemistry. 2010;**21**:589-597

[72] Wada S. Chemoprevention of tocotrienols: The mechanism of antiproliferative effects. Forum of Nutrition. 2009;**61**:204-216

[73] 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. Proceedings of the National Academy of Sciences of the United States of America. 2004;**101**:17825-17830

[74] Chen CS. Study Shows How Vitamin E Can Help Prevent Cancer. Available from: www.researchnews.osu. edu/archive/silenceakt.htm [Accessed: Dec 2013]

[75] 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**:1338-1347

[76] Goodman Y, Mattson MP. Secreted forms of beta-amyloid precursor protein protect hippocampal neurons against amyloid beta-peptide-induced oxidative injury. Experimental Neurology. 1994;**128**:1-12

[77] Behl C, Davis J, Cole GM, Schubert D. Vitamin E protects nerve cells from amyloid beta protein toxicity. Biochemical and Biophysical Research Communications. 1992;**186**:944-950

[78] Murphy TH, Schnaar RL, Coyle JT. Immature cortical neurons are uniquely sensitive to glutamate toxicity by inhibition of cystine uptake. The FASEB Journal. 1990;**4**:1624-1633

[79] Sano M, Ernesto C, Thomas RG, Klauber MR, Schafer K, Grundman M, et al. A controlled trial of selegiline, alphatocopherol, or both as treatment

*Medicinal Significance and Complications of Vitamin E DOI: http://dx.doi.org/10.5772/intechopen.112761*

for Alzheimer's disease. The Alzheimer's disease cooperative study. The New England Journal of Medicine. 1997;**336**:1216-1222

[80] 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. Journal of Alzheimer's Disease. 2010;**20**:1029-1037

[81] Pavlik VN, Doody RS, Rountree SD, Darby EJ. Vitamin E use is associated with improved survival in an Alzheimer's disease cohort. Dementia and Geriatric Cognitive Disorders. 2009;**28**:536-540

[82] 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. Journal of Internal Medicine. 2013;**273**:602-621

[83] Meydani M, Vitamin E. Lancet. 1995;**345**:170-175

[84] Tang AM, Graham NM, Semba RD, Saah AJ. Association between serum vitamin a and E levels and HIV-1 disease progression. AIDS. 1997;**11**:613-620

[85] Wang Y, Huang DS, Watson RR. Vitamin E supplementation modulates cytokine production by thymocytes during murine AIDS. Immunologic Research. 1993;**12**:358-366

[86] Ganser A, Greher J, Volkers B, Staszewski A, Hoelzer D. Azidothymidine in the treatment of ATDS. The New England Journal of Medicine. 1988;**318**:250-251

[87] 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. European Journal of Haematology. 1994;**53**:201-206

[88] Graham SM, Baeten JM, Richardson BA, Bankson DD, Lavreys L, Ndinya-Achola JO, et al. Higher preinfection vitamin E levels are associated with higher mortality in HIV-1-infected Kenyan women: A prospective study. BMC Infectious Diseases. 2007;**7**:63

[89] 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**:1380-1386

[90] Chavance M, Herbeth B, Fournier C, Janot C, Vernhes G. Vitamin status, immunity and infections in an elderly population. European Journal of Clinical Nutrition. 1989;**43**:827-835

[91] 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 Research International. 2013;**2013**:782067

[92] University of Maryland Medical Center. Vitamin E. Available from: www.umm.edu/health/medical/altmed/ supplement/vitamine#ixzz2c7gfq93R [Accessed: Dec 2013]

[93] 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**:1106-1110

[94] Office of Dietary Supplements, National Institutes of Health. Dietary Supplement Fact Sheet: Vitamin E.

Available from: www.ods. od.nih.gov/ factsheets/vitamine.asp [Accessed: Aug 2010]

[95] Food and Nutrition Board, Institute of Medicine. Dietary Reference Intakes for Vitamin C, Vitamin E, Selenium, and Carotenoids. Washington, DC: National Academy Press; 2000

[96] 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):2139-2142

[97] Slover HT. Tocopherols in foods and fats. Lipids. 1971;**6**:291-296

[98] United States Department of Agriculture (USDA), Agricultural Research Service. USDA National Nutrient Database for Standard Reference, Release 25. Available from: www.ars.usda.gov/SP2UserFiles/ Place/12354500/Data/SR25/nutrlist/ sr25a323.pdf [Accessed: Dec 2013]

[99] Colombo ML. An update on vitamin E, tocopherol and tocotrienol: Perspectives. Molecules. 2010;**15**:2103-2113

[100] Rathore GS, Suthar M, Pareek A, Gupta RN. Nutritional antioxidants: A battle for better health. Journal of Natural Pharmaceuticals. 2011;**2**:2-14
