Vitamin E in Human Health

Vitamin E

• 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 that qualitatively exhibit the biological activity of d-alpha-tocopherol
• Is the major lipid-soluble component in the cell antioxidant defense 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, aging, arthritis, and cataracts;
• vitamin E has been shown to be effective against these. Platelet hyper aggregation, 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.

• In humans, vitamin E deficiency primarily causes neurologic dysfunctions, but the underlying molecular mechanisms are unclear. Because of its antioxidative properties, vitamin E is believed to help prevent diseases associated with oxidative stress, such as cardiovascular disease, cancer, chronic inflammation, and neurologic disorders. However, recent clinical trials undertaken to prove this hypothesis failed to verify a consistent benefit. Given these findings, a group of European scientists met to analyze the most recent knowledge of vitamin E function and metabolism.
• An overview of their discussions is presented in this article, which includes considerations of the mechanisms of absorption, distribution, and metabolism of different forms of vitamin E, including the α-tocopherol transfer protein and α-tocopherol–associated proteins; the mechanism of tocopherol side-chain degradation and its putative interaction with drug metabolism; the usefulness of tocopherol metabolites as biomarkers; and the novel mechanisms of the antiatherosclerotic and anticarcinogenic properties of vitamin E, Given these findings, a group of European scientists met to analyze the most recent knowledge of vitamin E function and metabolism.
• There are eight naturally occurring forms of vitamin E; namely, the alpha, beta, gamma, and delta classes of tocopherol and tocotrienol, which are synthesized 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 homologs in varying proportions. Among the tocopherols, alpha- and gamma-tocopherols are found in the serum and the red blood cells, with the alpha-tocopherol present in the highest concentration.
• ?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 feces, 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.

Chemistry of Vitamin E

• The term ‘tocopherol’ signifies the methyl-substituted derivatives of tool 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 characterized by a long isoprenoid side chain attached at the 2 positions of a 6-chromanol ring.
• The term vitamin E covers 8 different forms that are produced by plants alone: α-, β-, γ-, and δ-tocopherol and α-, β-, γ-, and δ-tocotrienol. Tocotrienols have an unsaturated side chain, whereas tocopherols contain a phytyl tail with 3 chiral centers that naturally occur in the?RRR?configuration. Commercially available vitamin E consists of either a mixture of naturally occurring tocopherols and tocotrienols;?RRR-α-tocopherol (formerly called?d-α-tocopherol); synthetic α-tocopherol, which consists of the 8 possible stereoisomers in equal amounts (all rac-α-tocopherol, formerly called dl-α-tocopherol); or their esters. The bioavailability and bioequivalence of the different forms of vitamin E differ. For example, although the amount of γ-tocopherol in the diet is higher than that of α-tocopherol, the plasma γ-tocopherol concentration is only ≈10% of that of α-tocopherol, which is the most abundant form in plasma.

Absorption

The mechanism of vitamin E absorption is surprisingly unclear. All forms of vitamin E are taken up by intestinal cells and released into circulation with chylomicrons. At this step, there is probably no discrimination between the different forms. The vitamins reach the liver via chylomicron remnants. In the liver, a specific protein, α-TTP, selectively sorts out α-tocopherol from all incoming tocopherols for incorporation into VLDL. Other forms are much less well retained and are excreted via the bile, the urine [as carboxyethyl hydroxychromans (CEHCs)], or unknown routes. In addition, the capacity of the plasma to increase α-tocopherol concentrations is limited. In subjects with a normal α-tocopherol concentration of ≈25 μmol/L, the concentration cannot be increased > 2–3 fold, irrespective of the amount or duration of supplementation (10–13). This is apparently not due to limited absorption, because α-tocopherol is absorbed at a constant fractional rate with increasing doses (up to 150 mg). Moreover, newly absorbed α-tocopherol replaces old α-tocopherol in plasma lipoproteins, which may be the limiting step in the overall incorporation.

• Healthy subjects supplemented with α-tocopherol do not have equal increases in plasma α-tocopherol concentrations. In one study, the increase in plasma α-tocopherol concentration 12 h after an intake of 75 mg?d6-RRR-α-tocopherol ranged from 0.3 to 12.4 μmol/L (16). A 6-fold variation in α-tocopherol uptake by red blood cells was also seen. The underlying reasons are unknown but may include variations in α-TTP activity, metabolic rate, lipid content and composition, the status of other micronutrients that recycle α-tocopherol, and environmental conditions. Thus, it becomes clear that an adequate or optimal supply of vitamin E can differ tremendously between individuals.

METABOLISM OF VITAMIN E

• The liver plays a major role in vitamin E metabolism, which is one of the key mechanisms for the α-tocopherol preference, for limiting its accumulation, and for determining the circulating levels of various vitamin E forms. Vitamin E metabolism is nonspecific; the mechanisms involved are promiscuous in that these are general xenobiotic processes. Vitamin E is metabolized by ω-hydroxylation by cytochrome P 450 (CYP), followed by β-oxidation, conjugation, and excretion. All of the possible metabolites from α-, γ-, and δ-tocopherols and tocotrienols have been identified. The various steps in metabolism are described more fully below.

α-Tocopherol and non-α-tocopherol metabolism

• The α-tocopherol metabolite α-carboxyethyl hydroxychroman (CEHC) is tail-shortened but has an unoxidized head group. Nearly 60 years ago, Simon et al. described vitamin E metabolism and its oxidized product “Simon metabolites” or α-tocopheronolactone . Simon metabolites were thought to occur as a result of in vitro oxidation; they are decreased if an antioxidant is present during sample preparation. However, they have been found in increased concentrations in the urine of diabetic subjects. Thus, both CEHCs and tocopheronolactones may be biologically relevant vitamin E metabolites.

Phase I, CYP

• CYP4F2 was identified to ω-hydroxylate γ-tocopherol by analysis of individual human CYPs expressed in insect cells. Moreover, CYP4F2 activity toward α-tocopherol was limited relative to other forms of vitamin E. An inhibitor of CYP4F, an omega imidazole-containing compound 1,[(R)-2-(9-(1H-imidazol-1-yl)nonyl)-2,5,7,8-tetramethylchroman-6-ol], decreased CEHC production from γ-tocopherol in HepG2 cells in culture and increased plasma δ-tocopherol concentrations when δ-tocopherol and the inhibitor were simultaneously given to mice. Additionally, human CYP4F2 variants demonstrated varying ω-hydroxylation in vitro, but in a genome-wide association study, they were not found to dramatically change tocopherol concentrations or be associated with plasma γ-tocopherol concentrations. The CYP4F2 variant Rs2108622 was associated with increased circulating α-tocopherol in subjects from the ATBC trial, suggesting that this variant has reduced ω-hydroxylation activity.

Note that

CYP4F2’s function is not specific for vitamin E. CYP4 family members are major fatty acid ω-hydroxylases (reviewed in Ref. CYP4F2 ω-hydroxylates vitamin K1 (phylloquinone), and variants in the human population have been found to have altered responses to the vitamin K antagonist warfarin. CYP4F2 also converts arachidonic acid to 20-hydroxyeicosatetraenoic acid (20-HETE) and participates in leukotriene metabolism. Additionally, the CYP4 family modulates eicosanoids during inflammation and metabolizes some clinically significant pharmaceutical agents. Human variants in the CYP4F2 gene have been associated with hypertension and increased stroke risk. These clinical effects are thought to be a result of altered leukotriene metabolism. CYP4A and CYP4F genes are regulated in the opposite direction by peroxisome proliferators, starvation, and high-fat diets.

• Once the vitamin E-tail has been ω-hydroxylated, there is consensus that β-oxidation takes place. The process of β-oxidation may involve both peroxisomes and mitochondria, but the mitochondria are apparently a significant site for CEHC production.

Phase II, conjugation

Most investigators use a combination of glucuronidase and sulfatase to prepare their samples and thus report unconjugated metabolite concentrations because several different conjugates in urine and in plasma have been described. In addition to glucuronide conjugates of CEHC, CEHC sulfate and CEHC glycoside have been reported. Johnson et al. using a metabolomics approach, reported novel α-CEHC conjugates in both mouse and human urine, including α-CEHC glycine, α-CEHC glycine glucuronide, and α-CEHC taurine.

The mechanism for glucuronidation has not been investigated, but Hashiguchi et al. have demonstrated in vitro that sulfotransferase (SULT), specifically members of the SULT1 family, displayed sulfating activities toward both tocopherols and their metabolites by studying all 14 known human cytosolic SULTs. These findings support the hypothesis of Freiser and Jiang that sulfated intermediates may be important for cellular trafficking during vitamin E metabolism.

Phase III, transporters

There are no reports of transporters specifically involved in the transport of CEHCs or their conjugates. One of the hepatic responses to “excess” α-tocopherol is to upregulate α-tocopherol and metabolite biliary secretion. Both the mouse multidrug resistance (mdr1, p-glycoprotein) gene and the Slc22a5 gene (Solute carrier family 22, organic anion transporter, member 5) were upregulated in mice fed high vitamin E diets. The rat hepatic genes and proteins MDR (ABCB4) and breast cancer resistance (BCRP) are upregulated in response to increasing tissue α-tocopherol concentrations, whereas the organic anion transporter protein (OATP) was decreased. Previously, mouse mdr2, another ABC transport protein, was shown to be involved in the efflux of α-tocopherol into bile. These various transporters are possible candidates for the mechanism of metabolite efflux from the liver, but more research is needed to define the mechanisms for the export of vitamin E forms and their metabolites.

Interactions with Dietary Factors

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. Interactions were also found between thiols, tocopherols, and other compounds which enhance the effectiveness of the cellular antioxidant defense systems.

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.?In addition, vitamin E supplements in humans were also seen to increase the under-carboxylation of prothrombin, suggesting that vitamin E decreases the vitamin K status in humans.

Functions of Vitamin E

1- 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.

• 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 defense against lipid peroxidation, protecting the cell membranes from free radical attack. 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. Due to its peroxyl radical-scavenging activity, it also protects the polyunsaturated fatty acids present in membrane phospholipids and in plasma lipoproteins.?The tocopheroxyl radicals formed can either: oxidize other lipids; undergo further oxidation producing tocopheryl quinones; form non-reactive tocopherol dimers by reacting with another tocopheroxyl radical, or 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 neutralizes the existing free radicals. Oxidation has been linked to numerous possible conditions/diseases including cancer, aging, arthritis, and cataracts. Thus, vitamin E might help prevent or delay chronic diseases associated with reactive oxygen species molecules.

2- 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.?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 oxidized phospholipids that theoretically might interfere with the membrane fusion events.

3- 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 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, and cyclooxygenase-1, increases the release of prostacyclin, which is a potent vasodilator and inhibitor of platelet aggregation in humans.?A few other studies suggest that tocopherols appear to inhibit platelet aggregation through the inhibition of protein kinase C (PKC)?and the increased action of nitric oxide synthase.

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.?This occurs because of the attenuating effect of alpha-tocopherol on the generation of membrane-derived diacylglycerol (a lipid that 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.

Vitamin E in Disease Prevention

Vitamin E has been found to be very effective in 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.

4- Cardiovascular Diseases

Cardiovascular complications basically arise because of the oxidation of low-density lipoproteins present in the body and the consequent inflammation.?Gamma-tocopherol is found to improve cardiovascular functions by increasing the activity of nitric oxide synthase, which produces vessel-relaxing nitric oxide.?It does this by trapping the reactive nitrogen species (peroxynitrite) 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 clottings, such as platelet aggregation and cholesterol.?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, suggesting a synergistic platelet-inhibitory effect. Apart from tocopherols, tocotrienols were also found to inhibit cholesterol biosynthesis by suppressing 3-hydroxy-3-methylglutaryl-CoA (HMGCoA) reductase, resulting in less cholesterol being manufactured by the liver cells.?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 hemorrhagic stroke in the participants.?Thus, it was suggested that understanding the potential uses of vitamin E in preventing coronary heart disease might require longer studies with younger participants.

Deficiencies

Vitamin E deficiency symptoms include failure of placentation, neuromuscular impairments, hemolytic anemia, retinopathy, reduced immunity, and enhanced inflammation. Human vitamin E deficiency results from genetic abnormalities in α-TTP or in lipoprotein synthesis or occurs secondary to fat malabsorption syndromes. Genetic α-TTP defects are associated with a characteristic syndrome, ataxia with vitamin E deficiency, AVED.

• Vitamin E deficiency as a result of inadequate intake is difficult to assess. Circulating α-tocopherol concentrations can be elevated in the presence of hyperlipidemia. Thus, evaluation of circulating lipids or cholesterol should also be undertaken. Adipose tissue measurements have been used to assess status but have not been widely used. Vitamin E deficiency based on circulating α-tocopherol concentrations (<12 μmol/L serum or plasma) has been observed in large population studies in Africa, Southeast Asia, and the west Pacific. Prevalence may be increasing because of the increased intake of vegetable oils that may have become rancid by exposure to sunlight and prolonged heat through multiple uses.

CLINICAL ASPECTS OF VITAMIN E METABOLISM

CEHC as a biomarker of vitamin E status

Circulating α-tocopherol concentrations are not reliable for the assessment of vitamin E status, especially in subjects with abnormally high or low lipid concentrations. When urinary α-CEHC was initially suggested as a biomarker of adequate vitamin E status, the methodology at that time was not sufficiently sensitive to detect low urinary levels of α-CEHC excreted during times of vitamin E intake only from the diet, although plasma α-CEHC increases were reported with supplemental vitamin E intake. Refinements in methodology have shown that low levels of α-CEHC are continuously excreted in urine and do increase with higher α-tocopherol intake. There appears to be a threshold in α-CEHC excretion that corresponds to α-tocopherol intake; this increase in α-CEHC excretion has been proposed as an indicator of α-tocopherol adequacy. It is important to note that α-CEHC excretion does increase to a greater extent if supplements or foods fortified with all racemic α-tocopherol are consumed because α-CEHC levels increase to a greater extent in response to 2S-α-tocopherols. Additionally, biliary α-CEHC excretion may play an important role when supplemental vitamin E intake becomes excessive. Excretion via the bile may explain why the urinary α-CEHC concentration peaked prior to cessation of supplemental vitamin E intake in a study using deuterium-labeled vitamin E to study metabolism in smokers and nonsmokers.

REGULATION OF VITAMIN E CONCENTRATIONS BY TRAFFICKING AND METABOLISM

Vitamin E supplied in the diet is in relatively low concentrations, especially compared with amounts in supplements, and dietary vitamin E from plants is usually present in multiple vitamin E forms. When these low dietary amounts are absorbed and reach the liver, α-TTP facilitates α-tocopherol resection into plasma, while non-α-tocopherols are metabolized to CEHCs and excreted. Thus, as indicated in, prolonged, low intake of α-tocopherol can be associated with apparently adequate plasma α-tocopherol concentrations, as a result of the α-TTP salvage mechanism. Moreover, oxidative stress can increase the α-TTP gene expression, suggesting that hepatic α-TTP may increase with deficiency. Importantly, with high α-tocopherol administration e.g., 400 IU supplements, the liver secretion of α-tocopherol becomes limiting, plasma concentrations do not increase more than 2-4-fold, and xenobiotic metabolism is observed with high levels of circulating α-CEHC and high urinary α-CEHC excretion. Studies in rats administered vitamin E by subcutaneous injection with 40-fold increases in a hepatic α-tocopherol show that hepatic α-TTP, CYP4F2, and sult1 gene are unchanged, while xenobiotic efflux transporters are upregulated and influx transporters downregulated. It should be noted that the vitamin E-related substrates for the sulfotransferase and the transporters are unknown; the transporters are not involved in lipoprotein uptake. The net effect of these processes is, in the face of a high influx of α-tocopherol into the liver, to limit circulating α-tocopherol to a 2- to 4-fold increase, to increase α-CEHC excretion in urine, and potentially to increase both α-tocopherol and α-CEHC excretion in bile and thereby limit the delivery of α-tocopherol to extrahepatic tissues.

REFERENCES

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SAWSAN MAHDAWI