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Tocopherol

Tocopherols are a class of fat-soluble organic compounds that, along with tocotrienols, comprise vitamin E, consisting of four primary homologues—α-tocopherol, β-tocopherol, γ-tocopherol, and δ-tocopherol—that differ in the number and position of methyl groups on a chromanol ring attached to a phytyl side chain.^[1] These compounds, with α-tocopherol having the molecular formula C₂₉H₅₀O₂, function primarily as chain-breaking antioxidants, intercepting free radicals to prevent lipid peroxidation in cell membranes and other lipid-rich structures.^[2]^[3] α-Tocopherol is the most biologically active form, selectively retained by the liver via the α-tocopherol transfer protein, and plays key roles in maintaining membrane integrity and modulating enzymatic activities.^[4] Major dietary sources of tocopherols include vegetable oils such as sunflower, safflower, corn, and soybean oils, as well as nuts, seeds, and green leafy vegetables, with α- and γ-tocopherols being the predominant forms in most foods.^[5] In human nutrition, tocopherols contribute to the recommended intake of vitamin E, defined internationally as RRR-α-tocopherol equivalents to account for varying biological potencies among the forms.^[4] Discovered in the 1920s as a factor essential for rat reproduction, tocopherols were later recognized for their antioxidant properties, with the term "tocopherol" derived from Greek words meaning "to bear childbirth," reflecting early findings, though their broader roles extend to all vertebrates.^[1]

Forms and Structure

Tocopherols

Tocopherols represent the saturated subclass of vitamin E compounds, consisting of a chromanol ring attached to a phytyl side chain. The four primary isomers—alpha-, beta-, gamma-, and delta-tocopherol—differ in the number and positioning of methyl groups on the chromanol ring, which influences their chemical properties and biological efficacy. These differences arise from methylation at specific carbon positions: alpha-tocopherol features methyl groups at positions 5, 7, and 8 (5,7,8-trimethyltocol), beta-tocopherol at 5 and 8 (5,8-dimethyltocol), gamma-tocopherol at 7 and 8 (7,8-dimethyltocol), and delta-tocopherol solely at 8 (8-methyltocol). The natural form of alpha-tocopherol exhibits the RRR stereochemical configuration at chiral centers C2, C4', and C8'.^[6] The arrangement of methyl groups on the chromanol ring directly impacts vitamin E activity, with the fully methylated alpha form demonstrating the greatest potency due to enhanced stability in biological systems and superior interaction with binding proteins. Relative biological potencies, determined through classical rat fetal resorption assays, assign alpha-tocopherol a value of 1.0 IU/mg, beta-tocopherol 0.75 IU/mg, gamma-tocopherol 0.1 IU/mg, and delta-tocopherol 0.01 IU/mg. These values reflect their varying abilities to prevent vitamin E deficiency symptoms in vivo.^[7] Tocopherols are lipophilic molecules, soluble in lipids and oils but insoluble in water, allowing them to embed within cell membranes where they function as antioxidants by scavenging free radicals and inhibiting lipid peroxidation. Their stability is moderate; they resist oxidation under physiological conditions but degrade upon exposure to high temperatures, ultraviolet light, or pro-oxidants. In human physiology, alpha-tocopherol predominates in tissues, as it is selectively retained by the alpha-tocopherol transfer protein (α-TTP) in hepatocytes, which facilitates its incorporation into lipoproteins for systemic distribution.^[8]

Tocotrienols

Tocotrienols are a subclass of vitamin E compounds distinguished from tocopherols by their unsaturated isoprenoid side chains containing three double bonds.^[9] The four isoforms—α-tocotrienol, β-tocotrienol, γ-tocotrienol, and δ-tocotrienol—differ in the methylation patterns on their chromanol ring, similar to their tocopherol counterparts, but the unsaturation in the side chain imparts distinct physicochemical properties.^[5] Tocotrienols are predominantly found in plant-based sources, with high concentrations in palm oil (particularly γ- and δ-tocotrienols), rice bran oil, and annatto seeds.^[10] Unlike tocopherols, which are more ubiquitous in animal and plant tissues, tocotrienols are primarily of plant origin and less common in animal-derived foods.^[11] The unsaturated side chain of tocotrienols enables superior penetration into tissues with saturated fatty layers, such as the brain and liver, compared to the saturated phytyl chain of tocopherols.^[9] Additionally, tocotrienols exhibit non-antioxidant effects, including the inhibition of HMG-CoA reductase, an enzyme critical for cholesterol biosynthesis, with δ- and γ-tocotrienols showing potent suppressive activity.^[12] In terms of vitamin E biological potency, α-tocotrienol has approximately 0.3 IU/mg activity relative to α-tocopherol, reflecting lower efficiency in classical vitamin E functions like preventing oxidative damage in deficiency states.^[13] However, tocotrienols demonstrate superior efficacy in neuroprotection, such as mitigating stroke-induced brain damage, and anticancer effects, including suppression of tumor cell proliferation through pathways like HMG-CoA reductase downregulation and apoptosis induction.^[14]^[15] Tocotrienols are not retained as efficiently by the α-tocopherol transfer protein (α-TTP), which preferentially binds α-tocopherol, resulting in their faster metabolic turnover and shorter plasma half-life in humans.^[5] This selective retention mechanism contributes to the distinct bioavailability profile of tocotrienols compared to tocopherols.^[4]

Biological Functions

Mechanism of Action

Tocopherols, particularly α-tocopherol, serve primarily as lipid-soluble antioxidants that protect cell membranes by scavenging peroxyl radicals (ROO•) generated during lipid peroxidation. This chain-breaking action occurs through hydrogen atom transfer from the phenolic hydroxyl group of tocopherol (TOH) to the peroxyl radical, yielding a hydroperoxide (ROOH) and the relatively stable tocopheroxyl radical (TO•), as depicted in the reaction: TOH + ROO• → TO• + ROOH.^[16] This mechanism interrupts the propagation of oxidative damage in lipid bilayers, where tocopherols partition preferentially due to their hydrophobic phytyl tail.^[17] The tocopheroxyl radical (TO•) formed in this process is regenerated to its active form through a redox cycle involving water-soluble antioxidants such as ascorbic acid (vitamin C) or reduced glutathione (GSH). Vitamin C donates an electron to TO•, reducing it back to TOH while forming the ascorbyl radical, which is subsequently recycled by enzymes like glutathione reductase using GSH as a cofactor.^[18] This synergistic interplay enhances the overall antioxidant capacity, preventing accumulation of the less reactive but potentially pro-oxidant TO•. By safeguarding polyunsaturated fatty acids (PUFAs) in membrane phospholipids from peroxidation, tocopherols maintain membrane fluidity and integrity, averting cellular dysfunction from oxidative stress.^[17] Among tocopherol isoforms, α-tocopherol predominates in plasma and tissues due to its high-affinity binding to α-tocopherol transfer protein (α-TTP), a liver cytosolic chaperone with a dissociation constant (Kd) of approximately 25 nM for α-tocopherol, compared to much lower affinities for γ- or δ-tocopherols.^[19] This selective incorporation into very-low-density lipoproteins (VLDL) ensures efficient systemic distribution of α-tocopherol. Beyond antioxidation, tocopherols exert non-antioxidant effects, including inhibition of protein kinase C (PKC) activity, which modulates cell proliferation and signaling cascades, and suppression of 5-lipoxygenase (5-LOX), reducing leukotriene biosynthesis in inflammatory pathways.^[20] Additionally, long-chain metabolites of α-tocopherol act as allosteric inhibitors of 5-lipoxygenase, further limiting inflammation.^[21] α-Tocopherol metabolites also act as allosteric modulators of peroxisome proliferator-activated receptor gamma (PPARγ), influencing gene expression related to lipid metabolism and inflammation.^[22] These functions contribute to tocopherol's role in immune cell signaling, where it enhances T-cell membrane integrity and proliferation by altering signal transduction pathways.^[23]

Dietary Recommendations

The Recommended Dietary Allowance (RDA) for alpha-tocopherol, the primary form of vitamin E, is 15 mg per day (equivalent to 22 IU of the natural form) for adults aged 19 years and older, including both men and women.^[3] This value is set by the Institute of Medicine (IOM, now part of the National Academies of Sciences, Engineering, and Medicine) to meet the needs of nearly all healthy individuals, based on requirements for preventing deficiency and supporting antioxidant functions.^[24] For pregnant women, the RDA remains 15 mg per day, while it increases to 19 mg per day during lactation to account for additional demands on maternal nutrient stores.^[3] Infants require lower intakes, with an Adequate Intake (AI) of 4 mg per day for those aged 0-6 months and 5 mg per day for 7-12 months, reflecting limited data on exact requirements but sufficient to maintain plasma alpha-tocopherol levels.^[3] For the elderly (over 70 years), the RDA aligns with that for younger adults at 15 mg per day, as no age-specific adjustments are warranted due to similar absorption and utilization patterns.^[4] Vitamin E intake is measured in milligrams (mg) of alpha-tocopherol or International Units (IU), with conversions necessary for supplements: 1 mg of natural RRR-alpha-tocopherol equals 1.49 IU, while synthetic all-rac-alpha-tocopherol requires 2.22 IU per mg due to differences in biological potency.^[3] To account for mixed dietary forms, alpha-tocopherol equivalents (α-TE) are used, where alpha-tocopherol contributes 1.0 mg α-TE per mg, gamma-tocopherol 0.1 mg α-TE per mg, and tocotrienols vary (e.g., alpha-tocotrienol at 0.3 mg α-TE per mg), allowing standardized assessment of total vitamin E activity from foods or supplements.^[24] The Tolerable Upper Intake Level (UL) for alpha-tocopherol is 1,000 mg per day for adults, beyond which risks of adverse effects like hemorrhagic tendencies may increase, though data on long-term safety are limited.^[3] The World Health Organization (WHO) and Food and Agriculture Organization (FAO) endorse similar guidelines, recommending 10 mg per day as a safe intake level for adults based on preventing deficiency, with adjustments for vulnerable groups like infants aligning with IOM values where specific data are insufficient.^[25]

Sources and Intake

Natural Sources

Tocopherols, particularly α-tocopherol, are primarily obtained from plant-based foods, with vegetable oils serving as the richest sources. Wheat germ oil contains approximately 149 mg of α-tocopherol per 100 g, while sunflower oil provides about 41 mg per 100 g.^[26]^[27] Other notable oils include safflower and soybean, contributing significant amounts to dietary intake. Nuts and seeds also rank high, with almonds offering around 26 mg per 100 g^[28] and sunflower seeds approximately 26 mg per 100 g (dry roasted).^[3] Green leafy vegetables provide smaller quantities, such as spinach with 2 mg per 100 g.^[29] The distribution of tocopherol forms varies by source. In corn and soybean oils, γ- and δ-tocopherols predominate, often comprising the majority of total tocopherols, whereas olive oil is rich in α-tocopherol.^[30] Bioavailability of dietary tocopherols is influenced by several factors, with absorption efficiency typically ranging from 10% to 40%. Co-ingestion with dietary fat enhances uptake, as tocopherols are fat-soluble and require bile salts and pancreatic enzymes for micelle formation in the intestine; low-fat meals can reduce absorption to as low as 10%, while higher-fat meals (e.g., 20-30% fat) improve it to 30-40%.^[31] Food processing can lead to losses, with frying causing 20-50% reduction in tocopherol content due to heat-induced oxidation.^[32] Animal sources contain low levels of tocopherols, typically 0.5-1 mg per 100 g in meats like beef or poultry, primarily derived from the animals' feed rather than endogenous synthesis.^[33] Average daily intake of tocopherols in Western diets is 10-15 mg, largely from oils and nuts. Tropical oils, such as palm oil, are particularly rich in tocotrienols, a related form of vitamin E, with contents up to 800 mg/kg.^[34]^[35]

Supplementation and Fortification

Tocopherol supplementation is commonly available in capsule or tablet form, with typical dosages ranging from 100 to 400 International Units (IU) per serving, often provided as dl-alpha-tocopheryl acetate, a synthetic ester form of alpha-tocopherol.^[3]^[36] These supplements are frequently included in multivitamin formulations, contributing to their widespread use for addressing potential dietary shortfalls in vitamin E intake.^[37] Food fortification with tocopherols enhances the vitamin E content in various products to meet nutritional needs, particularly in cereals and infant formulas, where servings often provide 100% of the Recommended Dietary Allowance (RDA) of 15 mg for adults or age-appropriate amounts for infants.^[3]^[24]^[38] For instance, fortified infant cereals and formulas incorporate tocopheryl acetate to support early development, aligning with guidelines that emphasize adequate micronutrient delivery during complementary feeding.^[39] The global market for vitamin E, including tocopherols used in supplements and fortification, has shown steady growth, reaching approximately $2.99 billion in 2025, driven by increasing consumer demand for fortified foods and multivitamins amid rising health awareness.^[37] This expansion reflects broader trends in preventive nutrition, with tocopherol-fortified products gaining popularity in both developed and emerging markets. Synthetic tocopherols in supplements and fortified foods are typically esterified, such as in alpha-tocopheryl acetate, to improve stability during storage and processing, and these esters are subsequently hydrolyzed by pancreatic and intestinal enzymes in the gut prior to absorption.^[40] This process ensures bioavailability comparable to free tocopherols while preventing oxidation in commercial applications.^[41] In the European Union, fortification of foods with tocopherols is regulated under Regulation (EC) No 1925/2006, which harmonizes the addition of vitamins like vitamin E to foods, requiring that fortified products provide a significant amount of the nutrient without exceeding tolerable upper intake levels.^[42] For vegan consumers, tocopherol supplements can be sourced from plant extracts, such as non-GMO sunflower seeds, offering natural d-alpha-tocopherol without animal-derived components.^[4]

Deficiency

Causes and Symptoms

Tocopherol deficiency, commonly referred to as vitamin E deficiency, is rare in healthy populations with balanced diets, occurring in less than 0.1% of individuals in developed countries due to the widespread availability of vitamin E in foods.^[43] In contrast, incidence is higher in developing countries, particularly in areas affected by malnutrition and oxidative stressors like infections.^[44] The primary causes stem from impaired absorption and transport of this fat-soluble nutrient, including fat malabsorption syndromes such as cystic fibrosis, which disrupts bile acid secretion and pancreatic enzyme function, and cholestatic liver diseases that hinder bile flow.^[3] Genetic disorders like abetalipoproteinemia, characterized by defective lipoprotein production, severely limit tocopherol delivery to tissues, while prolonged low-fat diets can exacerbate deficiency by reducing overall intake and absorption efficiency.^[45] Clinical symptoms of tocopherol deficiency predominantly affect the nervous system, with progressive ataxia—manifesting as unsteady gait and coordination loss—and peripheral neuropathy, including numbness, tingling, and muscle weakness in the limbs, often emerging after 5-10 years of untreated deficiency.^[46] In premature infants, a key manifestation is hemolytic anemia, where red blood cells break down prematurely due to oxidative damage from insufficient antioxidant protection.^[3] Retinopathy, involving vision impairment and potential pigmentary changes in the retina, is another recognized symptom, particularly in cases of chronic malabsorption.^[3] Diagnosis relies on measuring plasma alpha-tocopherol levels, with concentrations below 5 μg/mL confirming deficiency in the context of normal lipid levels; the ratio of alpha-tocopherol to total serum lipids (below 0.8 mg/g) provides additional confirmation when lipids are elevated.^[43] To assess underlying fat malabsorption as a cause, diagnostic tests such as the 72-hour fecal fat collection or breath tests evaluating carbohydrate and fat digestion can be employed, helping differentiate primary from secondary deficiency.^[45] If identified early, symptoms like ataxia and neuropathy are often reversible upon addressing the underlying issue, but prolonged deficiency leads to irreversible nerve damage and degeneration.^[46]

Associated Health Risks

Chronic low tocopherol status, a form of vitamin E deficiency, is associated with increased oxidative stress, which contributes to neurodegeneration, immune dysfunction, and cardiovascular events. Oxidative damage from inadequate antioxidant protection impairs neuronal integrity, leading to progressive neurological impairments. In the context of immune function, low tocopherol levels weaken T-cell responses and increase susceptibility to infections, particularly in vulnerable populations. Cardiovascular risks arise from enhanced lipid peroxidation and endothelial dysfunction, elevating the likelihood of events such as myocardial infarction and ischemic stroke. Note that while clinical deficiency is rare, vitamin E inadequacy (intakes below recommended levels) is prevalent even in developed countries and may contribute to similar oxidative stress-related risks.^[47]^[3] Epidemiological evidence links low serum tocopherol concentrations to higher risks of specific neurodegenerative conditions. For instance, reduced vitamin E levels correlate with an elevated risk of Parkinson's disease, as deficiency exacerbates dopaminergic neuron loss through unchecked oxidative stress. Similarly, in the elderly, low tocopherol is associated with accelerated cognitive decline and increased incidence of mild cognitive impairment and Alzheimer's disease, with meta-analyses showing significantly lower alpha-tocopherol levels in affected individuals compared to controls. These associations highlight the role of tocopherol in maintaining cognitive and motor function over time.^[48]^[49] Certain populations face heightened risks from chronic tocopherol deficiency. Premature infants, often born with marginal vitamin E stores, are prone to retinopathy of prematurity due to oxidative damage in developing retinal vessels, a condition exacerbated by the high oxygen environments of neonatal care. In patients with abetalipoproteinemia, a genetic disorder impairing fat-soluble vitamin absorption, prolonged deficiency leads to spinocerebellar degeneration, manifesting as ataxia, hyporeflexia, and proprioceptive loss. Among the elderly, trials indicate that low tocopherol status increases infection risk, with vitamin E supplementation shown to reduce the odds of respiratory infections by up to 20% due to improved immune surveillance.^[50]^[51]^[52] Notably, while oxidative stress from deficiency may contribute to carcinogenesis, no direct causal link has been established between low tocopherol and cancer incidence.^[3] High-dose tocopherol supplementation can mitigate these risks in genetic deficiency cases. For abetalipoproteinemia patients, oral doses of 100-300 IU/kg/day have been shown to halt the progression of spinocerebellar degeneration and associated neuropathy, stabilizing neurological function when initiated early.^[51] Such interventions underscore the potential to reverse or arrest deficiency-related damage in targeted populations, though broader applications require further validation.

Commercial Production

Synthesis Methods

Tocopherols are primarily produced through natural extraction, chemical synthesis, and emerging biotechnological methods, with global annual production estimated at approximately 70,000 tons as of 2023 to meet demand in food, pharmaceuticals, and cosmetics.^[53] Natural extraction involves vacuum distillation of deodorizer distillates obtained as by-products during the refining of vegetable oils such as soybean, sunflower, and palm oils. These distillates contain tocopherols at concentrations typically ranging from 5% to 20%, and the distillation process under high vacuum (around 0.1-1 mbar) separates the tocopherols, yielding mixed tocopherol concentrates with overall extraction efficiencies of 0.1-1% relative to the original oil volume. This method preserves the natural RRR stereochemistry of the tocopherols, making it suitable for "natural" vitamin E products.^[54]^[55]^[56] Chemical synthesis, which accounts for the majority of industrial production, focuses on dl-alpha-tocopherol, a racemic mixture, via the condensation of isophytol (derived from petrochemicals or microbial sources) with 2,3,5-trimethylhydroquinone (TMHQ). The reaction is catalyzed by acid agents such as zinc chloride or boron trifluoride in an organic solvent, proceeding through a Friedel-Crafts-type alkylation to form the chroman ring structure, followed by purification via molecular distillation or chromatography. The industrial chemical synthesis route, first achieved in 1938 by Paul Karrer and later scaled up by companies including BASF, established this approach as the standard for large-scale production of the synthetic racemic form. Pharmaceutical-grade dl-alpha-tocopherol from this method achieves purity levels exceeding 97%.^[57]^[58]^[59] Biotechnological approaches, though not yet dominant, utilize engineered microorganisms for sustainable production of tocopherols or precursors like isophytol. For instance, Escherichia coli strains have been genetically modified to express the tocopherol biosynthetic pathway, achieving low titers such as around 4 mg/L for δ-tocotrienol in fed-batch fermentation. Saccharomyces cerevisiae has also been engineered for de novo production of tocotrienols (related vitamin E forms) via two-stage fermentation, reaching up to 320 mg/L under cold-shock temperature control to enhance pathway flux. These methods aim to reduce reliance on petrochemical feedstocks but currently yield lower quantities compared to chemical synthesis.^[60]^[59]^[61]

Available Forms

Tocopherols are commercially available in several forms, primarily categorized by their source, composition, and chemical modification for stability and application. Synthetic forms include all-rac-α-tocopherol (also known as dl-α-tocopherol), a racemic mixture produced through chemical synthesis, which exhibits approximately 50% of the biological activity of the natural enantiomer due to only the RRR configuration being fully bioactive.^[3] In contrast, the natural enantiomer, d-α-tocopherol (or RRR-α-tocopherol), is derived from plant sources and provides full bioactivity, often used in supplements as a standalone ingredient.^[2] Mixed tocopherols, sourced naturally from vegetable oils such as soybean, consist of a blend of α-, β-, γ-, and δ-tocopherols, with γ- and δ-forms typically comprising 80-95% of the total composition to maintain antioxidant synergy among the homologs.^[62] These mixed forms are valued for their complementary antioxidant properties, where γ- and δ-tocopherols enhance overall efficacy beyond α-tocopherol alone by improving uptake and reducing lipid peroxidation more effectively.^[63] The United States Pharmacopeia (USP) establishes standards for mixed tocopherol concentrates, ensuring minimum tocopherol content and purity for use in dietary supplements and food fortification.^[64] Esterified forms, such as α-tocopheryl acetate and α-tocopheryl succinate, are chemically modified versions of tocopherols designed for enhanced stability against oxidation and heat, commonly incorporated into cosmetics, pharmaceuticals, and fortified foods.^[65] For instance, tocopheryl acetate is widely used in topical products due to its oil-soluble nature and prolonged shelf life. Additionally, tocotrienol-rich fractions (TRF) derived from palm oil provide a specialized form containing a mixture of tocotrienols (α-, β-, γ-, δ-) alongside α-tocopherol, standardized by USP monographs to support antioxidant applications.^[66] Labeling regulations distinguish natural vitamin E as requiring d-form (RRR) configurations from plant sources, while synthetic dl-forms must account for their reduced potency in nutritional declarations, often expressed in international units (IU) where 1 mg of natural d-α-tocopherol equals 1.49 IU compared to 1.1 IU for synthetic dl-α-tocopherol.^[3] Products claiming "natural vitamin E" must derive at least the active d-enantiomers to comply with these standards, avoiding misrepresentation of synthetic blends.^[3]

Therapeutic Uses

Antioxidant Applications

Tocopherols function as chain-breaking antioxidants in free radical chain reactions by scavenging lipid peroxyl radicals, thereby interrupting the propagation of oxidative damage in lipid environments.^[4] This mechanism is central to their role in preventing lipid peroxidation, a process where free radicals attack polyunsaturated fatty acids in cell membranes and other biological structures.^[67] In human health, tocopherols are widely used in supplements to prevent lipid peroxidation, with typical daily doses ranging from 15 mg (the recommended dietary allowance for adults) to 200 mg for enhanced antioxidant support.^[4] These doses help maintain cellular integrity by neutralizing reactive oxygen species in fats and oils within the body.^[68] Tocopherols exhibit synergy with ascorbate (vitamin C) in multivitamin formulations, where ascorbate regenerates oxidized tocopherol, amplifying their combined antioxidant efficacy.^[69] In the food industry, tocopherols are approved as preservatives under codes E306 (dl-α-tocopherol), E307 (dl-α-tocopheryl acetate), E308 (γ-tocopherol), and E309 (δ-tocopherol), particularly in oils and fats to inhibit oxidation and extend shelf life in vegetable oils.^[70] This application prevents rancidity and preserves nutritional quality during storage and processing.^[71] Tocopherols stabilize cosmetic formulations by preventing the oxidation of ingredients such as oils and emollients, and they provide skin protection against ultraviolet (UV) radiation at concentrations of 0.5-2%.^[72] In topical products, they reduce UV-induced oxidative stress in keratinocytes, enhancing photoprotection without replacing sunscreen agents.^[73] Beyond consumer applications, tocopherols serve as antioxidants in industrial processes, such as biodiesel production, where they improve oxidation stability and fuel stability against degradation by mitigating peroxide formation in fatty acid methyl esters, supporting longer storage and performance.^[74]^[75]

Disease-Specific Research

Research on tocopherol's role in specific diseases has yielded mixed results, with some evidence supporting its use in ocular conditions but limited or inconsistent benefits for neurodegenerative, cardiovascular, and oncologic disorders. The Age-Related Eye Disease Study (AREDS), a large randomized controlled trial, demonstrated that supplementation with 400 IU of vitamin E (as alpha-tocopherol) combined with vitamin C, beta-carotene, and zinc reduced the progression from intermediate to advanced age-related macular degeneration (AMD) by approximately 25% over five years in high-risk participants.^[76] This formulation, refined in AREDS2 by replacing beta-carotene with lutein and zeaxanthin, maintained similar protective effects against AMD progression without increasing lung cancer risk in former smokers.^[76] For Alzheimer's disease, clinical evidence is mixed, with early trials suggesting potential benefits in slowing progression but later studies showing no preventive effect in mild cognitive impairment. A landmark randomized trial involving patients with moderate Alzheimer's found that 2,000 IU/day of alpha-tocopherol delayed functional decline by about 19% compared to placebo, extending the time to nursing home placement or death by roughly 7 months.^[77] However, a 2022 meta-analysis of dietary and supplemental vitamin E intake indicated a significant reduction in dementia and Alzheimer's risk with higher consumption (relative risk 0.74 for highest vs. lowest intake), though treatment trials in established disease remain inconsistent.^[78] In cancer prevention, large-scale trials have generally not supported tocopherol's efficacy, with some evidence of harm in specific contexts. The Selenium and Vitamin E Cancer Prevention Trial (SELECT), involving over 35,000 men, showed that 400 IU/day of alpha-tocopherol neither prevented nor reduced prostate cancer incidence and was associated with a 17% increased risk after 7 years of follow-up.^[36] For breast cancer, observational data suggest a potential protective association, with a 2023 umbrella review reporting an inverse relationship between vitamin E intake and risk (odds ratio approximately 0.82 for highest vs. lowest categories across multiple studies), though randomized trials are lacking.^[79] Regarding cardiovascular disease (CVD), major trials indicate no overall benefit from tocopherol supplementation. The Heart Outcomes Prevention Evaluation (HOPE) study, a randomized trial of 9,297 high-risk patients, found that 400 IU/day of natural-source vitamin E for 4.5 years did not reduce the composite endpoint of myocardial infarction, stroke, or CVD death compared to placebo (relative risk 1.01).^[80] Subgroup analyses in diabetic participants, however, suggested modest benefits, including a 22% reduction in microvascular complications like nephropathy progression.^[81] Other disease-specific investigations include cataracts and preeclampsia. Cohort studies have linked higher dietary vitamin E intake to a 10-20% reduced risk of age-related cataracts, with a 2023 meta-analysis reporting a dose-response effect where intakes above 7 mg/day lowered odds by up to 18% in population-based samples.^[82] In pregnancy, a 2024 review, citing the 2019 Cochrane systematic review of 15 trials, concluded that vitamin E supplementation, often combined with vitamin C, does not reduce preeclampsia incidence or severity in high-risk women, with no significant differences in outcomes versus placebo.^[83] Recent preclinical research highlights the promise of tocotrienols, unsaturated analogs of tocopherols, in neurodegeneration. A 2025 scoping review of tocotrienol-rich fractions noted neuroprotective effects, including prevention of tau hyperphosphorylation by α-tocotrienol and inhibition of amyloid-beta aggregation in cellular models of Alzheimer's.^[84]^[85] These findings suggest tocotrienols may offer advantages over traditional tocopherols for tau-related pathologies, though human trials are needed.

Safety and Interactions

Side Effects

Tocopherol supplementation, particularly at doses exceeding recommended levels, can lead to various adverse effects, though it is generally well-tolerated at lower intakes. Common side effects include gastrointestinal upset such as nausea and diarrhea, as well as fatigue and headache, which become more frequent at doses greater than 400 IU per day.^[86]^[87]^[88] Rare but serious effects, such as bleeding tendencies due to its anticoagulant-like properties, have been reported at doses over 1,000 IU per day, potentially increasing the risk of hemorrhagic events.^[89]^[90] High-dose tocopherol supplementation has been associated with elevated health risks in clinical trials and analyses. The Selenium and Vitamin E Cancer Prevention Trial (SELECT) demonstrated a 17% increased risk of prostate cancer (hazard ratio 1.17) among healthy men taking 400 IU of vitamin E daily compared to placebo.^[91] Additionally, a 2005 meta-analysis of randomized trials found that high-dosage vitamin E (≥400 IU/day) may increase all-cause mortality, with a dose-response analysis indicating progressively increased risk starting at dosages greater than 150 IU/day; as of 2025, recent reviews continue to reference these potential mortality risks from high-dose supplementation, though subsequent analyses have not consistently replicated increased all-cause mortality and recommend caution for doses exceeding 400 IU/day in certain populations.^[92]^[93] These findings underscore the potential for long-term supplementation to exacerbate mortality risks, particularly in older adults or those with chronic conditions. Certain vulnerable groups face heightened risks from tocopherol supplementation. In individuals with hemophilia or bleeding disorders, tocopherol can prolong clotting time, amplifying the potential for hemorrhage due to its interference with platelet aggregation and coagulation factors.^[89] Premature infants receiving vitamin E supplementation exhibit an increased risk of sepsis, alongside other complications like necrotizing enterocolitis, despite benefits in reducing intracranial hemorrhage in some cases.^[94] No toxicity is observed from natural food sources of tocopherol, as dietary intake does not reach levels associated with adverse effects. In animal studies, the median lethal dose (LD50) exceeds 2 g/kg body weight in rats, indicating low acute toxicity.^[95]^[86] For long-term use of tocopherol supplements, especially at higher doses, monitoring coagulation parameters such as prothrombin time and partial thromboplastin time is recommended to detect early signs of bleeding risk.^[96]^[89] This precaution is particularly relevant in patients with compromised vitamin K status, where excess tocopherol may induce reversible coagulopathy.^[97]

Drug Interactions

Tocopherols, forms of vitamin E, can interact with various pharmaceuticals, primarily through their antioxidant properties and influence on lipid absorption or coagulation pathways. High doses (≥300 mg/day) of tocopherol supplementation may potentiate the effects of anticoagulant medications such as warfarin and cyclosporine by enhancing their antithrombotic activity, potentially leading to increased bleeding risk.^[98] Specifically, tocopherol can amplify warfarin's anticoagulant response, necessitating closer monitoring of international normalized ratio (INR) levels to avoid excessive anticoagulation.^[99] Similarly, interactions with cyclosporine have been noted, where tocopherol may alter the drug's immunosuppressive efficacy through shared metabolic pathways.^[100] With statins like simvastatin, tocopherol levels play a role in muscle health; statin therapy can deplete tocopherol concentrations, potentially contributing to myopathy risk as observed in case reports and hypotheses linking vitamin E deficiency to statin-induced muscle toxicity.^[101] In chemotherapy contexts, tocopherol may reduce the efficacy of tamoxifen in estrogen receptor-positive breast cancer by modulating estrogen receptor activity and decreasing the drug's antiproliferative effects on cancer cells.^[102] Additionally, tocopherol's antioxidant action can interfere with radiation therapy by protecting cancer cells from oxidative damage, thereby potentially reducing treatment effectiveness and increasing recurrence risk, particularly in head and neck cancers.^[103] Orlistat, a lipase inhibitor, diminishes tocopherol absorption by blocking fat digestion, which can lead to reduced serum levels of this fat-soluble vitamin.^[104] According to 2024 European Food Safety Authority guidelines on vitamin E upper intake levels, caution is advised for individuals on anticoagulant or antiplatelet therapies due to interaction risks, though no specific new directives on spacing from other fat-soluble drugs were issued beyond general absorption considerations.^[105] Tocopherol exhibits no significant interactions with most antihypertensive medications, showing no clinically relevant impact on blood pressure control in treated hypertensive patients.^[106] Management of these interactions typically involves dose adjustments to tocopherol supplementation, therapeutic drug monitoring (e.g., INR for anticoagulants), and timing separations—such as administering tocopherol at least 2 hours before or after orlistat or other fat-malabsorbing agents—to optimize absorption and minimize risks.^[107] Patients on interacting regimens should undergo regular clinical assessments to balance benefits and adverse outcomes.^[89]

History and Research

Discovery and Development

The discovery of tocopherol began in 1922 when researchers Herbert McLean Evans and Katharine Scott Bishop at the University of California, Berkeley, identified a fat-soluble dietary factor essential for preventing reproductive failure in rats. In their experiments, rats fed a purified diet lacking this factor exhibited fetal resorption in females and sterility in males, leading to its initial designation as the "X factor" or anti-sterility vitamin, later recognized as vitamin E.^[108]^[109] These early rat sterility studies laid the foundation for understanding tocopherol's role in fertility and nutrition.^[110] By 1936, Evans and colleagues isolated α-tocopherol from wheat germ oil, crystallizing it as a viscous oil and naming it "tocopherol" from the Greek terms "tokos" (childbirth) and "pherein" (to bear), combined with "ol" for its alcohol nature.^[111] This isolation confirmed its biological activity, and in 1939, α-tocopherol was officially established as the primary component of vitamin E following structural elucidation by Erhard Fernholz.^[111] Despite its significance, the discovery of vitamin E did not receive a Nobel Prize, unlike several other vitamins identified around the same era.^[112] Key milestones in the 1940s included the first total synthesis of α-tocopherol by Paul Karrer in 1938, followed by industrial-scale production pioneered by Hoffmann-La Roche, which enabled commercial availability.^[113] The first vitamin E supplements, initially derived from natural sources like wheat germ oil and later synthetic forms, entered the market in the early 1940s, targeting nutritional deficiencies observed in animal and human studies.^[111] In the 1950s, clinical observations revealed vitamin E deficiency in premature infants, manifesting as hemolytic anemia due to low plasma tocopherol levels and increased red blood cell fragility, prompting early supplementation trials.^[108] By the 1960s, the Recommended Dietary Allowance (RDA) for vitamin E was formalized at 30 international units (IU) per day for adults by the Food and Nutrition Board, based on balance studies and deficiency prevention data.^[114] Commercial development advanced further in the 1970s with patents for processes involving mixed tocopherols, such as catalytic conversions to enhance stability and yield from natural oils, broadening their use in supplements and fortified foods.^[115]

Recent Advances

Recent genomic research has advanced the understanding of ataxia with vitamin E deficiency (AVED), a neurodegenerative disorder caused by mutations in the α-tocopherol transfer protein (α-TTP) gene, which impairs vitamin E transport and leads to low plasma tocopherol levels.^[116] While the genetic basis was established in the 1990s, 2020s studies have highlighted long-term therapeutic strategies, including high-dose oral α-tocopherol supplementation (up to 800 mg/day), which has stabilized neurological symptoms in patients for over 36 years as of 2020 in documented cases.^[117] Recent case reports from 2022 identified novel TTPA mutations in diverse populations, such as a Chinese patient with a homozygous c.473C>T (p.Phe185Ser) mutation, underscoring the need for genetic screening and early intervention to prevent ataxia progression.^[118] Tocotrienols, unsaturated analogs of tocopherols, have shown promise in neuroprotection during the 2010s through clinical trials targeting stroke outcomes. The 2014 randomized controlled trial investigating palm vitamin E tocotrienols (200 mg/day for two years) in patients with white matter lesions demonstrated reduced progression of cerebral white matter damage, suggesting neuroprotective effects against ischemic injury.^[119] Similarly, a phase III trial (NCT02263924) evaluated mixed tocotrienols (400 mg/day) post-stroke.^[120] In oncology, 2025 advancements include biotech applications of δ-tocotrienol, with an ongoing randomized trial (NCT06519097) assessing its role in preventing progression of intraductal papillary mucinous neoplasms, a pancreatic cancer precursor, at doses of 200-400 mg/day, building on preclinical evidence of tumor suppression via Wnt signaling inhibition.^[121] Nutritional guidelines have evolved to incorporate tocotrienols alongside tocopherols in vitamin E assessments. The 2023 Nordic Nutrition Recommendations scoping review recognized all eight vitamin E forms (four tocopherols and four tocotrienols) for their antioxidant contributions, recommending intake calculations based on α-tocopherol equivalents while noting tocotrienols' superior bioavailability in certain contexts.^[122] Emerging research on gut microbiome interactions reveals that tocopherols modulate microbial composition, with supplementation increasing beneficial taxa like Lactobacillus and Bifidobacterium, which enhance short-chain fatty acid production and potentially improve tocopherol absorption in aging models.^[123] A 2023 study further linked vitamin E intake to microbiome-driven reductions in inflammation, potentially amplifying its nutritional efficacy.^[124] Re-evaluations of high-dose tocopherol supplementation have intensified concerns over potential harms. The 2024 European Food Safety Authority (EFSA) opinion set a tolerable upper intake level of 300 mg/day for α-tocopherol, citing increased bleeding risk due to anticoagulant effects observed in doses exceeding 400 IU/day, particularly in cardiovascular trials.^[105] This aligns with a 2025 review highlighting associations between high-dose (>400 mg/day) vitamin E and elevated all-cause mortality, hemorrhagic stroke, and prostate cancer incidence, prompting revised guidelines to limit supplementation in at-risk populations.^[93] Innovations in delivery systems and crop enhancement address bioavailability challenges. Nanotechnology approaches, such as liposomal formulations of α-tocopherol, have shown potential for improved delivery and cellular uptake.^[125] In plant breeding, 2025 genetic analyses identified key loci for tocopherol biosynthesis, enabling marker-assisted selection in various crops to enhance vitamin E content.^[126] Despite these advances, research gaps persist, particularly regarding long-term low-dose tocopherol benefits. Umbrella reviews from 2023 indicate inconsistent evidence for preventive effects against chronic diseases at doses below 100 mg/day, with calls for longitudinal studies to clarify impacts on cognitive decline and cardiovascular health.^[79] For immune support in COVID-19, early 2022 trials reported no significant reduction in severity with vitamin E supplementation (400 IU/day), but protocols for long COVID are revisiting combined low-dose tocopherol (200-400 IU/day) with other antioxidants to assess anti-inflammatory and antithrombotic roles in post-viral neuroinflammation.^[127]^[128]

References

[1]
6 Vitamin E | Dietary Reference Intakes for Vitamin C, Vitamin E ...
FIGURE 6-1 Structures of tocopherols and tocotrienols. The four tocopherols are shown in A and the four tocotrienols in B. All tocopherols are in the RRR-form.
[2]
Vitamin E | C29H50O2 | CID 14985 - PubChem - NIH
Vitamin E or tocopherol is a fat-soluble vitamin that functions as an antioxidant, protecting the cell membrane. As with all vitamins, the body does not form ...
[3]
Vitamin E - Health Professional Fact Sheet
Vitamin E is a fat-soluble antioxidant that stops the production of ROS formed when fat undergoes oxidation.
[4]
Vitamin E | Linus Pauling Institute | Oregon State University
Vitamin E is defined as α-tocopherol, while tocochromanols describes a family of eight fat-soluble molecules with antioxidant activities.Missing: chemistry biology
[5]
Tocopherols and Tocotrienols—Bioactive Dietary Compounds
Jun 9, 2021 · The main sources of tocopherols are almond oil and other nut oils, olive oil, sunflower oil, rapeseed oil, corn oil, linseed oil, and soybean ...
[6]
Tocopherols in cancer: an update - PMC - NIH
α-Tocopherol (T) is trimethylated at the 5-, 7-and 8-positions of the chromanol ring and β-T is dimethylated at 5- and 8-positions, whereas γ-T is dimethylated ...
[7]
Delta Tocopherol - an overview | ScienceDirect Topics
The structures of α-, β-, γ-, and δ-tocopherols are shown in Figure 1. α-Tocopherol is methylated at C5, C7, and C8 on the chromanol ring, whereas the other ...
[8]
Alpha-tocopherol: roles in prevention and therapy of human disease
Within with each group, there are four isoforms, α, β, γ, and δ named for specific methyl group substitutions at positions 5, 7 and 8 of the chromanol ring [1].
[9]
Tocotrienol - an overview | ScienceDirect Topics
The unsaturated side chain of tocotrienol allows for more efficient penetration into tissues that have saturated fatty layers, such as the brain and liver [32].
[10]
A review of characterization of tocotrienols from plant oils and foods
Tocotrienols are of four types, viz. alpha (α), beta (β), gamma (γ) and delta (δ). Unlike tocopherols, tocotrienols are unsaturated and possess an isoprenoid ...
[11]
Pharmacological potential of tocotrienols: a review
Nov 12, 2014 · Unlike tocopherols, tocotrienols are unsaturated and possess an isoprenoid side chain. Tocopherols are lipophilic in nature and are found in ...
[12]
Inhibitory effect of delta-tocotrienol, a HMG CoA reductase ... - PubMed
We have previously shown that alpha-tocotrienol (alpha-T3), a vitamin E analogue and HMG CoA reductase (HMGR) inhibitor, markedly inhibited ...
[13]
Alpha-Tocotrienol - an overview | ScienceDirect Topics
Of the tocotrienols, only α-tocotrienol has significant biological activity (0.3 mg α-TE mg-1). Lengthening or shortening of the side chain results in a ...
[14]
Pharmacological potential of tocotrienols: a review - PMC
Tocotrienols exhibit biological activities that are also exhibited by tocopherols, such as neuroprotective, anti-cancer, anti-inflammatory and cholesterol ...
[15]
Revisiting the therapeutic potential of tocotrienol - IUBMB Journal
Jun 20, 2022 · This review will focus on the systemic intracellular anti-cancer, antioxidant, and anti-inflammatory mechanisms that are stimulated and/or regulated by ...
[16]
Lipid Peroxidation and Antioxidant Protection - PMC - NIH
In the case of phenols like α-TOH, the reaction with ROO• occurs by formal HAT from the phenolic -OH group, to afford a stabilized phenoxyl radical α-TO ...
[17]
Role of Vitamin E as a Lipid-Soluble Peroxyl Radical Scavenger
Role of Vitamin E as a Lipid-Soluble Peroxyl Radical Scavenger: In Vitro and in Vivo Evidence ... Radical scavenging is one of the essential roles of antioxidants ...
[18]
Vitamins C and E: Beneficial effects from a mechanistic perspective
The tocopheryl radical (Vit E-O•) reacts with vitamin C (or other hydrogen donors, AH), thereby oxidizing the latter and returning vitamin E to its reduced ...
[19]
Vitamin E, Antioxidant and Nothing More - PMC - NIH
... action of α-tocopherol result from its role as a lipid soluble antioxidant. ... Vitamin E's antioxidant function, as a peroxyl radical scavenger that ...
[20]
Regulatory role of vitamin E in the immune system and inflammation
Vitamin E modulates T cell function through directly impacting T cell membrane integrity, signal transduction, and cell division.
[21]
Vitamin E - Dietary Reference Intakes for Vitamin C ... - NCBI - NIH
The Tolerable Upper Intake Level (UL) for adults is set at 1,000 mg (2,325 µmol)/day of any form of supplemental α-tocopherol based on the adverse effect of ...
[22]
[PDF] Human Vitamin and Mineral Requirements
At present, data are not sufficient to formulate recommendations for vitamin E intake ... Recommendations for iron intake for infants, children, younger and older.
[23]
Top 10 Foods Highest in Vitamin E
Nov 10, 2024 · Foods High in Vitamin E (Alpha-Tocopherol) by Nutrient Density (100 Gram Serving Size) ; 1. Wheat Germ Oil · 996% DV (149.4mg) ; 2. Chili Powder ...
[24]
5 Foods With More Vitamin E Than Sunflower Seeds - Health
Oct 15, 2025 · Vitamin E content: 39.2 milligrams of vitamin E per 100 grams of almond oil. One tablespoon (14 grams) provides 5.3 milligrams of vitamin E ...3. Sunflower Oil · 4. Almond Oil · 5. Cottonseed Oil
[25]
[PDF] ALMOND COMPOSITION
When ABC submits almond nutrient data sets, USDA also requests the ... Vitamin E (alpha-tocopherol) mg. 26.22. 23.75. 25.97. 25.97. 23.80. 23.80. Thiamin.
[26]
The 10 best foods high in vitamin E - MedicalNewsToday
Jan 29, 2019 · Wheat germ oil: 20.32 ... Swiss chard is a dark green leafy vegetable that contains 1.89 mgTrusted Source of vitamin E in a 100 g serving.
[27]
Analytical Strategies for Tocopherols in Vegetable Oils - NIH
Generally, γ-tocopherol tends to be the principal form in oils such as soybean, corn, and sesame, whereas α-tocopherol is more prominent in oils like sunflower ...
[28]
Human vitamin E requirements assessed with the use of apples ...
The mean (±SD) estimated percentage d6-α-tocopherol absorbed increased from 10 ± 4% during the 0% fat trial to 20 ± 3% and 33 ± 5% during the 6% and 21% fat ...
[29]
Effect of antioxidants on losses of tocopherols during deep-fat frying
It has been found that α-tocopherol is lost much faster than β-, γ- or δ tocopherol, with a reduction of 50% α-tocopherol after 4–5 frying operations compared ...
[30]
Meats Highest in Vitamin E (Alpha-Tocopherol) - Nutrition Data Tools
Meats Highest in Vitamin E (Alpha-Tocopherol) ; +, 3. Pepperoni (Pepperoni, beef and pork, sliced) 3 oz. 0.9mg (6% DV). Standard Release (Common) ; +, 4. Raw ...
[31]
Vitamin E (α- and γ-Tocopherol) Levels in the Community - MDPI
Dec 21, 2017 · The median intakes of dietary α-tocopherol were 11.6 mg/day (men: 11.9 mg/day, women: 11.3 mg/day). 36.3% of men and 41.2% of women met the ...<|separator|>
[32]
Tocotrienols: The Emerging Face of Natural Vitamin E - PMC
Natural vitamin E includes eight chemically distinct molecules: α-, β-, γ- and δ-tocopherol; and α-, β-, γ- and δ-tocotrienol. In the current literature, ...
[33]
Selenium and Vitamin E Cancer Prevention Trial (SELECT)
Jul 7, 2015 · The form of vitamin E given was dl-alpha tocopheryl acetate, the form of vitamin E found to reduce prostate cancer incidence in the ATBC. Did ...
[34]
Vitamin E Market Report 2025 - Share & Insights By 2034
$$4,490.00 In stockThe vitamin e market size has grown strongly in recent years. It will grow from $2.77 billion in 2024 to $2.99 billion in 2025 at a compound annual growth rate ...
[35]
Impact of Fortified Whole Grain Infant Cereal on the Nutrient Density ...
Mar 19, 2025 · The aim of this study was to evaluate the impact of fortified whole grain infant cereal (WGIC), a complementary food, among 6- to 12-month-old infants on the ...
[36]
Micronutrient intake and the contribution of dietary supplements in ...
Mar 4, 2019 · However, in the present sample, the main contributors for vitamin E were infant formula, almond milk and some starchy vegetables, while for ...
[37]
Vitamin E and Metabolic Health: Relevance of Interactions with ... - NIH
Vitamin E in food, but especially in dietary supplements, is often present as an esterified molecule. After hydrolysis by pancreatic and intestinal digestive ...Missing: gut | Show results with:gut
[38]
Vitamin E Bioavailability: Mechanisms of Intestinal Absorption in the ...
Nov 22, 2017 · This review describes the fate of vitamin E in the human gastrointestinal lumen during digestion and focuses on the proteins involved in the intestinal ...
[39]
Addition of vitamins and minerals - Food Safety
Regulation (EC) No 1925/2006 harmonises the provisions regarding the addition of vitamins and minerals and of certain other substances to foods.
[40]
Vitamin E Deficiency - StatPearls - NCBI Bookshelf
Not as common symptoms include muscle weakness and visual-field constriction. The most severe symptoms are blindness, dementia, and cardiac arrhythmias. If ...Introduction · Etiology · History and Physical · Differential Diagnosis
[41]
Vitamin E Deficiency in Developing Countries - Sage Journals
Jun 16, 2011 · Results from multiple studies suggest that poor nutritional status and higher prevalence of other oxidative stressors such as malaria and HIV infection ...
[42]
Human Vitamin E Deficiency, and what is and is NOT vitamin E? - NIH
Tocopherols and tocotrienols have similar ring structures: trimethyl (α-), dimethyl (β- or γ-), and monomethyl (δ-) chromanols; however, tocopherols have a ...
[43]
Vitamin E Inadequacy in Humans: Causes and Consequences - PMC
Sep 1, 2014 · Human vitamin E deficiency symptoms include a progressive neurologic disorder, spinocerebellar ataxia, which occurs as a result of a dying back ...
[44]
Parkinson's Risk Factors: Environmental & Biologic
Apr 5, 2024 · Vitamin E deficiency has been shown to be associated with increased PD risk, and an RCT including 60 participants with PD showed clinical ...<|control11|><|separator|>
[45]
A meta-analysis of peripheral tocopherol levels in age ... - PubMed
These results suggest that lower α-tocopherol levels have a strong association with AD and MCI supporting evidence for the role of diet and vitamin E in AD ...
[46]
Vitamin E Protects Against Retinopathy of Prematurity ... - PubMed
Vitamin E supplementation above the deficient plasma levels of these infants suppresses gap junction formation and clinically reduces the severity without ...
[47]
Abetalipoproteinemia - GeneReviews® - NCBI Bookshelf
Oct 25, 2018 · Malabsorption of fat-soluble vitamins (A, D, E, and K) can result in an increased international normalized ratio (INR). Untreated individuals ...Summary · Diagnosis · Clinical Characteristics · Management
[48]
Vitamin E and immune response in the aged - PubMed Central - NIH
... vitamin E supplementation significantly reduces the risk for acquiring respiratory infections in elderly. In particular, vitamin E supplementation reduced ...
[49]
(PDF) Arrest of neuropathy and myopathy in abetalipoproteinemia ...
Aug 6, 2025 · It was concluded that treatment with high doses of vitamin E was responsible for the arrest of the usually progressive neuropathy and myopathy.
[50]
Revolution of vitamin E production by starting from microbial ...
May 10, 2022 · The de novo production of δ-tocotrienol from glucose with a titer of 4.1 mg/L in fed-batch fermentation was achieved in S. cerevisiae.
[51]
Free fatty acid separation from vegetable oil deodorizer distillate ...
Natural tocopherols are recovered from vegetable oil deodorizer distillates (VODD), a valuable by-product obtained during the deodorization of vegetable oil ...
[52]
Molecular Distillation Processes for Tocopherol Extraction from ...
Sep 10, 2025 · Deodorized distillate (DOD), a by‐product of the vegetable oil refining process, is a major source of these natural tocopherols.Missing: yield | Show results with:yield
[53]
[PDF] Recovery of Vitamin E from Edible Oil – A Review
Vitamin E, a fat-soluble antioxidant, is found in edible oils, especially deodorized soya oil. It's recovered from oil byproducts and used in food, cosmetics, ...
[54]
US3708505A - Process for preparation of d,l-alpha tocopherol
D,1-ALPHA-TOCOPEROL IS PREPARED BY REACTING TRIMETHYLHYDROQUINONE (TMHQ) AND ISOPHYTOL IN THE PRESENCE OF A COMBINED ACID CONDENSATION AGENT WHICH COMPRISES ...
[55]
Understanding the Production Process of Vitamin E - ChemAnalyst
Sep 1, 2025 · Vitamin E production involves natural extraction from vegetable oils or synthetic methods using petrochemicals, including preparation, chemical ...
[56]
Fermentative production of Vitamin E tocotrienols in Saccharomyces ...
Oct 14, 2020 · A cold-shock-triggered temperature control system is designed for efficient control of two-stage fermentation, leading to production of 320 mg/L tocotrienols.
[57]
Microbial Cell Factories for Green Production of Vitamins - Frontiers
The vitamin B6 production was enhanced to 78 mg/L within 31 h in E. coli ... (2015) increased the production of vitamin B12 to 198 ± 4.60 mg/L by optimizing the ...
[58]
[PDF] Stability of α-, γ-, or δ-Tocopherol during Soybean Oil Oxidation
The initial contents of α-, γ-, and δ-tocopherol in soybean oil were 53, 750, and 268 ppm, respectively. The degradation rates of α-, γ-, and δ-tocopherol for ...
[59]
Mixed tocopherols have a stronger inhibitory effect on lipid ...
Mixed tocopherols have a stronger inhibitory effect on lipid peroxidation than alpha-tocopherol alone, due to higher uptake of gamma- and delta-tocopherol.Missing: synergy | Show results with:synergy
[60]
[PDF] TOCOPHEROL CONCENTRATE, MIXED
Mixed Tocopherol Concentrate contains tocopherols such as d-alpha-, d-Я-, d-gamma-, d-delta-tocopherols. C.A.S. number. No single definite C.A.S. number is ...
[61]
NATURAL VS. SYNTHETIC VITAMIN E - Chiro.org
On a supplement label, natural vitamin E is listed as d-alpha tocopherol, d-alpha tocopheryl acetate, or d-alpha tocopheryl succinate. In contrast, synthetic ...
[62]
USP publishes monograph for palm oil tocotrienols and tocopherols
Sep 26, 2022 · Based on the USP Monograph, Palm Oil Tocotrienols and Tocopherols consist mainly of a mixture of α-, β-, γ-, and δ-tocotrienols and α- ...
[63]
Here for you with answers to vitamin E labeling questions
Conversions are as follows: 1 mg alpha-tocopherol = 1 mg RRR-alpha tocopherol = 2 mg all rac-alpha tocopherol; 1 IU RRR-alpha tocopherol = 0.67 mg alpha ...
[64]
Potential Antiatherogenic Mechanisms of Ascorbate (Vitamin C) and ...
α-Tocopherol, the most abundant antioxidant in LDL, can act as a chain-breaking antioxidant by scavenging highly reactive lipid peroxyl and alkoxyl radicals, ...
[65]
The Role of Vitamin E in Human Health and Some Diseases - PMC
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 ...
[66]
Interaction of ascorbate and alpha-tocopherol - PubMed
Vitamin C regenerates vitamin E by reducing vitamin E radicals formed when vitamin E scavenges the oxygen radicals. This interaction between vitamin C and ...
[67]
Re-evaluation of tocopherols (E 306–E 309) as food additives | EFSA
Sep 30, 2015 · The Panel concluded that tocopherols (E 306–E 309) are not of safety concern at the levels used in food.
[68]
Vitamin E as an essential micronutrient for human health
Nov 20, 2021 · Vitamin E has important applications in the food industry. As a food additive, it inhibits the oxidation of foods to extend their shelf life and ...
[69]
[PDF] Safety Assessment of Tocopherols and Tocotrienols as Used in ...
Apr 4, 2014 · The tocopherols are reported to function in cosmetics as antioxidants or skin conditioning agents; in contrast, tocotrienols is not reported to ...
[70]
α-Tocopherol protects keratinocytes against ultraviolet A irradiation ...
This study aimed to investigate whether α-tocopherol is able to protect keratinocytes against ultraviolet A (UVA) radiation by increasing glutathione ...
[71]
The role of antioxidants in improving biodiesel's oxidative stability ...
Jul 3, 2022 · This review discusses the inhibitory role of antioxidants on biodiesel's oxidation stability, poor cold flow, and their effects on engine operation.<|separator|>
[72]
The Influence of Tocopherols on the Oxidation Stability of Methyl ...
Aug 6, 2025 · Tocopherols were found to stabilise methyl esters by reducing the rate of peroxide formation while present. The deactivation rates of ...
[73]
AREDS/AREDS2 Clinical Trials - National Eye Institute - NIH
Dec 3, 2024 · Major AREDS/AREDS2 findings: Taking AREDS or AREDS2 supplements reduces the risk of progression from intermediate to advanced AMD by about 25 ...
[74]
Effect of Vitamin E and Memantine on Functional Decline in ...
Importance Although vitamin E and memantine have been shown to have beneficial effects in moderately severe Alzheimer disease (AD), evidence is limited in ...
[75]
Association of vitamin E intake in diet and supplements with risk of ...
Aug 1, 2022 · Due to the neuroprotective effects of vitamin E, a large number of researchers have explored whether vitamin E can reduce the risk of dementia.
[76]
Vitamin E intake and multiple health outcomes: an umbrella review
Jul 12, 2023 · The intake of VE was inversely associated with the risk of breast cancer, lung cancer, esophageal cancer, gastric cancer, pancreatic cancer, kidney cancer, ...Abstract · Methods · Results · Discussion<|control11|><|separator|>
[77]
Vitamin E Supplementation and Cardiovascular Events in High-Risk ...
Jan 20, 2000 · Observational and experimental studies suggest that the amount of vitamin E ingested in food and in supplements is associated with a lower risk of coronary ...Missing: deficiency | Show results with:deficiency
[78]
Effects of Vitamin E on Cardiovascular and Microvascular Outcomes ...
Nov 1, 2002 · Experimental and observational studies suggest that vitamin E may reduce the risk of cardiovascular (CV) events and of microvascular complications in people ...
[79]
Vitamin E and risk of age-related cataract: a meta-analysis - PMC - NIH
The risk of ARC decreased with dietary vitamin E intake from 7 mg/d. In addition, a protective role was found in the stratified analyses for serum tocopherol on ...
[80]
Prevention of preeclampsia - ScienceDirect.com
On the other hand, supplementation with omega 3 or antioxidants such as vitamin C, vitamin E, or selenium does not seem to prevent preeclampsia and is not ...
[81]
Scoping Review: The Role of Tocotrienol-Rich Fraction as a Potent ...
Aug 8, 2025 · Tocotrienol-rich fraction (TRF), a subtype of vitamin E, has recently been reported to demonstrate promising neuroprotective properties.
[82]
Vitamin E - Mayo Clinic
Mar 21, 2025 · The recommended daily amount of vitamin E for adults is 15 milligrams a day. What the research says. Research on vitamin E use for certain ...
[83]
Vitamin E - Uses, Side Effects, and More - WebMD
The risk of side effects increases with higher doses. Side effects can include nausea, fatigue, headache, and bleeding.
[84]
Vitamin E Excess - Disorders of Nutrition - Merck Manuals
High doses of vitamin E may cause bleeding, muscle weakness, fatigue, nausea, and diarrhea, especially for those on anticoagulants.
[85]
Vitamin E Toxicity - StatPearls - NCBI Bookshelf
Feb 13, 2023 · [7] A patient on vitamin E supplementation may have plasma levels of 30 micromoles/liter or greater.[7] The normal lab range for circulating ...
[86]
Vitamin E Overdose: Symptoms, Side Effects, and Treatment
May 5, 2020 · Vitamin E overdose may cause excessive blood thinning and lead to a stroke or an increased risk of death.Overdose · Who needs to supplement? · Side effects & symptoms
[87]
the Selenium and Vitamin E Cancer Prevention Trial (SELECT)
Oct 12, 2011 · Dietary supplementation with vitamin E significantly increased the risk of prostate cancer among healthy men.
[88]
Meta-analysis: high-dosage vitamin E supplementation ... - PubMed
High-dosage (> or =400 IU/d) vitamin E supplements may increase all-cause mortality and should be avoided.
[89]
Vitamin E Supplementation for Prevention of Morbidity and Mortality ...
Vitamin E supplementation in preterm infants reduced the risk of intracranial hemorrhage but increased the risk of sepsis.Missing: hemophiliacs | Show results with:hemophiliacs
[90]
[PDF] Opinion of the Scientific Committee on Food on the Tolerable Upper ...
Apr 23, 2003 · Vitamin E has a very low acute oral toxicity. The LD50 for a-tocopherol per se is greater than. 2000 mg/kg body weight in mice, rats (adult and ...
[91]
Reversible coagulopathy associated with vitamin E excess - PubMed
Jun 10, 2025 · Excessive vitamin E supplementation can cause a reversible coagulopathy in the setting of compromised vitamin K absorption or function.
[92]
Effect of vitamin E supplementation on vitamin K status in adults with ...
Conclusions: High-dose vitamin E supplementation increased PIVKA-II in adults not receiving oral anticoagulant therapy. The clinical significance of these ...
[93]
Vitamin E-drug interactions: molecular basis and clinical relevance
Consumption of high-dose vitamin E supplements ( ≥ 300 mg/d), however, may lead to interactions with the drugs aspirin, warfarin, tamoxifen and cyclosporine A.
[94]
Drug Interactions between vitamin e and warfarin - Drugs.com
Products containing vitamin E may increase the effects of warfarin and cause you to bleed more easily. You may need a dose adjustment or more frequent ...
[95]
Vitamin E–drug interactions: molecular basis and clinical relevance
Sep 16, 2014 · Consumption of high-dose vitamin E supplements ( ≥ 300 mg/d), however, may lead to interactions with the drugs aspirin, warfarin, tamoxifen and cyclosporine A ...
[96]
Do statins cause myopathy by lowering vitamin E levels? - PubMed
Statins and other lipid lowering drugs have been repeatedly described to decrease blood levels of minor fat soluble components such as vitamin E.
[97]
Effect of vitamin E on tamoxifen-treated breast cancer cells - PubMed
Conclusions: These studies suggest that supplemental vitamin E decreases the inhibitory effect of TAM on the proliferation of ER+ breast cancer cells and ...Missing: efficacy | Show results with:efficacy
[98]
Vitamin E | Memorial Sloan Kettering Cancer Center
Sep 28, 2023 · Vitamin E also had no effect on lung, urinary tract, pancreas, mouth or stomach cancer risks. Another trial in patients with head and neck ...
[99]
Orlistat and vitamin e Interactions - Drugs.com
Orlistat may interfere with the absorption of vitamin E and reduce its effectiveness. You should generally take vitamin E at least 2 hours before or 2 hours ...
[100]
Scientific opinion on the tolerable upper intake level for vitamin E
Aug 2, 2024 · The ULs for vitamin E from all dietary sources, which were previously established by the Scientific Committee on Food, are retained for all population groups.
[101]
Effects of vitamin E on clinic and ambulatory blood pressure in ...
Vitamin E supplementation thus seems to have no clinically relevant effect on BP in hypertensive patients already under controlled treatment. Publication ...
[102]
Vitamin E: Side Effects, Uses, Dosage, Interactions, Warnings - RxList
... drug interactions or side effects and may be monitoring you for them. Do not start, stop, or change the dosage of this medicine or any medicine before ...
[103]
History of vitamin E in infant nutrition - PubMed
Vitamin E was discovered by Evans and Bishop in 1922. Work in the 1930s revealed the chemical structure and the biological function of alpha-tocopherol.
[104]
Vitamin E: the enigmatic one! - PMC - PubMed Central
Vitamin E was first identified more than 90 years ago by Evans and Bishop as an essential dietary factor that is required by rats to maintain normal ...
[105]
VITAMIN IN SEARCH OF A DISEASE - JAMA Network
In 1922, Evans and Bishop1 discovered a dietary substance essential for animal reproduction. After confirming its essential nature, later investigators ...
[106]
A Century of Vitamin E: Early Milestones and Future Directions in ...
In 1936, Evans and his co-workers suggested the nomenclature α-tocopherol, the childbirth-bearing alcohol, for the new compound based on the Greek terms “tokos” ...
[107]
A history of vitamin E - PubMed
Vitamin E (α-tocopherol) was discovered nearly 100 years ago because it was required to prevent fetal resorption in pregnant, vitamin E-deficient rats.
[108]
Vitamins - C&EN
Jun 20, 2005 · TO YOUR HEALTH. Otto Isler (left) did pioneering work for Roche in the 1940s on the synthesis of vitamins A, E, and K. He is shown in his ...<|control11|><|separator|>
[109]
A Better Understanding of Vitamin E - WholeFoods Magazine
Jun 14, 2016 · The RDA was not established until 1968. The RDA has changed over the years, but not dramatically. Please see Table 1, which shows the ...
[110]
[PDF] United States Patent Office - Googleapis.com
3, 1970. 1. 3,538,119. CATALYTIC PROCESS FOR CONVERTNG. TOCOPHEROL TO ... 90-100% of mixed tocopherols (alpha, gamma, beta, or delta), all by weight ...
[111]
Ataxia with Vitamin E Deficiency - Symptoms, Causes, Treatment
Mar 23, 2023 · Ataxia with vitamin E deficiency (AVED) is a rare progressive neurodegenerative disorder affecting movement and motor control caused by very low vitamin E ...
[112]
First Recognized Patient with Genetic Vitamin E Deficiency Stable ...
Jul 3, 2020 · VED [1] is caused by mutations of the TTPA gene (HGNC 12404) [2] and subsequent deficiency of α-tocopherol transfer protein (αTTP), which is ...
[113]
Clinical and genetic study of ataxia with vitamin E deficiency - NIH
We identified a Chinese AVED female patient caused by a novel mutation in the TTPA gene. This finding widens the known TTPA gene mutation spectrum.Missing: 2020s | Show results with:2020s
[114]
Clinical Investigation of the Protective Effects of Palm Vitamin E ...
Apr 3, 2014 · Previous cell-based and animal studies showed mixed tocotrienols are neuroprotective, but the effect is yet to be proven in humans.
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Study Details | Stroke and Tocotrienol: Unique Role in Neuroprotection
150 patients will be recruited and randomized to receive either placebo or mixed tocotrienol 200mg twice a day for 6 months. Patients will be followed up and ...Missing: TOCOM | Show results with:TOCOM
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Study of IPMN Progression Prevention With Tocotrienol (SIPP-T3 ...
This is a randomized, double-blind, placebo-controlled trial, investigating whether treatment with δ-tocotrienol (a.k.a. Delta-tocotrienol, abbreviated as ...
[117]
Vitamin E – a scoping review for Nordic Nutrition Recommendations ...
Although plants make eight different forms of vitamin E, namely four tocopherols (α-, β-, γ- and δ) and four tocotrienols (α-, β-, γ- and γ), only α-tocopherol ...
[118]
Effects of Vitamin E on the Gut Microbiome in Ageing and Its ...
Sep 28, 2023 · According to some studies, the consumption of vitamin E causes a change in the gut microbiota composition. However, there have not been much ...
[119]
Interplay of dietary antioxidants and gut microbiome in human health
Interaction of vitamin E with gut microbiome. In humans, dietary vitamin E is absorbed in the intestinal lumen via the formation of chylomicron and sent to ...
[120]
Vitamin E (α-Tocopherol): Emerging Clinical Role and Adverse ... - NIH
Feb 7, 2025 · The meta-analysis showed reduced ischemic stroke risk related to Vitamin E; however, the increase in hemorrhagic stroke risk with Vitamin E ...
[121]
Alpha-Tocopherol-Infused Flexible Liposomal Nanocomposite ...
This study developed a novel delivery system for retinal (RAL) using flexible liposomes (FLPs) infused with α-tocopherol succinate (α-TS) to improve stability, ...
[122]
Advances in plant tocopherol biosynthesis: from pathway elucidation ...
Jan 17, 2025 · Crossbreeding and hybridization are traditional methods used to combine the genetic material of plants with high tocopherol content, leading to ...
[123]
Dynamic identification of candidate genes associated with higher ...
Jun 5, 2025 · Total tocopherol content increased progressively during seed development, reaching a plateau at 50–60 DAF ( Figures 1b, c ). Among different ...
[124]
The effect of vitamin E and vitamin C in patients with COVID-19 ...
The combination of oral vitamins C (1000 mg daily) and E (400 IU daily) has no beneficial effect in COVID-19 patients.
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An Orthomolecular Protocol for Long COVID - ISOM
Jul 24, 2024 · In addition, some studies suggest that vitamin E has antiplatelet and antithrombotic effects (González-Correa, 2005; Dowd, 1995), which might be ...<|separator|>