Vitamin E

Vitamin E is an integral part of the skin's antioxidant defenses. Oral vitamin E supplements may not provide adequate protection to the skin, but topical vitamin E is an effective photoprotectant that may also help improve skin moisturization and alleviate wrinkles.

Effects


Grade Level of Evidence
A Multiple double-blind, controlled clinical trials.
B 1 double-blind, controlled clinical trial.
C At least 1 controlled or comparative clinical trial.
D Uncontrolled, observational, animal or in-vitro studies only.
Grade Effect Size of Effect Comments

C

Photoprotection

Strong

Reduces sunburn, UV-induced immunosuppression, DNA damage and photodamage to the skin by absorbing UV light and through its antioxidant action.

C

Skin lightening

Moderate

Decreases melanin synthesis by inhibiting the melanogenic enzymes tyrosinase, TYRP1 and TYRP2.

C

Healing

Moderate

Hastens the healing of cutaneous wounds in rats and in patients suffering from burns. May also be used to improve healing after dermatocosmetic procedures such as laser resurfacing and chemical peeling. Does not necessarily improve scars however.

C

Increased skin hydration

Mild

Appears to moisturize the skin more effectively over both the short-term and long-term, than vitamin C or calcium ascorbate.

D

Antioxidant

Strong

Protects the skin from oxidative stress by inhibiting lipid peroxidation and synergizing with other skin antioxidants such as vitamin C.

D

Wrinkle treatment

Mild

May efface wrinkles as it increases collagen production and inhibits its alteration and degradation in vitro.

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Scientific Research


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Table of contents:

1. Sources

1.1 In food

VItamin E is the common name for 8 naturally occurring compounds, 4 tocopherols (α-, β-, γ-, and δ-) and four tocotrienols (α-, β-, γ-, and δ-).[1][2] Vitamin E is produced by a large variety of plants[3][4] as an antioxidant in photosynthetic membranes[5] and in response to environmental stresses[6] and is therefore found in many foods especially vegetables, fruits, nuts and grains.[7]

Fruits and vegetables containing vitamin E include lettuce,[8][9] spinach,[10] corn,[1] cucumber,[11] pepper,[12] sweet potato,[13] tomato,[14] pumpkin,[15] avocado,[16] kiwifruit[17] and mango.[18][19]

Whole grains such as rice,[20][21] bran,[22] barley,[23][24][25] oat[26] and wheat[27] also have varying quantities of tocopherols and tocotrienols, as do nuts like almonds,[28] chestnuts,[29] peanuts[30] and hazelnuts.[31][32]

Edible oils and seeds are among the richest natural sources of vitamin E. The seed oil of the desert plant Citrullus colocynthis has been found to contain 1218 mg/kg of tocopherols,[33] while sunflower seeds contain between 524-880 mg/kg of tocopherols[34] and almond oil contains 215-569 mg/kg of tocopherols.[35] Vitamin E has also been detected in barley oil,[36] palm oil,[36] safflower seed oil,[37] hazelnut oil,[38] bran oil,[22] oat grain oil[26] and rapeseed oil.[39]

Although γ-tocopherol is the major form of vitamin E in US diets, it is α-tocopherol that is the best studied and which is generally found in supplements.[2] α-tocopherol is considered more desirable because of its higher biological activity.[1]

1.2 In the skin

Vitamin E is a major antioxidant protecting the skin from oxidative stress.[40] The epidermis contains more vitamin E than the dermis, with the concentration of α-tocopherol as much as 90% higher in the epidermis.[41][42] There are also regional differences in the distribution of vitamin E on the skin, with much more α-tocopherol on the cheeks and forehead than on the upper arm due to variations in the density of sebaceous glands, the major physiologic route of vitamin E delivery to the skin.[43]

In one study, an analysis of the different vitamin E isoforms in the epidermis revealed that 87% is α-tocopherol, 9% γ-tocopherol, 3% γ-tocotrienol and 1% α-tocotrienol,[44] but tocotrienols have also been found to comprise 15% of vitamin E in the skin in a separate study.[45]

Surprisingly, long-term oral administration of β-carotene lowers the concentrations of α-tocopherol in the skin and plasma, with levels decreasing progressively and significantly between 6 and 9 months of dosing.[46]

The concentration of α-tocopherol is also markedly reduced in the epidermis (but not the dermis) of photoaged and intrinsically aged skin, which have only 56% and 61% of the α-tocopherol level in young skin respectively.[47]

2. Bioavailability

2.1 Oral administration

Vitamin E is lipid-soluble and is absorbed by the same pathway as other lipophilic dietary bioactives such as the carotenoids. After being released from the food matrix in the stomach and transferred into oil droplets, the vitamin E isoforms are transformed into mixed micelles in the small intestine. They are then absorbed by the enterocytes lining the small intestine and packed into prechylomicrons. These are exocytosed into the extracellular space, entering the lymphatic system and eventually the general blood circulation, where they can be distributed to all bodily tissues, including the skin.[48]

The consumption of fruit juice and vegetables (broccoli) have been shown to raise serum levels of α- and γ-tocopherols respectively in humans,[49][50] and high dose dietary supplementation of δ-tocopherol similarly increased its plasma concentration in rats.[51]

Food processing and the food matrix can affect the bioaccessibility of tocopherols. A study of 12 beverages made with fruit juice and milk, for instance, found that whole milk (as opposed to skimmed milk or soy milk) had the greatest tocopherol accessibility which was significantly decreased by thermal but not high pressure processing.[52] Curiously, co-administration with sesamin, a component of sesame seeds, alters the pharmacokinetics of tocopherols, elevating the plasma concentrations of α-tocopherol, γ-tocopherol and α-tocotrienol in rats,[53][54][55][56] and δ-tocopherols in mice.[51]

The sebaceous glands serve as a transport mechanism for vitamin E, taking it from the blood to the skin surface.[57] However, while the plasma concentration of vitamin E in humans increases within 24 hours after supplementation, its concentration in sebum rises only after 7 days.[58] This delay may be related to the process of sebum production, as it takes an average of 8 days for newly synthesized lipids in the sebaceous glands to be secreted onto the skin surface.[59]

Due to the presence of 3 chiral atoms, tocopherols have 8 different stereoisomers. The RRR-configuration occurs naturally, while synthetic tocopherols is a racemic mixture of all 8 stereoisomers. The predominant form of vitamin E, α-tocopherol, has the highest oral bioavailability, and natural RRR-α-tocopherol has approximately twice the systemic availability of synthetic α-tocopherol.[60] The delivery of vitamin E to the skin also seems to be specific for certain isomeric forms. For instance, although both the natural and synthetic forms of α-tocopherol arrive in the blood circulation, only RRR-α-tocopherol appears in sebum,[58] suggesting that a specific protein may be responsible for selectively transporting this form of vitamin E into the sebum.[48]

The pharmacokinetics and pharmacodynamics of tocotrienols are less clear, but both α- and γ-tocotrienols have been detected in the skin of mice and rats following dietary consumption.[61] The oral bioavailability of tocotrienols is known to be significantly lower than that of α-tocopherol however, due to their poorer intestinal permeability.[62][63][64] Moreover, the liver contains a transfer protein that preferentially enriches very-low-density lipoproteins (VLDL) with α-tocopherol.[65]

It is also worth noting that topical supplementation with 400 IU α-tocopherol daily did not increase serum vitamin E levels and therefore poses no systemic risk.[66] In fact, supplementation with α-tocopherol actually decreases plasma and tissue γ-tocopherol and α-tocotrienol.[60][67]

2.2 Topical administration

Topical application leads to far higher levels of vitamin E in the skin than oral administration.[68] In a double-blind, vehicle-controlled study, women who used a commercial body wash containing 0.15% vitamin E and 0.1% vitamin E acetate (Palmolive Vitamins Shower Creme or Softsoap Vitamins Body Wash) daily saw a >50-fold increase in surface vitamin E, compared to an 8-fold increase in women who took dietary supplements of 400 IU α-tocopherol daily.[66] A similar study published a year later demonstrated that the increased vitamin E deposition levels resulting from the use of a α-tocopherol-enriched rinse-off product were maintained for at least 24 hours.[69] Concomitant oral administration of α-tocopherol acetate seems beneficial, as it does increase the level of vitamin E in the stratum corneum.[70]

Due to its high lipophilicity, α-tocopherol is much more soluble in the stratum corneum and diffuses much less through it than through the viable skin layers.[71] This is advantageous as the upper stratum corneum has been recognized as the main cutaneous oxidation target of oxidative stressors such as UV radiation and ozone.[72] It also explains the observation that 30% of α-tocopherol topically applied to mouse skin exists as a bound form with the lipid components of the stratum corneum, rather than simply partitioned into the different skin layers.[71] The papillary dermis, which contains the sebaceous glands, and the epidermis also have high affinity for topically applied vitamin E.[73][74]

The cosmetic formulation affects the permeation of vitamin E.[75] A 2003 study of several delivery systems including simple solution, gels, emulsions and microemulsions found that a microemulsion containing isopropyl myristate was the best delivery system for α-tocopherol,[76] but many others have since been developed including hydrogels,[77][78] liposomal gels,[77][79][80] nanoparticles,[81][82][83] nanofiber mats[84] and nanoemulsions.[85]

In some formulations, vitamin E is combined with other actives like vitamin C[86][87][88][89] or lipoic acid[90] for simultaneous delivery.

The use of pro-vitamins and penetration enhancers have also been explored to improve delivery or to release other active moieties in order to obtain a synergic effect.[91][92][93]

3. Effects on the skin

3.1 Antioxidant effect

Due to its role as the outermost barrier of the body, the skin is subject to many external sources of oxidative stress, especially UV irradiation.[94] Vitamin E, as a major antioxidant in the stratum corneum,[95] contributes to the skin's antioxidant defenses by scavenging free radicals[96] and by upregulating the skin's network of enzymatic and non-enzymatic antioxidants.[74][97]

Many in vitro studies indicate that vitamin E has significant protective effects against oxidative stress. In a double-blind, placebo-controlled study on 30 dry-skinned elderly volunteers, topical or oral supplementation of antioxidant-enriched formulations containing vitamin C, vitamin E, alpha lipoic acid, melatonin and emblica for 8 weeks decreased lipid peroxidation in the blood serum, free radicals in the blood serum and on the skin and the induction of reactive oxygen species through UVB irradiation.[98]

Vitamin E also stabilized the pH, intracellular glutathione levels and membrane potential of human skin fibroblasts subjected to UV irradiaton,[99] reduced the increase in malonaldehyde and peroxide levels and the depletion of thiols in human fibroblasts subjected to heat shock or incubated with hydrogen peroxide,[100] and diminished free radical generation by photoirradiated pheomelanin.[101] Ex vivo experiments have also shown that topical α-tocopherol prevented the epidermal lipid peroxidation induced by UV radiation on pig skin explants.[102] α-tocopherol also counteracted the induction of hydrogen peroxide and inhibited the activities of myeloperoxide, xanthine oxidase and lipid peroxidation when applied prior to treatment of the skin with 12-O-tetradecanoylphorbol-13-acetate (TPA), a tumour promotor that produces massive inflammatory and oxidative stress responses in the skin.[103]

In humans topical treatment with a rinse-off formulation containing α-tocopherol has been demonstrated to significantly inhibit the photo-oxidation of squalene,[69] the most abundant oxidisable component of skin surface lipids.[104] The products of squalene's photo-oxidation may mediate or induce metabolic and inflammatory responses of keratinocytes to UV rays.[105]

The biological activities of γ- and δ-tocopherols are not well established, but γ-tocopherol is significantly more effective than α-tocopherol in inhibiting lipid peroxidation induced by peroxynitrite,[106] a powerful mutagenic oxidant and nitrating species that plays a key role in skin tissue response to stresses.[107] δ-tocopherol has also been found to be more effective than γ-tocopherol and α-tocopherol in protecting against peroxyl radical-induced membrane oxidation in human intestinal cell lines, though the relevance of this finding to the skin is not clear.[108]

The antioxidant activity of tocotrienols is greater than that of tocopherols.[109] The efficacy of α-tocotrienol, for example, in protecting against Fe(II)+ NADPH-induced lipid peroxidation was 40 times higher than that of α-tocopherol, and it also protected cytochrome P450 against oxidative damage 6.5 times better than α-tocopherol. The higher antioxidant potency of α-tocotrienol has been attributed to its quicker recyling from chromanoxyl radicials, its more uniform distribution in the membrane bilayer and its stronger disordering of membrane lipids, which make its interaction with lipid radicals more efficient.[110] α-tocotrienol can also mitigate the lipid peroxidation induced by benzoyl peroxide, a commonly used drug in the treatment of acne vulgaris.[111]

Although vitamin E has limited radical scavenging ability on its own,[96] it interacts synergistically with other skin antioxidants to retard cellular damage caused by free radicals. Topical application of α-tocopherol increased the activity of dermal superoxide dismutase by 30%, raised dermal ascorbate levels by 40%, and protected epidermal glutathione and superoxide dismutase from depletion after UV irradiation.[74] The water-soluble vitamin C not only scavenges free radicals directly in the aqueous phase of cells, but also helps in the recycling of membrane-bound vitamin E at the membrane-cytosol interface[112][113] by donating electrons to α-tocopheroxyl (chromanoxyl) radicals.[114] Glutathione and coenzyme Q10 are also capable of regenerating the antioxidant form of vitamin E.[112][113] Further, there is evidence that glycolic acid can potentiate the antioxidant action of vitamin E,[115] and that α-tocopherol augments the antioxidant properties of the flavonoid luteolin.[116]

3.2 Photoprotection

UV radiation harms the skin, causing sunburn, local immunosuppression, photoaging and cutaneous malignancies.[117] It also impairs the skin's antioxidant defense system[118][119] -- in 2 experiments on human skin, a single suberythemogenic dose of solar simulated UV radiation resulted in 45% and 35% decreases in the levels of α- and γ-tocopherols,[120] while 4 minimal erythema dose (MED) UV exposures led to an 84% depletion of vitamin E, a 70% depletion of coenzyme Q10 and a 13% depletion of squalene.[121] A separate experiment on mouse skin also found declines in 2 other antioxidants, vitamin C and glutathione.[42] Furthermore, exposure to even low levels of ozone potentiates the depletion of vitamin E by UV radiation.[122][123][124] Fortunately, prior application of vitamin E or a P. umbellata root extract gel, is able to preserve cutaneous vitamin E.[125][126][127]

Numerous studies have investigated the photoprotective effects of vitamin E through experiments on mice. In one, mice treated with a 5% α-tocopherol lotion had reduced inflammation and skin pigmentation and a lower incidence of skin cancer when exposured to UVB radiation thrice weekly, indicating significantly less acute and chronic skin damage.[128] In another, topical 1% vitamin E in ethanol applied before irradiation decreased lipid peroxidation and restored thymidine incorporation.[129] Mice skin treated with a 1:1 mixture of α-tocopherol and ethanol before UVB irradiation also experienced a statistically significant increase in epidermal thickness versus controls or vehicle alone, as well as a reduction in the number of sunburn cells.[130] Experiments on hairless mice have also demonstrated that α-tocopherol provides the best protection among the tocopherols, with β-, γ-, and δ-tocopherols giving only 42%, 72% and 40%, respectively, of the protection against post-UV edema relative to α-tocopherol.[131]

Moreover, a single, low dose (2.5 to 10 nmol/cm2) of α-tocopherol was sufficient to prevent UV-induced systemic immunosuppression in mice as measured by the contact hypersensitivity response.[132] Similarly, another study found that a 5 mg dose of α-tocopherol dissolved in acetone completely protected against a UV radiation protocol that that induced a 55% reduction in the contact hypersensitivity response to 2,4,6-trinitrochlorobenzene and a 23% reduction in epidermal Langerhans cell density. This dosage inhibited UV-induced epidermal lipid peroxidation, hinting at a possible mechanism by which α-tocopherol prevents UV-induced local immunosuppression.[133]

Experiments on pig skin also show that topical vitamin E prevents UVB-induced lipid peroxidation, thereby reducing cell death and apoptosis. Remarkably, compared to vitamin E, a 500-fold higher vitamin C dose was needed to completely protect against UVB-induced lipid peroxidation.[102][134]

Many in vitro studies on human skin cells have also been conducted. These have provided further evidence of α-tocopherol's photoprotective efficacy, demonstrating its suppression of the cytotoxic effect of UVB radiation on human skin fibroblasts and keratinocytes.[135][136][137]

Additionally, pre-treatment with a topical agent containing 10% tocopherols and 0.3% tocotrienols (Monodermà ET10) on the skin of the forearm and buttock of human volunteers highly protected against photosensitivity, leading to significantly lower erythema, edema, itch and vesciculation after UVB irradiation compared to treatment with vehicle or a formulation containing 0.15% retinol (Monodermà A15).[138]

There is no consensus on whether vitamin E works better when applied before or after UV exposure. In one study, vitamin E did not reduce erythema formation when applied after UV exposure, indicating that it may only prevent UV-induced skin damage when present at the beginning of and during periods of oxidative stress.[139] However, another study had opposite results, finding that tocopherol inhibited UV-induced erythema by 27% when topically applied after UVB irradiaton but not if applied before UVB irradiation.[140]

The photoprotective effect of vitamin E is often attributed to its capacity as an antioxidant, but there are also other possible explanations.[141] α-tocopherol itself has a UV-absorbance spectrum that extends well into the solar spectrum.[114] Because of its strong UV absorbance, α-tocopherol has been hypothesized to act as a sunscreen to prevent photodamage. Indeed, a 1% α-tocopherol dispersion inhibited the formation of thymine dimers in mouse skin by 57% relative to controls, which compared favourably with a variety of sunscreen products that contained proprietary formulations of oxybenzone, octyl methoxycinnamate, octyl salicylate or 4-aminobenzoic acid esters as active ingredients. However, since γ- and δ-tocopherols have slightly greater absorbances within the UV range than α-tocopherol but α-tocopherol is approximately 5 times more potent, the extent of UV absorbance is probably not the only factor influencing the photoprotective capabilities of the different vitamin E isoforms.[142][143] When topically applied onto the skin, α-tocopherol is rapidly photo-oxidized by UVB, yielding a mixture of dimers and trimers that also absorb UV light.[144][145] In addition, γ-tocopherol is known to inhibit the activity of COX-2, an important mediator of early photo-inflammation, independently of its antioxidant function.[146]

Another important finding with respect to vitamin E's photoprotective effect is the ability of α-tocopherol to reduce the formation of cyclobutane pyrimidine dimers in the murine epidermal p53 gene. This is significant as mutations or alterations in the p53 gene are observed in >50% of UV-induced squamous cell carcinomas in humans and animals.[147] This suppression of premutagenic DNA lesions may be responsible for topical α-tocopherol's observed capacity to effectively reduce tumorigenesis in mice.[148]

Vitamin E works in tandem with other antioxidants to protect the skin against solar radiation. The combination of vitamin C and vitamin E that is used by virtually all plants and animals[149] provides superior protection against sunburn and erythema[149][150] as vitamin C regenerates oxidized vitamin E.[151] The incorporation of the plant antioxidant ferulic acid yields further benefits, stabilizing the vitamins and doubling the amount of photoprotection as measured by erythema and sunburn cell formation.[152] Compared to its vehicle, a commercial formulation (SkinCeuticals C E Ferulic) of 15% ascorbic acid, 1% α-tocopherol and 0.5% ferulic acid was also particularly effective in reducing thymine dimer mutations in human skin.[153] In contrast, although both topical vitamin E alone and SkinCeuticals C E Ferulic decreased the development of malignant skin tumours in mice with chronically UVB-damaged skin, mice treated with topical vitamin E alone developed an increased tumour number and burden. It has been hypothesized that vitamin E alone may be more effective in the late phase of tumorigenesis, thus affecting tumour progression but not tumour development.[154] Another study on 12 Chinese women also demonstrated the photoprotective efficacy of SkinCeuticals C E Ferulic in humans, as it significantly reduced sunburn cell formation, decreased the overexpression of p53, attenuated the formation of thymine dimers and inhibited the depletion of epidermal Langerhans cells, a sign of UV-induced immunosuppression.[155]

Oral administration of vitamin E may also achieve some photoprotection of the skin, though the evidence is inconsistent. In one study, oral feeding of α-tocopherol lowered the tumour incidence and tumour multiplicity in the skin of hairless mice.[156] Another showed that a diet containing both tocopherols and tocotrienols reduced sunburn severity and tumour incidence to a greater extent than a diet containing just α-tocopherol, and the addition of sesamin to the tocopherol- and tocotrienol-rich diet also increased the level of tocotrienols in the skin as well as further decreased sunburn and tumour incidence, supporting the idea that dietary tocotrienols protect the skin more strongly than α-tocopherol.[157] However, in human subjects vitamin C supplementation only had a minor effect on the concentration of malondialdehyde in the skin and did not affect other measures of UV-induced oxidative stress.[158] Cohort studies and case-control studies also found no significant associations between dietary vitamin E intake or serum levels of vitamin E and the risk of skin cancer.[159][160][161][162][163]

Ingesting vitamin E with other antioxidants may be beneficial. Oral vitamin E + vitamin C raised the minimal erythema dose, the threshold UV dose that elicits sunburn in 2 controlled trials,[164][165] whereas antioxidant combinations of vitamin E, lycopene, β-carotene and selenium both elevated the minimal erythema dose and suppressed UV-induced erythema, p53 expression and lipoperoxide levels, indicating an improved defense against UV-induced skin damage.[166][167]

3.3 Lightening effect

Nearly all forms of vitamin E have shown antimelanogenic activity in vitro. α-tocopherol significantly inhibited melanization in human melanoma cells and normal human melanocytes[168][169] while β- and γ-tocopherols at a concentration of 250 µg/ml suppressed melanin synthesis in mouse B16 melanoma cells by 28% and 39% respectively due to their 34% and 45% inhibition of tyrosinase activity. Although δ-tocopherol is more effective than β- and γ-tocopherols in reducing melanogenesis with >90% inhibition of tyrosinase activity at concentrations below 31 µg/ml, it is cytotoxic, prohibiting its inclusion into skin care products.[170] γ- and δ-tocotrienols are also capable of suppressing melanogenesis through inhibiting the activation of tyrosinase.[171] Vitamin E also downregulates other melanogenic enzymes as well, such as TYRP1 and TYRP2.[172][173]

Further, combination treatment is more effective in lightening the skin than vitamin E alone; a preparation of vitamin E + vitamin C reduced skin luminosity between hyperpigmented and normal areas to a greater extent and led to significantly better clinical improvement of melasma than a single preparation of vitamin E in a double-blind, controlled clinical trial.[174]

Vitamin E has the potential to moisturize the skin, as evidenced by the results of a single-blind and placebo-controlled study. The study included a short-term and a long-term trial, and involved 10 Caucasian women applying a placebo cream or an active cream containing vitamin E, vitamin C or calcium ascorbate to their inner forearms. Skin hydration readings were taken up to 6 hours after the first application for the short-term trial, and the women continued to apply the creams twice daily for 4 weeks, with readings taken every weekend for the long-term trial. In both cases, the creams containing vitamin E gave higher moisturization values than the creams containing vitamin C or calcium ascorbate.[175] However, cross-sectional studies did not find associations between vitamin E consumption and skin hydration.[176][177]

Vitamin E may also improve the appearance of wrinkles, as tocopherols and tocotrienols are able to enhance collagen synthesis and inhibit collagen degradation in cultures of human skin fibroblasts,[178][179][180] as well as prevention alterations to collagen and glycosaminoglycan synthesis induced by reactive oxygen species.[181] A case has been reported of a 48-year old female patient who achieved a decrease in periorbital rhytids after daily treatment with 5% α-tocopherol for 4 months.[68] An open-label study on healthy Japanese adults also found that usage of a topical gel containing 2% phytonadione, 0.1% retinol and 0.1% magnesium ascorbyl phosphate + vitamin E for 8 weeks slightly decreased wrinkles of the lower eyelid in addition to reducing dark under-eye circles, though these effects may or may not be due to vitamin E.[182]

Although plasma levels of α-tocopherol are significantly lower in patients with actinic keratoses,[183] topical application of 12.5% synthetic α-tocopherol for 6 months was ineffective in reducing the numbers of actinic keratoses on the sun-damaged forearms of human volunteers.[184]

Other in vitro experiments have revealed that γ-tocotrienol prevents telomere shortening and modulates the upstream apoptosis cascade by inhibiting the release of mitochondrial cytochrome c and suppressing the activation of caspase-3 and caspase-9, hence delaying the premature senescence of human skin fibroblasts induced by oxidative stress.[185][186]

Whether oral vitamin E improves skin parameters is open to question, as the studies conducted so far have been inconclusive. A placebo-controlled study found that supplementation with antioxidants including α-tocopherol did not change skin density or thickness after 12 weeks compared to placebo, and that the smoothness and wrinkling of the skin were also unaffected.[187] This is not unexpected, as α-tocopherol has been shown to inhibit the proliferation of human skin fibroblasts by as much as 40% in 72 hours in vitro.[188] Scaling and roughness had statistically significant improvements relative to baseline, but between-groups comparisons with the placebo group were not reported.[187] Dietary intake of mixtures of 5 mg vitamin E, 3 or 13 mg β-carotene, 30 mg vitamin C and 2 or 3 mg lycopene meanwhile led to increases in skin melanin concentrations after 8 weeks and is thought to be related to vitamin E and β-carotene's role in the glutathione redox cycle in melanocytes, which regulates tyrosinase activity.[189]

3.5 Wound healing

Oral administration of α-tocopherol accelerated the closure of dermal wounds in both normal and diabetic rats,[190] and topical administration of tocopherol cream has also been shown to enhance the cutaneous wound healing process in diabetic rats.[191] Palm vitamin E, a rich source of tocotrienols, on the other hand is more effective than α-tocopherol in improving wound repair when administered orally to diabetic rats, but does not have an impact on normal rats.[190][192]

Vitamin E is included in therapies for burns. It dramatically improved cell-mediated immunity in burned mice,[193] and protected erythrocytes from hemolysis after thermal skin injury[194][195][196] When systemic vitamin E + vitamin C was used in combination with topical povidone-iodine ointment on burn patients, parameters including oxidative stress, mortality rate, healing time and cost were improved, though it is not clear if the vitamins provided additional benefits to topical treatment with povidone-iodine ointment alone.[197] Oral supplementation of vitamin E, vitamin C and zinc also lowered the time for wound healing in burned children in a double-blind and placebo-controlled study, presumably through enhanced antioxidant protection against oxidative stress.[198]

Additionally, topical vitamin E can mitigate the skin injury caused by the extravasation of cytotoxic drugs used in chemotherapy during IV infusions.[199][200]

Vitamin E can be useful as an adjunct to skin rejuvenation techniques and cosmetic surgery. In a rat model designed to reproduce the effects of laser resurfacing and chemical peeling, α-tocopherol and other pro-/antioxidant-based nutraceuticals had beneficial effects on skin healing, trophism and re-epithelization.[201] Topical vitamin E used on incision sites thrice daily for at least 15 days before surgery and twice daily for at least 30 days after surgery was also found to improve surgical wound healing and cosmetic results.[202]

Despite the benefits it brings to wound healing, vitamin E does not always have positive effects on scarring or the appearance of scar tissue. Neither topical vitamin E nor 5% topical tocotrienol reduced postoperative scar formation or improved the cosmetic outcome of surgical scars.[203][204] In fact, it sometimes worsened scar appearance, and also caused contact dermatitis in a third of the patients in one study.[205] Vitamin E added to silicone gel sheets and a topical vitamin E lotion combined with hydrocortisone and silicone did improve the treatment of hypertrophic scars and keloids however.[206][207]

Other experiments have shown that α-tocopherol significantly improved the survival of ischemic skin flaps over saline controls in rats,[208] but did not improve arsenic-induced skin lesions in humans.[209]

3.6 Other uses

Topical vitamin E can also treat yellow nail syndrome.[210][211]

Systemic vitamin E in combination with pentoxifylline effectively prevents radiation-induced fibrosis,[212][213][214][215][216] even though vitamin E alone does not protect against acute skin reactions such as erythema and necrosis caused by radiotherapy.[217]

It has also been used to reduce the incidence of spherical contracture around silicone implants,[218] in the treatment of vitiligo,[219] psoriasis,[220] chemotherapy-induced oral mucositis,[221][222][223] and genital atrophy[224] when combined with other agents, and as a long-term maintenance therapy for vulvar lichen sclerosus.[225]

4. Side Effects

α-tocopherol is a Generally Recognized As Safe (GRAS) food ingredient when used as a nutrient or as a chemical preservative in food when used in in accordance with good manufacturing practices. It is also considered safe as used in cosmetics.[60][226]

4.1 Risk of systemic toxicity

In rats, tocopherol was not toxic in a 60-day study, but in a 90-day study, 7 of 10 male rats dosed orally with 2 g/kg α-tocopherol died in 9-11 weeks from internal haemorrhage.[60][226] Rats fed a diet containing 3% tocotrienols had statistically significant changes in the weight of various organs and haematological parameters, but most changes were thought to have little toxicological significance.[227]

Oral administration of tocopherol did not have reproductive or developmental effects in rats. Tocopherol is also not mutagenic or genotoxic.[60][226]

Topical vitamin E leads to much lower systemic exposure than oral vitamin E supplements and therefore poses a much smaller risk of systemic toxicity. In rats, the dermal median lethal dose is more than 3 g/kg for tocopherol.[60][66]

4.2 Allergic contact dermatitis

1% tocopherol is a weak skin irritant in rabbits and guinea pigs,[226] but a palm tocotrienol-rich fraction (TRF) composed of 50% tocotrienol/tocopherol complex, with 20% γ-tocotrienol, 5% δ-tocotrienol, 13% α-tocotrienol, and 12% α-tocopherol was practically non-irritating to rabbit skin, though it did induce slight to well-defined erythema.[228] Synthetic α-tocopherol was a moderate sensitizer in a guinea pig maximization test and in a local lymph node assay.[60][229]

In humans, tocopherol is only very rarely an irritant or a sensitizer. Out of 1814 patients patch-tested with tocopherol at the Mayo Clinic in Arizona from 1987-2007, only 12 (0.66%) had positive reactions.[230] Similarly, 4454 patch tests by the North American Contact Dermatitis Group in 2005-2006 found only a 0.7% frequency of positive reactions to undiluted synthetic α-tocopherol.[231] TRF is also not an irritant or a sensitizer at concentrations of 5% and below, though irritant reactions are observed at higher concentrations.[228]

In fact, there is some evidence that topical vitamin E may inhibit contact dermatitis. A 20% vitamin E ointment suppressed allergic and irritant contact dermatitis induced by chemical agents applied to rats and mice by reducing the damage to keratinocytes and blocking the down-regulation of the skin barrier function.[232] Tocotrienol has also been shown to reduce allergic dermatitis in mice.[233]

These results indicate that the reports in the literature of contact dermatitis and contact allergy[234][235][236][237][238][239][240] induced by topical vitamin E in cosmetic products should not be a major concern in most cases. The use of topical vitamin E on surgical wounds should be discourage however, as when an emollient mixed with vitamin E was applied to surgical scars twice daily for 4 weeks after skin surgery, 33% of patients developed contact dermatitis.[205]

4.3 Tumour promotion

In one study, mice treated with topical vitamin E after UVB exposure had elevated levels of DNA damage and increased tumour number and burden compared to vehicle-treated mice, though fewer tumours were malignant than in the controls.[154] This is in concordance with the results of earlier studies, which showed that pre-treatment of human fibroblasts with vitamin E exacerbates DNA damage upon UVA irradiation[241] and that high concentrations of vitamin E acts as a tumour promoter in mouse skin.[242][243]

On the contrary, dietary administration of mixed tocopherols to rats suppressed the growth of mammary tumours[244] and inhibited azoxymethane-induced aberrant crypt foci, a possible precursor of colon cancer.[245] Supplementation with tocotrienols also delayed the development of mammary tumours in mice.[246]

In humans, a double-blind, placebo-controlled primary prevention trial investigated the effect of daily supplementation with a capsule of antioxidants (120 mg vitamin C, 30 mg vitamin E, 6 mg β-carotene, 100 μg selenium, and 20 mg zinc) on the risk of skin cancer. After follow-ups for a median of 7.5 years, there were no differences in the incidence of skin cancer between men in the antioxidant group and men in the placebo group, but women in the antioxidant group had a higher incidence of skin cancer than women in the placebo group.[247]

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