Antioxidant, photoprotection, wound healing
Important Chemical Components:
Vitamin E is actually a family of eight fat-soluble isomers that include four tocopherols and four tocotrienols. The molecular formula of α-tocopherol, the most active form of vitamin E, is C29H50O2. By contrast, the molecular formula of α-tocotrienol is C29H44O2. The molecular formula for γ-tocopherol, the most frequently consumed form of vitamin E in the U.S. is C28H48O2.1
Vitamin E is found naturally in many vegetables, oils, seeds, nuts, and other foods. Most topical formulations contain synthetic laboratory-made α-tocopherol or one of its many esters or ethers.
Personal Care Category:
Antioxidant, moisturizing, antiaging
Recommended for the following Baumann Skin Types:
DRNW, DRPW, DSNW, DSPW, ORNW, ORPW, OSNW, and OSPW
Obtained in the diet through fresh vegetables (especially green leafy vegetables), vegetable oils, seeds, nuts, grains, corn, soy, whole wheat flour, margarine, and in some meat and dairy products, vitamin E, or tocopherol, is the main lipid-soluble antioxidant found in human skin (via sebum), membranes, plasma, and tissues that protects cells from oxidative stress (Table 56-1).2–5 Meeting the definition of a vitamin, it is not synthesized by humans. Vitamin E is frequently used to treat minor burns, surgical scars, and other wounds, although its use for dermatoses has not been approved by the United States Food and Drug Administration (USFDA). The use of vitamin E is thought to mitigate lipid peroxidation and protect against cardiovascular disease.6 Similarly, it protects cutaneous cell membranes from peroxidation. In addition to its antioxidant activity, it is now understood to regulate cell signaling and gene expression.7 The main biologically active form of vitamin E is α-tocopherol.8
TABLE 56-1Pros and Cons of Tocopherol ||Download (.pdf) TABLE 56-1 Pros and Cons of Tocopherol
Potent antioxidant activity and primary lipophilic antioxidant
Dearth of evidence in controlled trials to support use for dermatologic conditions
Synergistically interacts with other antioxidants
Risk of contact dermatitis
Exhibits emollient activity
Easy to formulate
Can be regenerated back into its reduced form by hydrophilic antioxidants vitamin C and glutathione
Tocopherols, unlike tocotrienols, are found in olive, peanut, sunflower, and walnut oils.9 One of the most abundant sources of tocotrienols is palm oil, which is free of trans-fatty acids, accounting for its increasingly widespread popularity, particularly in the United States.9,10 Tocotrienols are also found in edible sources such as rice bran, coconut oil, cocoa butter, soy bean, barley, and wheat germ, as well as inedible ones such as latex (Hevea brailiensis).9–11
Herbert Evans and Katherine Bishop are credited with discovering vitamin E in 1922.12–14 After inducing sterility in rats, they found that feeding the animals lettuce or wheat germ oil, but not cod liver oil or wheat flour or chaff, restored fertility. Initially, they labeled an essential dietary ingredient as “factor X.”13 They adopted the expression “vitamin E,” as suggested by Sure, in 1924.7,13 The first description of the antioxidant activity of vitamin E is attributed to Olcott and Mattill in 1931, with the first recorded isolation of α-tocopherol occurring in 1936.13,14 Also in 1936, George Calhoun, professor of Greek at the University of California, Berkeley, suggested the name “tocopherol” based on the Greek words tokos (offspring or childbirth) and phero or phérein (to bear or to bring forth), to Evans and colleagues, who also worked at Berkeley; the “-ol” indicates the alcohol characteristics of the compound.7,13 In 1938, Karrer, Fritzche, Ringier, and Salomon became the first to synthesize α-tocopherol.9,13 In the 1940s, vitamin E became known as a “chain-breaking” antioxidant for its role in suppressing the chain reaction induced by free radicals.14
Vitamin E is a family of compounds called tocopherols, including, α-, β-, γ-, and δ-tocopherol, of which α-tocopherol is the most active form, and four tocotrienols (α-, β-, γ-, and δ-tocotrienol). Tocotrienols, with three unsaturated bonds in the carbon side chain with one chiral center, have an isoprenoid instead of a phytyl side chain (long saturated carbon side chain with a chiral center).3,9 The four forms differ by the number of methyl groups found on the chromanol nucleus (α- has three; β- and γ- each have two; and δ- has one).3 The side chain is linked to position 2 of the chroman ring in all cases.7 The chemical names for all vitamin E types begin with either “d” for the natural form or “dl” (or “all-rac”) for the synthetic form. Natural vitamin E is more active and better absorbed. Synthetic vitamin E supplements contain only α-tocopherol, while food sources contain various tocopherols, including α-, δ-, and γ-tocopherol. Forms of vitamin E are labeled as either “tocopherol” or the esterified “tocopheryl” followed by the name of the substance to which it is attached, as in “tocopheryl acetate.”
Although less studied than tocopherols (approximately one percent of the literature on vitamin E addresses tocotrienols),10 tocotrienols have been reported to act as stronger antioxidants but exhibit lower biovailability;9,15–17 the δ-tocotrienol form is thought to be especially effective in combating actinic damage.18 Of note, some believe that α-tocotrienol is a more potent antioxidant than α-tocopherol.9 Tocotrienols are not only members of the vitamin E family based on structure, but function as well. For instance, tocotrienols can alleviate symptoms engendered by α-tocopherol deficiency.10 In addition, tocotrienols reportedly display hypocholesterolemic, anticancer, and neuroprotective activity seldom associated with tocopherols.10 Tocopherols are much more widely dispersed in the plant kingdom than are tocotrienols.10,19
Vitamin E, CoQ10, curcumin, and feverfew are among the antioxidants found in the lipophilic portion of the cell membrane (see Chapter 57, Coenzyme Q10; Chapter 66, Feverfew; and Chapter 69, Turmeric). Other fat-soluble antioxidants include carotenoids, particularly lycopene, and idebenone, the synthetic analog of CoQ10 (see Chapter 61, Idebenone). But several investigations have shown that vitamin E is the predominant antioxidant in the skin barrier.20 One of the primary functions of α-tocopherol is the scavenging of lipid peroxyl radicals (one molecule of tocopherol has the capacity to scavenge two molecules of peroxyl radicals); γ-tocopherol is better at scavenging reactive nitrogen oxide species (up to six times the reactivity).7,14,21–23 In addition, α-tocopherol has twice the capacity of γ-tocopherol in scavenging oxygen radicals; γ-tocopherol has 10 percent of the biological activity of α-tocopherol.7 Concentrations of vitamin E are found to be highest in the lowest layers of the stratum corneum (SC).24 Exogenous factors such as ultraviolet (UV) exposure are known to deplete the stores of vitamin E in the skin.
Oral vitamin E has been used in a wide range of cutaneous conditions as a treatment or prophylaxis, including skin cancer, dystrophic epidermolysis bullosa, discoid lupus erythematosus, atopic dermatitis, yellow nail syndrome, granuloma annulare, pemphigus, and lichen sclerosus et atrophicus.25 Results have varied significantly. Vitamin E has also been used in oral form to treat cutaneous ulcers, vibration disease, as well as claudication, and to stimulate collagen synthesis and wound healing.3,26
In 2002, Tsoureli-Nikita et al. conducted a single-blind clinical study in 96 patients with atopic dermatitis randomly divided into a group given 400 international units (IU) of natural vitamin E or a placebo, once daily for eight months. The subjects in the vitamin E group experienced significantly better results than those on placebo, with nearly complete remission in seven of the 50 vitamin E subjects and none on placebo. Great improvement was observed in 23 of the 50 using vitamin E and only one in the placebo group. Slight improvement was seen in 10 using vitamin E and four in the placebo group, with no changes recorded in six of the vitamin E group and five in the placebo cohort. Thirty-six patients using the placebo experienced an exacerbation of their symptoms, compared to four patients using vitamin E. A reduction of 62 percent in serum immunoglobulin E levels was noted in the vitamin E patients who exhibited great improvement and near remission. The difference was approximately 34.4 percent in those taking placebo. The investigators reported significant improvements in facial erythema, lichenification, and the appearance of normal-looking skin, concluding that vitamin E is promising as a therapeutic agent for atopic dermatitis.27
Some authors have reported that the use of oral vitamin E will reduce the side effects of retinoids;28 however, other studies have not shown this benefit.29
Thiele and Ekanayake-Mudiyanselage note that oral vitamin E doses ranging from 50 to 1000 IU have been well tolerated in human beings with minimal or no side effects.30 Oral supplementation with tocotrienols has been shown to protect against stroke.31,32 When incorporated into oral supplements tocotrienols are typically processed into softgel capsules.9
Several studies have demonstrated a protective effect against prostate cancer purportedly delivered by α-tocopherol supplementation.33,34 However, in a 2007 prospective study analyzing the relationship of vitamin E supplementation and dietary consumption of α-, δ-, γ- and δ-tocopherol to prostate cancer risk in 295,344 men (between 50 and 71 years old) free of cancer at enrollment in 1995–1996, investigators found that α-tocopherol did not impart protection but higher intake of γ-tocopherol was associated with a lowered risk of clinically relevant disease.21
A 2013 study suggests a role for argan oil improving the vitamin E profile and attenuating the symptoms of disorders seen more often in postmenopausal women. In a study of 151 menopausal women in Morocco, serum level of vitamin E was increased in women consuming edible argan oil but not in women in an olive oil group. Investigators suggested that an argan-rich diet increases antioxidant status and may contribute to the prevention of some postmenopausal disorders (see Chapter 10, Argan Oil).35
Vitamin E is generally used in 1 to 5 percent concentrations as α-tocopherol or tocopherol acetate in over-the-counter products.24 When topically applied, vitamin E has been shown to hydrate the SC and improve water-binding capacity.24
In a 2005 study with 13 volunteers, Ekanayake-Mudiyanselage et al. examined whether a one-time use of an α-tocopherol-enriched rinse-off product could yield effective deposition of α-tocopherol on the SC. The α-tocopherol-enriched product or an α-tocopherol-free vehicle control was applied. Skin surface lipids were analyzed after extraction from all volunteers, including a group subjected to irradiation of their forearms with low-dose UVA (8 J/cm2). The investigators found that the α-tocopherol product increased α-tocopherol levels in surface lipids whereas such levels were decreased in the control group. Deposition levels remained consistent for at least 24 hours. The α-tocopherol rinse-off product also significantly suppressed photooxidation of squalene. The researchers concluded that α-tocopherol-enriched rinse-off products can contribute skin barrier integrity maintenance by protecting it at the surface lipid level against photooxidative insult.8
In a small study of nine patients in 2008, Murray et al. found that a stable topical preparation of 15 percent L-ascorbic acid, 1 percent α-tocopherol, and 0.5 percent ferulic acid protected human skin in vivo from UV-induced damage, specifically erythema and apoptosis [see Chapter 54, Ferulic Acid, and Chapter 55, Ascorbic Acid (Vitamin C)]. The formulation also suppressed p53 activation and limited thymine dimer mutations, which are associated with skin cancer.36
Topically applied vitamin E is considered an effective ingredient for conferring skin protection and to treat atopic dermatitis.3,37
Oxygen radicals form in response to injury and further inhibit recovery by attacking DNA, cellular membranes, proteins, and lipids. It is believed that antioxidants act to ameliorate wounds by reducing the damage induced by free oxygen radicals, which are released by neutrophils in the inflammatory phase of the healing process.38 In the late 1960s, Kamimura et al. performed quantitative research demonstrating that topically applied vitamin E penetrates into the deep dermis and subcutaneous tissue.39 Numerous scientists, as well as many laypersons, have interpreted this to mean that topically applied vitamin E may improve wound healing. Contradictory results have emerged from animal studies undertaken to evaluate the effects of vitamin E on wound healing, however. This may be explained by the fact that unlike other vitamins, tocopherols exhibit species-specific mechanisms of action.26
In a prospective, double-blind, randomized study on humans, Jenkins et al. tried to diminish scarring in burn patients following reconstructive surgery by applying topical vitamin E. The researchers observed no difference between the control and treatment groups, however, and nearly 20 percent of the patients reported local reactions to the vitamin E cream.40 In another study, Baumann et al. assessed the cosmetic benefit resulting from the use of topically applied vitamin E to surgical scars.37 In a double-blind fashion, patients applied 320 IU of D-α-tocopheryl/g of Aquaphor to one side of the scar and Aquaphor alone to the other side of the scar. The patients were followed for six months. At the conclusion of the study, the vitamin E preparation failed to improve the cosmetic appearance of surgical scars, and resulted in contact dermatitis in a few subjects.
In 1999, Funasaka et al. showed in a pigmented human melanoma cell line that α-tocopherol and ferulic acid, connected by an ester bond in the compound α-tocopheryl ferulate, appears to be a viable facial skin-whitening agent, inhibiting melanogenesis as well as biological responses to reactive oxygen species (see Chapter 54, Ferulic Acid).41 In addition, the compound more efficiently hindered melanin formation than the well-known skin-lightening agents arbutin, kojic acid, magnesium-L-ascorbyl 2-phosphate (esterified vitamin C), and tranexamic acid [see Chapter 35, Arbutin; Chapter 37, Kojic Acid; and Chapter 40, Vitamin C (Ascorbic Acid)].41
In 2013, Burns et al. demonstrated in female SKH-1 hairless mice that topical treatment with a combination of vitamins C (15 percent L-ascorbic) and E (1 percent α-tocopherol) and 0.5 percent ferulic acid (C E Ferulic®) for 15 weeks reduced squamous cell cancer (SCC) tumor burden and inhibited the development of new tumors after 10 weeks of exposure to UVB. They also found that treatment with topical 5 percent α-tocopherol alone may actually augment SCC formation.42
The incidence of contact dermatitis elicited by topical vitamin E application may be relatively high for certain forms of tocopherol,37,40 particularly tocopherol acetate,43 with allergy to dl-α-tocopheryl nicotinate also reported.44 Contact urticaria, eczematous dermatitis, and erythema multiforme-like reactions have also been reported in association with the topical application of vitamin E.45 In 1994, Swiss researchers evaluated 1,000 cases of an atypical papular and follicular contact dermatitis provoked by vitamin E linoleate used as an additive to cosmetics. They concluded that oxidized vitamin E derivatives can operate synergistically in vivo as haptens or as irritants and were responsible for the allergic reaction, not the vitamin E ester.3,46 Reports of allergic contact dermatitis or irritation in response to topical vitamin E are rare overall, though, and it is considered safe for use in topical skin care products.
Bendich and Machlin conducted a comprehensive literature review in 1988, finding extended use of oral vitamin E up to 3,000 mg/d to be safe.47 Kappus and Diplock later established as absolutely safe vitamin E doses up to 400 mg/d, with doses between 400 mg and 2,000 mg deemed as unlikely to cause adverse reactions, and doses greater than 3,000 mg/d over a prolonged period as a potential source of side effects.48 Patients on anticoagulant therapy are advised to avoid high doses of vitamin E (>4,000 IU) because the nutrient can contribute to blood thinning.49 In addition, patients are often counseled to suspend vitamin E supplementation, although a clinically significant reduction in platelet aggregation in those with normal platelets is unlikely. Such a suspension is necessary for patients who have abnormal platelets or vitamin K deficiency, or who are taking antiplatelet agents.50
Tocopherol is used in concentrations up to 5 percent in cosmetic formulations, with tocopheryl acetate and tocopheryl linoleate used in concentrations up to 36 and 2 percent, respectively.51 The Cosmetic Ingredient Review (CIR) Expert Panel has found that tocopherol and its ester and ether derivatives, tocopheryl acetate, tocopheryl linoleate, tocopheryl linoleate/oleate, tocopheryl nicotinate, tocopheryl succinate, dioleyl tocopheryl methylsilanol, potassium ascorbyl tocopheryl phosphate, and tocophersolan are safe as used in skin care formulations.51
Organic forms of vitamin E are widely available. It is unlikely that the synthesis of topical products featuring tocopherols exacts an environmental toll. More likely, as in the case of vitamin C, is the potential of ambient toxins, particularly pesticides, affecting plants that contain forms of vitamin E. However, the cultivation and extraction of the oil palm fruit (Elaies guineensis) for palm oil (a semi-solid fat rich in palmitic and oleic acids) should not be ignored insofar as vitamin E (30 percent tocopherols, 70 percent tocotrienols) is a significant minor component in palm oil and the oil palm is the highest yielding oil crop in the world.9,52,53 The desire to cultivate and capitalize on the economic potential of the two oils derived from E. guineensis (native to West Africa but grown for commercial purposes mainly in Southeast Asia, particularly Malaysia), palm oil (primarily used for edible qualities in food preparation and processing) and palm kernel oil (used for commercial food preparation as well as oil and chemistry industries), has contributed to widespread and continuing deforestation and threats to biodiversity in Southeast Asia.52,54–56
The lipophilic nature of vitamin E renders it conducive to topical application and percutaneous absorption through the skin.57,58 The form of vitamin E used in formulation is a key factor in its potential efficacy in a skin care product. Because vitamin C can restore oxidized vitamin E, the combination of the antioxidants is a stabilizing factor in topical formulations [see Chapter 55, Ascorbic Acid (Vitamin C)].42,59 Further, ferulic acid has been shown to stabilize both vitamins, with the topical combination exerting photoprotective effects against UVB exposure, including the significant reduction in thymine dimer formation (see Chapter 54, Ferulic Acid).42,58,60 Vitamin E is often incorporated in its esterified forms, typically as acetates and succinates, as these compounds are more stable.61
Oral ingestion of tocotrienols sufficient to achieve biologic activity is exceedingly difficult. Dietary supplements are therefore recommended. The highest bioavailability among the natural vitamin E isomers is exhibited by α-tocopherol and is the standard by which other forms of vitamin E are compared.10
Tocopherol displays better absorption, while tocopheryl exhibits slightly better shelf life. The most common oral supplementation forms of vitamin E are D-α tocopherol, D-α-tocopheryl acetate, and α-tocopheryl succinate. In cosmetic products, the most common vitamin E forms are α-tocopheryl acetate and α-tocopheryl linoleate, which are less likely to provoke contact dermatitis than D-α-tocopheryl and more stable at room temperature. Notably, the tocopherol esters are less well absorbed by the skin than tocopherols,62 and may not render as much photoprotection. In one study, α-tocopheryl acetate or α-tocopheryl succinate may have actually enhanced photocarcinogenesis, rather than protected against it.63 Such α-tocopherol esters are included in many skin lotions, cosmetics, and sunscreens; therefore, more research is necessary to determine if esterified vitamin E forms indeed foster photocarcinogenesis.
Dietary deficiency of vitamin E has been correlated with an increase in oxidative stress and cell injury.2 In 1993, Tanaka et al. observed that reactive oxygen species induce alterations in the biosynthesis of collagen and glycosaminoglycans (GAGs) in cultured human dermal fibroblasts.64 The addition of α-tocopherol to the fibroblasts prevented such changes. Vitamin E has also been demonstrated to decrease prostaglandin E2 production,65 and increase interleukin (IL)-2 production, yielding anti-inflammatory and immunostimulatory activity. This stabilizing effect is thought to potentially play a role in collagen biosynthesis.66 However, in vivo attempts to measure and correlate changes in collagen production with vitamin E concentration changes have not yet yielded conclusive results.
In 1992, Trevithick et al. noted that topical D-α-tocopherol acetate diminished erythema due to sunburn, edema, and skin sensitivity in mice when application occurred following exposure to UVB radiation.67 In a study in which tocopherol 5 percent was applied to mice prior to UVB exposure, Bissett et al. observed a 75 percent decrease in skin wrinkling, a rise in tumor latency, and a reduction of cutaneous tumors; however, vitamin E failed to affect UVA-induced skin sagging.68 Indeed, the topical application of α-tocopherol to animal skin has been repeatedly shown to be effective in reducing sunburn cell production,69,70 attenuating chronic UVB-induced damage,71,72 and inhibiting photocarcinogenesis.73 Specifically, oral and topical vitamin E supplementation in certain animals diminishes the effects of photoaging, inhibits skin cancer formation, and reverses UV-induced immunosuppression.74–76 In mice, the topical application of D-α-tocopherol has been demonstrated to be much more effective than D-α-tocopheryl succinate in protecting against acute and chronic UV-induced damage.4
As mentioned in the previous chapter, Cho et al. found that female SKH-1 hairless mice orally administered an antioxidant formulation containing vitamins C and E, Pycnogenol, and evening primrose oil (see Chapter 49, Pycnogenol), given during a 10-week period that included three weekly doses of UVB, exhibited significantly reduced wrinkle formation and epidermal thickness compared to controls.77
Antioxidant Activity and Photoprotection
Depletion of cutaneous vitamin E is considered an early indication of extrinsically caused oxidative damage.20,37 Studies on elderly subjects that exhibit high plasma tocopherol levels reveal a lower incidence of infectious disease and cancer than in the age-matched population.78–80 Therefore, vitamin E is thought by many to be a potent and essential antioxidant. As an ingredient in skin care agents, significant evidence has been amassed to suggest its effectiveness as a photoprotective agent. It also appears to deliver photoprotection when taken orally or applied topically.
In a study in which subjects facially applied tocopherol 5 to 8 percent cream for four weeks, observations included diminished skin roughness, shorter length of facial lines, and reduced wrinkle depth as compared to placebo.81 In addition, in a study in which vitamin E (5 percent) was applied to human skin under light-tight occlusion 24 hours before UV treatment, UV-induced expression of human macrophage metalloelastase, a member of the matrix metalloproteinase family involved in degradation of elastin, appeared to be inhibited.82
There are studies that cast doubt on the efficacy of vitamin E alone in imparting photoprotective effects, however. A double-blind, placebo-controlled six-month study of the protective effects of orally administered vitamin E (400 IU/day) against UV-induced epidermal damage in humans considered minimal erythema dose (MED) and histologic response at baseline, one month, and six months. There was no significant difference between the placebo group and those treated with vitamin E and the researchers concluded that daily ingestion of 400 IU of oral α-tocopherol daily yielded no meaningful photoprotection.83 Other authors have suggested that if vitamin E provides any photoprotection at all, it may do so only in cooperation with other antioxidants, such as vitamin C.59 In fact, Lin et al., in a study with Yorkshire pigs, demonstrated that the combined application of 1 percent α-tocopherol with 15 percent L-ascorbic acid rendered superior protection against erythema and sunburn cell development compared to either 1 percent α-tocopherol or 15 percent L-ascorbic acid alone.58 Of note, some data suggest a cumulative benefit derived from using oral and topical antioxidant products in combination, including vitamins C and E in particular.84–86
Sorg et al., who noted that vitamins A and E absorb UV radiation in the solar spectrum range most responsible for photodamage, suggested that these vitamins perform complementary functions in the skin, with topical vitamin E shown in mice to prevent UV-induced oxidative stress as well as cutaneous and systemic immunosuppression. Topical vitamin A has been demonstrated in mice to prevent epidermal hypovitaminosis engendered by UV exposure. The authors contend that combining these topical agents can reinforce the activities of each.87
Nevertheless, a 2009 six-month study in healthy human volunteers with actinic keratoses revealed that while topically applied dl-α-tocopherol, of which cutaneous levels were significantly increased at the conclusion of the study, did not markedly change already present lesions, changes in polyamine metabolism indicated that squamous cell carcinogenesis potential was significantly reduced.88
Overall, several studies using topical E have yielded evidence of photoprotective activity against erythema, edema, sunburn cell formation, and additional indicators of acute UV-induced damage as well as responses to chronic UVA and UVB exposure, including skin wrinkling and skin cancer.3,58,68,74,89–91
Antioxidant activity emerges as the primary but not exclusive reason for research into the dermatologic use of vitamin E. Combination with other antioxidants appears to enhance the potency of vitamin E and, likely, the other interacting antioxidants. The potential therapeutic benefits of vitamin E in the prevention and treatment of skin cancer and photoaging remain an important focus of research. As an ingredient in topical antiaging skin care preparations, vitamin E exhibits emollient properties and is stable, easy to formulate, and relatively inexpensive, rendering it a popular additive. Much more research, in the form of randomized controlled trials, is necessary, though, to establish the role of vitamin E in treating various dermatoses. Tocotrienols have gained increasing attention in the last two decades and warrant much more investigation to elucidate a fuller role of the vitamin E family in dermatology.
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