INTRODUCTION

Vitamin E was discovered in 1922 at the University of California in Berkeley by Evans and Bishop. ‘Tocopherol’ is derived from the Greek words ‘tocos’, meaning ‘offspring’, and ‘phero’, meaning ‘to provide a person with power’. While some antioxidants, such as glutathione or ubiquinol-10, can be synthesized by humans, vitamin E is supplied by oral intake only. The main natural sources of vitamin E are fresh vegetables, vegetable oils, cereals, and nuts. Recent studies suggest that the majority of men and women in the US fail to meet the current recommendations for vitamin E intake. The lipophilic antioxidant vitamin E has been used for more than 50 years in clinical and experimental dermatology. However, while a large number of case reports were published, there is still a lack of controlled clinical studies providing a rationale for clinical indications and dosage. In contrast, advances in basic research on the physiology, mechanism of action, penetration, bioconversion, and photoprotection of vitamin E in human skin has led to the development of numerous new formulations for use in cosmetics and skin care products. This chapter reviews basic mechanisms and possible cosmeceutical as well as clinical implications of the recent advances in cutaneous vitamin E research.

TERMINOLOGY AND DEFINITIONS

Vitamin E is the major lipophilic antioxidant in plasma, membranes, and tissues. The term ‘vitamin E’ collectively refers to the eight naturally occurring molecules (four tocopherols and four tocotrienols) which exhibit vitamin E activity. Tocotrienols differ from tocopherols in that they have an isoprenoid instead of a phytyl side chain; the four forms of tocopherols and tocotrienols differ in the number of methyl groups on the chromanol nucleus (α- has three, β- and γ- have two, and δ- has one; Fig. 7.1). In humans, α-tocopherol is the most abundant vitamin E homolog, followed by γ-tocopherol. To compare the potency of different vitamin E derivates, their biologic activities are measured and compared to RRR-α-tocopherol. The potency is expressed as international units (IU) α-tocopherol equivalents (α-TE) and was developed for oral supplementation.

Fig. 7.1 Chemical structure of tocopherols and tocotrienols.

Tocopherols (α: R₁ = R₂ = CH₃, 430.7 g mol⁻¹; β: R₁ = CH₃, R₂ = H, 416.7 g mol⁻¹; γ: R₁ = H, R₂ = CH₃, 416.7 g mol⁻¹; δ: R₁ = R₂ = H, 402.7 g mol⁻¹);

Tocotrienols (α: R₁ = R₂ = CH₃, 424.7 g mol⁻¹; β: R₁ = CH₃, R₂ = H, 410.6 g mol⁻¹; γ: R₁ = H, R₂ = CH₃, 410.6 g mol⁻¹; δ: R₁ = R₂ = H, 396.6 g mol⁻¹)

INDICATIONS AND BIOLOGIC ACTIVITY

After more than half a century of research there is still little convincing evidence of vitamin E’s effectiveness in treating specific dermatologic disorders. In trials and case reports, oral vitamin E supplementation is recommended in the therapy of yellow nail syndrome, vibration disease, epidermolysis bullosa, cancer prevention, claudication, cutaneous ulcers, collagen synthesis, and wound healing. Clearly, with vitamin E not being a pharmaceutical, there is a lack of placebo-controlled studies for treatment of these conditions. However, in the field of skin care, which includes cosmeceuticals, there is a large body of experimental evidence pointing to, in particular, photoprotective effects (for review, see Table 7.1). Moreover, recent studies indicate that vitamin E may reveal dermatologic benefits that exceed the purpose of cosmetics and may extend into an area that has recently been termed ‘cosmeceuticals’.

Recently, Tsoureli-Nikita et al performed a clinical single-blind, placebo-controlled study in which 96 atopic dermatitis patients were treated with either placebo or oral vitamin E (400 IU/day) for 8 months. They found an improvement and near remission of atopic dermatitis and a 62% decrease in serum IgE levels based on initial conditions in the vitamin E-treated group. The correlation between α-tocopherol intake, IgE levels, and the clinical manifestations of atopy indicates that oral vitamin E could be an excellent therapeutic adjunct for atopic dermatitis (Tsoureli-Nikita et al 2002). Other multi-clinical double-blinded studies revealed a significant improvement of chloasma and pigmented contact dermatitis lesions using topical vitamins E and C, with the combination clearly proving superior to the single vitamin treatment groups. Topical formulations used for depigmentation that contain, besides the commonly used hydroquinone and sunscreen, vitamins C and E, appear to be safe and efficient. Further research in well-designed controlled trials is needed to clarify the role of vitamin E and its derivates in the above-mentioned and further skin disorders.

MECHANISMS OF ACTION

Vitamin E is among the early recognized biologic antioxidants, and its redox and free radical chemistry are well documented. The major antioxidant role of vitamin E is generally considered to be the arrest of chain propagation by scavenging lipid peroxyl radicals. The initial oxidation product of tocopherol is the metastable tocopheroxyl radical, which can be either reduced to tocopherol by co-antioxidants, or reacts with another lipid peroxyl radical, yielding tocopherol-quinone. Thus, one molecule of tocopherol has the ability to scavenge two peroxyl radical molecules. Since the physiologic molar ratio of tocopherols to polyunsaturated phospholipids, first-line targets of oxidative attack, is less than about 1 : 1000 in most biologic membranes, regeneration of tocopherol is essential for its high antioxidant efficacy in vivo. Several hydrophilic co-antioxidants, such as ascorbate and glutathione, can regenerate vitamin E from the tocopheroxyl radical and thus enhance the antioxidant capacity of vitamin E. Furthermore, there is some in vitro evidence that ubiquinol-10 (‘coenzyme Q’) protects α-tocopherol from photo-oxidation by recycling mechanisms. Hence, the lack of such ‘co-antioxidants’ from the antioxidant network may diminish the antioxidant properties of vitamin E and result in limited antioxidant protection of lipid bilayers or other lipophilic domains.

A series of studies investigating nonenzymatic stratum corneum antioxidants have demonstrated that, in human skin, vitamin E is the predominant physiologic antioxidant of the skin barrier (Thiele et al 2001). When compared to nucleated epidermal layers, there is a lack of important co-antioxidants such as vitamin C in the stratum corneum as well as in the dermis. Taken together, these findings suggest that the skin barrier as well as the upper dermis reveal a lack of antioxidant protection. Accordingly, upon solar ultraviolet (UV) exposure, these are the cutaneous sites exhibiting the most pronounced oxidative protein damage (Sander et al 2002). Thus, antioxidant supplementation with vitamin E as well as synergistically active co-antioxidants, such as vitamin C, may enhance photoprotective strategies using sunscreens. While single studies have demonstrated significant penetration of topical vitamin E into dermal layers in vitro and in animals, there is still controversy about the efficacy of such strategies for dermal targets in human skin.

DOSAGE AND PRACTICAL USAGE REGIMENS

CAUTIONS, CONTRAINDICATIONS, AND ADVERSE EFFECTS

Although vitamin E is widely used in many topical cosmetic products, reports of side effects such as allergic or irritant skin reactions are rare. Nevertheless, clinical side effects have been described after topical application of vitamin E-containing products, e.g. local and generalized contact dermatitis, contact urticaria, and erythema multiforme-like eruptions. In 1992, an ‘epidemic outbreak’ of about 1000 cases of allergic papular and follicular contact dermatitis caused by α-tocopherol linoleate in a cosmetic line was reported in Switzerland. The authors found that this compound was easily oxidized under the storage conditions used. Therefore, secondary or tertiary oxidation products of α-tocopherol linoleate, rather than the reduced vitamin E ester, are likely to have caused irritation or even the oxidation of proteins and subsequent hapten formation. Furthermore, positive patch test reactions were reported in several cases after application of α-tocopherol acetate, a widely used water-soluble derivate of α-tocopherol.

In conclusion, reported positive patch test results due to α-tocopherol are rare and need to be critically reviewed. Investigators used the oil of vitamin E capsules for patch testing without further evaluating the contained tocopherol derivates, source or further components of these capsules. However, it could not be excluded in many cases that the symptoms were caused by soybean oil, glycerin or gelatin, all of which were also present in the topically applied vitamin E capsules (Harris & Taylor 1997).

Doses of 50 IU up to 1000 IU α-tocopherol per day have been tolerated in humans with no or minimal side effects. Vitamin E supplements for pregnancy usually contain smaller doses of vitamin E, but adverse effects have not been observed even with higher doses. Theoretically, however, due to the involvement of the cytochrome P450 system in the metabolism of orally supplemented RRR-α-tocopherol, drug interactions have to be taken into account when supranutritional dosages of vitamin E are provided. Since tocopherols and their oxidation products are able to inhibit platelet aggregation, simultaneous supplementation of anticoagulants and vitamin E is not recommended, which has implications for surgical procedures (Thiele et al 2005).

CURRENT RESEARCH AND POSSIBLE FUTURE APPLICATIONS

As indicated above, topical strategies alone may not be sufficient to bolster the skin’s antioxidative defense in the dermis and thus to prevent or lessen photoaging in this skin compartment. Therefore, current research on vitamin E focuses on systemic delivery of vitamin E to the various compartments of human skin. It was recently discovered that human sebum contains high amounts of α-tocopherol and that sebaceous gland secretion is a relevant physiological route of α-tocopherol delivery to sebaceous gland-rich skin regions, such as facial skin (Thiele et al 1999). Similarly, orally administered drugs have been reported to be transported to the skin surface and the stratum corneum by the sebaceous gland secretion route (Ekanayake-Mudiyanselage et al 2004). Ongoing studies are investigating the relevance and time course of this delivery pathway for increasing the levels of vitamin E in human skin. A further ongoing study is focusing on the relevance of this mechanism for the physiologic vitamin E levels in skin surface lipids in different age groups. The outcome of these studies will certainly have implications for conditions of sebostatic, dry skin (e.g. as in atopic dermatitis), as well as for the skin of prepubertal children, who have a low activity of sebaceous glands.