Relevance of the Cutaneous Vitamin D Endocrine System for Skin Physiology
4.3 Vitamin E
4 Photoprotection of the Skin with Vitamins C and E: Antioxidants and Synergies 49
treatment with 15% topical vitamin C on the right and placebo cream on the left, the right periorbital wrinkles were clearly reduced, and the skin acquired a healthy, more youthful glow.
Topical vitamin C has also been shown to increase the synthesis of several specific sphingolipids of the skin surface (Uchida et al. 2001). With these lipids, vitamin C helps the natural moisturization of the skin as it enhances the protective barrier function (C. Catiel-Higournenc Ferrais, C. Guey, R. Schmidt, et al. L’Oréal Advanced Research Laboratories, Clichy and Aulnay-sous-Bois, France. Personal communication).
50 K.E. Burke
the esterified forms of vitamin E to the active free tocopherol form, so the antioxidant potential of the esters is minimal (Gensler et al. 1996; van Hanegouwne et al. 1995).
Furthermore, the all-rac form of vitamin E has been reported to cause allergic contact dermatitis (Hart 1990) and erythema multiforme (Saperstein et al. 1984) when applied topically. No such adverse reaction has been reported with d-a-tocopherol.
Many studies have demonstrated protection from UV-induced damage to the skin by applying various topical vitamin E formulations. Even various forms of topical vitamin E that are less metabolically potent when applied topically than the nones- terified d-a-tocopherol have demonstrated protection from the acute (Burke et al.
2000; Trevithick et al. 1992; Record et al. 1991; Marenus et al. 1990; Berton et al.
1998) UV-induced damage of inflammation (erythema, sunburn) and hyperpig- mentation (tanning) as well as protection from the chronic UV-induced damage of actinic keratosis and skin cancer (Marenus et al. 1990; Berton et al. 1998; Bissett et al. 1992a, b; Gensler and Magdaleno 1991; Gerrish and Gensler 1993).
Few controlled studies have directly compared the efficacy of the various forms of topical vitamin E for photoprotection. Topical a-tocopheryl acetate was shown to be less effective than a-tocopherol in protecting against UV-induced erythema in rabbits (Gensler et al. 1996; Roshchupkin et al. 1979) and against UV-induced photoaging in mice (Bissett et al. 1990). In one mouse model, topical a-tocopheryl succinate and a-tocopheryl acetate not only failed to inhibit UVB-induced immu- nosuppression and carcinogenesis but appeared to enhance carcinogenesis (Gensler et al. 1996). In a 44-week mouse study (longer than most other published experi- ments), both d-a-tocopherol and d-a-tocopheryl succinate were proven effective in protecting against all acute and chronic UV-induced damage, with d-a-tocopherol most effective for all parameters (i.e., decreasing sunburn, tanning, skin cancer incidence) (Burke et al. 2000).
The results tabulated in Table 4.1 (Burke et al. 2000) show that topical d-a- tocopherol inhibited blistering sunburn by 73% and tanning by 40%. The topical ester d-a-tocopheryl succinate was more effective than oral vitamin E but less effective that the nonesterified topical d-a-tocopherol for both inhibition of acute
Fig. 4.4 Molecular structure of tocopherol isomers
4 Photoprotection of the Skin with Vitamins C and E: Antioxidants and Synergies 51
sunburn and tanning (Burke et al. 2000). Similarly, topical d-a-tocopherol was most effective in decreasing the incidence of UV-induced skin cancer, although all three forms of vitamin E were effective at earlier time points, with topical d-a-to- copheryl succinate almost as effective long term as topical d-a-tocopherol, as seen in Fig. 4.5 (Burke et al. 2000).
Table 4.1 Protection from acute UVB-induced damage with vitamin E
Treatmenta Blistering sunburnb (%) Degree of tanningc
d-a-Tocopherol lotion (5%) 27 1.93
d-a-Tocopheryl succinate lotion (5%) 67 2.07
Oral d-a-tocopheryl acetate 73 2.43
Vehicle lotion 100 3.75
Data are from Burke et al. (2000)
aSkh:2 female mice were treated daily (5 days/week) for 2 weeks prior to UVB exposure and through- out the period of irradiation (three exposures per week), as described in detail in reference 7
bPercentage of mice (in each group of 15) that developed a blistering sunburn as the UV exposure was begun at low doses of 0.75 minimum erythema dose and increased sequentially to the final maintenance exposure time
cUV-induced pigmentation of each mouse after exposure to UV radiation was subjectively graded by two “blinded” investigators after 12 weeks. Values are averages of all 15 mice in each treatment group: 0, no hyperpigmentation; 4, maximum hyperpigmentation
Fig. 4.5 Mean number of tumors ³2 mm in ultraviolet B (UVB)-irradiated Skh:2 female mice treated with vitamin E and vitamin E esters. Beginning 2 weeks before UV exposure, 15 mice in each treatment group were treated thrice weekly throughout the duration of the experiment with vehicle lotion (open squares and filled squares), topical d-a-tocopherol lotion (5%) (filled triangles), or topical d-a- tocopheryl succinate (5%) (open triangles) ³30 min before UV exposure. In addition, one group (filled squares) was fed a diet supplemented with d-a-tocopheryl acetate. The mice were exposed to UVB radiation thrice weekly for 24 weeks, and topical and oral treatments were continued. The number of tumors ³2 mm on each mouse was counted, and the mean number of tumors per mouse was calculated based on the total number of the mice in each treatment group (Burke et al. 2000)
52 K.E. Burke
A new formulation of vitamin E with both dl-a-tocopherol in lecithin and dl-a- tocopheryl ferulate in lecithin showed a measureable decrease in UV-induced DNA damage as measured by reduced d-OHdG (Ichihashi et al. 1999). This formulation was found to inhibit the enzyme tyrosinase and to decrease melanogenesis in human melanoma cells (Ichihashi et al. 1999).
Clinically, vitamin E reverses photoaging dramatically, decreasing unattractive wrinkles and solar lentigos. Figure 4.6 shows a woman in her late forties who was treated with topical d-a-tocopherol (5%) once daily for 4 months. The marked improvement in her skin tone and in the periorbital wrinkles is impressive.
This correction of UV-induced damage was confirmed by histological examination of mice photoaged by exposure to UVB for 6 weeks. After UV exposure, epidermal hypertrophy with thickened stratum corneum, an increased incidence of damaged
“sunburn cells” in the basal layer, disruption of dermal collagen with degradation of dermal elastin, and dermal inflammation were noted. Each group was then treated for 8 weeks with vehicle cream, retinoic acid cream (0.05%), or d-a-tocopherol cream (5%). The degree of damage was subjectively graded by “blinded” examination of histological slides of multiple biopsies from each of 10 mice per treatment group by two experienced dermatopathologists. Each parameter—epidermal thickness, hyperkeratosis, collagen disruption, solar elastosis—was assessed separately on a scale of 0 (no damage) to 4 (maximum damage), and a net score was determined, as shown in Fig. 4.7.
Histological improvement in all parameters of photoaging was noted, with a marked decrease in hyperkeratosis and epidermal hypertrophy, repair of damaged dermal collagen and elastin, and clearing of dermal inflammation after treatment with retinoic acid or with d-a-tocopherol. In this limited experiment, topical d-a- tocopherol was shown to be even more effective in reversing photoaging than retinoic acid, the topical medication considered to be the “gold standard”
for treatment of photoaging (K.E. Burke, L. Ricotti, E.G. Gross, unpublished observations).
Fig. 4.6 This woman in her early 1940s was photographed (a) before treatment and (b) after treatment with topical d-a-tocopherol (5%) once daily for 4 months. Note the marked improvement with a decrease in her periorbital wrinkles (b)
4 Photoprotection of the Skin with Vitamins C and E: Antioxidants and Synergies 53