In a review of epidemiologic literature, McNaughton et al. found evidence of a weak protective effect of vitamin E in nonmelanoma carcinoma (BCC and SCC)[22]. Of the 12 studies examined, two identified an inverse relationship between intake and BCC risk while one demonstrated a positive relationship. Six found no relationship between plasma or intake of vitamin E and BCC risk. Four studies found no association between vitamin E and SCC. More recently, two studies in an Australian population reported no association between serum α-tocopherol and nonmelanoma carcinoma but a positive association between dietary supplements, and BCC [23,24]. However, in these two studies a single baseline serum measurement or dietary assessment was compared to cancer incidence during an eight year period. These unexpected findings may reflect the possible inability of a single measure of vitamin E to accurately reflect vitamin E status and a change in eating habit cannot be ruled out over the 8 year period. Furthermore, these studies analyzed the association between cancer, which is a long-term outcome, and short-term markers of vitamin E intake or status such as dietary assessment and serum concentration. Cancer may be closer related to skin concentrations which were not compared in any of these studies.

There are no epidemiological studies assessing the relationship between topically applied α-tocopherol and skin cancer.

Clinical trials suggest that dietary vitamin E may act as a photoprotectant with the aid of other antioxidants and topical vitamin E may provide protection as well, although reports have not been entirely consistent.

One study showed subjects treated with 400 IU/d α-tocopherol for eight weeks had reduced skin malondialdehyde (MDA) after UV exposure but this intervention provided no protection from erythema, the reddening of the skin commonly referred to as sunburn [14]. Wernignaus et al. [25] showed no photoprotective effect after 6 months of daily dietary supplementation of α-tocopherol acetate (400 IU) in 12 subjects of skin types II-IV. Both clinical measure of minimal erythema dose (MED), the minimum dose of UV necessary to induce erythema in a subject, and histologic measure of sunburn cells were compared. No difference was seen in skin α-tocopherol concentrations between treatment and placebo groups. Plasma α-tocopherol concentrations increased by 65% in the treatment group and 18% in the placebo group, so there was no question of bioavailability. Although a very modest increase in MED was observed in the treatment group after 6 months, the sample size of this study may have been too small to observe significant changes. It is possible that α-tocopherol will provide the most benefit in subjects with a limited range in skin types of increased risk for photodamage (very light to light). Additionally, repetitive UV doses lower than necessary to produce erythema are enough to cause local immunosuppression and skin carcinogenesis [15], suggesting that other markers of damage may be important such as DNA damage.

Other dietary studies have shown vitamin E as a photoprotectant when combined with other antioxidants. Fuchs et al. [26] reported no protection when vitamin C (3 g) and α-tocopherol (2 g or 3000 IU) were supplemented individually, but in combination these nutrients provided protection as assessed by increased MED after 50 days of daily supplementation. Eberlein-Konig et al. [27] also showed increased MED in subjects supplemented daily with a combination of vitamin C (2 g) and α-tocopherol (1000 IU) after only 8 days. A similar study showed increased MED in subjects supplemented daily with α-tocopherol (1200 IU) for 7 days, but when combined with vitamin C (2 g) a greater increase in MED was observed [28]. Placzek et al. [29] demonstrated a photoprotective effect after 3 months of daily dietary supplementation with vitamin C (1 g) and α-tocopherol (500 IU). Participants showed increased resistance to UVB-induced sunburn, as assessed by MED, and protection from DNA damage. This study provides evidence of long-term photoprotection of lower doses than had been previously tested.

Clinical trials suggest that vitamin E applied topically also provides photoprotection. Chung et al. demonstrated topical application of 5% vitamin E (24 hours prior to UV exposure) inhibited UV-induced MMP-12 mRNA by 47% [30]. Other groups have reached opposing conclusions on the protection that vitamin E can provide from erythema. One group demonstrated reduced erythema when vitamin E was applied prior to UV exposure but not after [31]. Another group found vitamin E application after UV exposure protective, but not pretreatment [32].

UVB irradiated mice fed α-tocopheryl acetate had less cancer incidence in a dose-dependent manner [33]. Dietary α-tocopherol esters are readily cleaved and free α-tocopherol is absorbed into the circulatory system. It should be noted that the doses used in this study were considered toxic given that more treated mice died compared to control mice. A more recent experiment tested an oral combination of vitamin C, vitamin E, pycnogenol (a pine bark extract rich in polyphenols and procyanidins), and evening primrose oil in mice [34]. The nutrient cocktail treatment significantly inhibited UVB-induced wrinkling and many associated events, including expressions of MMPs, MAPK and activation of activator protein (AP)-1 transcriptional factor. While these results support a role for nutrient effects in photoprotection, specific effects of vitamin E could not be determined.

Studies in mice treated topically with α-tocopherol provide strong evidence of photoprotection [18]. Mice treated topically with 25 mg α-tocopherol three times per week for three weeks before and during twelve weeks of UVB irradiation had significantly less incidence of skin cancer compared to untreated mice [35]. Four additional murine studies demonstrated photoprotection, assessed as skin tumor incidence, from topical α-tocopherol treatment [36,37,38,39]. A follow-up study using this same α-tocopherol treatment reduced induction of DNA damage by UVB [40]. Later studies by this group found acetate and succinate esterified forms of α-tocopherol applied in the same manner did not provide the same chemoprevention [41]. This difference may be due to the limited capacity to cleave acetate or succinate when applied topically. This limitation may compromise the antioxidant activity given that ester forms do not have a free hydroxyl group on the aromatic ring necessary for scavenging free radicals.

An additional 15 animal studies have consistently found topical pretreatment with vitamin E photoprotective using variety of outcome measures including erythema, lipid peroxidation, wrinkling and sunburn cell formation [42,43,44,45,46,47,48,49,50,51,52,53,54,55,56].

A human skin model has previously shown absorption of topical α-tocopherol -glucoside, α-tocopherol and α-tocopherol acetate into epidermal and dermal compartments [57]. α-Tocopherol was not included in this study. Pig skin biopsies have been cultured showing pretreatment with topical α-tocopherol reduced UVB-induced cytotoxicity, apoptosis and lipid peroxidation [20]. In cultured mouse skin, media pretreatment of 9 μM α-tocopherol-6-O-phosphate, a water-soluble form of α-tocopherol, reduced UVB-induced apoptosis and lipid peroxidation [58]. Media pretreatment of α-tocopherol in human melanocytes prevented UVA- and UVB-induced glutathione loss and diminished apoptosis [59].

Epidemiologic evidence suggests an association between flavonoid-rich foods and skin cancer incidence. A case-control study in an Italian population found a negative correlation between cutaneous melanoma and daily tea drinking, high consumption of vegetables, particularly carrots, cruciferous and leafy vegetables, and fruits, especially citrus [68]. In the “Food Habits in Later Life” study, tea consumption was negatively correlated with actinic skin damage in Anglo-Celtic Australians [69].

The acute and long-term photoprotective effects of consumption of a flavanol-rich cocoa beverage was studied in double-blind, placebo controlled clinical trials. Epicatechin and its stereoisomer catechin are the major flavanols found in this beverage, contributing 61 and 20 mg/serving, respectively to a total of 329 mg cocoa flavanols. Two hours after a single dose of the flavanol-rich cocoa, dermal blood flow and oxygen saturation of hemoglobin significantly increased by 1.7- and 1.8-fold, respectively [70]. Long-term, daily ingestion of the same flavanol-rich cocoa beverage decreased UV-induced erythema by 15% after only six weeks [71]. After twelve weeks, additional protection was evident as erythema was decreased by 25%. Blood flow of cutaneous and subcutaneous tissues, skin density and skin hydration were also increased while skin roughness and scaling were significantly decreased. None of these skin improvements was observed in the control group.

Green tea contains the flavanols catechin and epicatechin. An eight week clinical trial evaluating the clinical and histological effects of combined topical and oral green tea supplementation (300 mg twice daily) found improvements in elastic tissue content [72]. However no significant differences in clinical grading of appearance were found. All subjects were asked to apply sunscreen daily which may have attenuated differences between groups.

Immunosuppression was inhibited in participants after a single topical application of either green or white tea treatment (2.5 mg/cm²) as evaluated by hypersensitivity to dinitrochlorobenzene [73]. The same topical treatments prevented DNA damage. Another study found a single topical dose of green tea treatment (1–4 mg/2.5 cm²) protective of DNA damage, in a dose-dependent manner [74]. Long-term topical application of green tea treatment significantly reduced UV-induced p53 expression and apoptosis in keratinocytes, but not erythema [75].

Topical application of an extract of Culcitium reflexum H.B.K. leaves which contain isorhamnetin, quercetin and kaempferol significantly decreased erythema when applied after UVB irradiation [76].

Investigations of foods rich in flavanoid nutrients demonstrate their efficacy as photoprotectants against UV carcinogenesis in animal models. Grape seed proanthocyanidins are polymers of flavanol monomers such as catechin and epicatechin [74]. In SKH-1 hairless mice, dietary supplementation with these compounds resulted in a dose-dependent reduction in photocarcinogenesis. Green tea as well as black tea consumption also resulted in significantly fewer UV-induced tumors in mice [77]. The administration of green tea polyphenols in drinking water or the topical application of EGCG, a major tea flavanol, also induced partial regression or inhibition of tumor growth of established skin papillomas in mice [78]. Gensler et al. also investigated EGCG in BALB/cAnNHsd mice. They found induction of skin tumors by UV irradiation was significantly reduced by topical but not by oral treatment of EGCG [79]. Other research has focused on acute photoprotection of EGCG. In Wistar rats, topical EGCG treatment for 30 minutes prior to UVA irradiation significantly decreased sunburn cell occurrence and dermo-epidermal activation compared to untreated rats [80]. The same protection was not observed with topical EGCG application 30 minutes after UVA exposure. UVA-induced oxidative stress was significantly attenuated in Sprague-Dawley rats by intraperitoneal injections of quercetin prior to UV exposure [81]. Markers of oxidative stress included increased plasma malondialdehyde (a product of lipid peroxidation), decreased erythrocyte glutathione peroxidase and reductase activities, and decreased catalase and superoxide sidmutase activities. Topical quercetin treatment was found protective of UVB-induced oxidative stress in mouse skin as well [82].

Positive photoprotective results from the above animal studies lead researchers to investigate the mechanism of protection. Dietary supplementation of green tea polyphenols in mice, during 8 weeks of UVB irradiation, inhibited UV-induced expression of MMPs, including MMP-2, -3, -7, and -9 [83]. All of these MMPs have been shown to be involved in the degradation of types-I and -III collagen fragments generated by collagenases and type IV collagen of the basement membrane.

In human dermal fibroblasts, both quercetin and kaempferol inhibited MMP-1 (collagenase) activity and expression induced by UVA [34]. EGCG inhibited MMP-2 and -9 activity (gelatinases)[84]. Adult human skin fibroblasts and normal human epidermal keratinocytes, cultured separately, had significantly less DNA damage from UVA irradiation when treated with EGCG [85].

Ex vivo cultured human skin experiments demonstrated pretreatment with topical green and white tea (2 mg/cm²) provided protection from UV induced immunosuppression, measured by depletion of Langerhans cells [73]. Another ex vivo human skin experiment found topical cocoa polyphenol extract (containing catechin and epicatechin) improved skin structure after five days of application [86]. Glycosaminoglycans increased as well as collagen I, II and IV expression, indicating improved elasticity and skin tonus, respectively. In UVA exposed artificial skin models, composed of differentiated epidermis on a dermal substitute, pretreatment with topical EGCG decreased expression of MMP-1 and -3 and activity of MMP-2 and -9 [87]. Tissue inhibitor of metalloproteinase-1 (TIMP-1) expression increased simultaneously.

Epidemiological studies have provided some evidence that fruit and vegetable intake may improve skin health and decrease the risk of skin cancer. However, in most cases, the specific effect of an individual carotenoid was not evaluated. Nonetheless, they provide evidence to support a role for carotenoids, and other phytonutrients, in skin health.

In a cross-sectional study investigating the association between skin wrinkling and dietary intake, a significant negative association was found with eggs and green leafy vegetables [69]. Eggs are a highly bioavailable source or lutein [100] and green leafy vegetables are good sources of both β-carotene and lutein [89]. This relationship between carotenoids intake and skin wrinkling may be due to an ability to prevent extracellular matrix breakdown [101]. An association of green leafy vegetables with decreased risk of skin cancer has also been reported [102]. In this prospective study, a higher consumption of fruits and vegetables was related to decreased risk of SCC risk by 54%. This protective effect was mostly explained by the association with green leafy vegetables.

In an observational study of an Italian population, high intake (at least 3 times per week) of dark green leafy vegetables was associated with decreased risk of cutaneous melanoma after adjustment for sex, age, education, hair color, skin phototypes, number of nevi, presence of freckles and sunburns in childhood [68]. In another observational study which looked at BCC and SCC, a decreased risk of SCC in persons with a history of skin cancer and high dietary intake of lutein and zeaxanthin was reported [23]. Other studies show a mix of results including no association between serum lutein/zeaxanthin and BCC or SCC [24] and a positive association between serum lutein/zeaxanthin and risk of SCC in participants with a history of BCC [103]. Dietary lutein (combined with zeaxanthin) showed a slightly positive relationship with SCC and BCC incidence in women [104,105]. However, vitamins A, C, and E, folate and total carotenoids were also found to have a positive relationship. The mixed results of these studies could be due to limitations in dietary assessment or individual variability in the ability to accumulate certain phytonutrients in skin tissue.

β-Carotene is in the carotene class of carotenoids (Figure 3). It is a strongly-colored red-orange pigment. As a carotene with beta-rings at both ends, it is the most common form of carotene. It is a precursor of vitamin A. Rich sources of β-carotene include yellow and orange fruits, such as mangoes and papayas, orange root vegetables such as carrots and yams and in green leafy vegetables such as spinach, kale, sweet potato leaves, and sweet gourd leaves [89]. β-Carotene inhibits free radical and singlet oxygen-induced lipid peroxidation in liposomes and the biologic system. It is a photoprotective agent and is thought to quench photochemical reactions in the epidermis involving singlet oxygen and oxygen radicals generated by UV exposure [106].

Lycopene (Figure 4) is a carotene found in primarily in tomatoes but also in other red fruits and vegetables, such as red carrots, watermelons and papayas [89]. Unlike β-carotene, lycopene has no vitamin A activity [128]. Lycopene is considered to be the most the most efficient biological carotenoid singlet oxygen quencher [129]. A suggestion that lycopene may be protective in skin health comes from the work of Darvin et al. in which it was reported that there was a significant correlation between skin roughness and lycopene concentrations in the skin [130]. Topical application of lycopene contained in monoglyceride or triglyceride microemulsions was found to result in lycopene penetration in the stratum corneum (6- and 3.6-fold, respectively) and in viable layers of porcine ear skin (from undetected to 172.6 and 103.1 ng/cm², respectively) compared to a control solution. Furthermore, the antioxidant activity of skin treated with lycopene was found to be 10-fold higher than untreated skin [131].

Lutein is a member of the xanthophyll class of carotenoids (Figure 5). Carotenoids are a family of more than 600 lipid-soluble compounds that are plant pigments. All carotenoids have a backbone composed of conjugated double bonds which is essential for their antioxidant activity. Xanthophylls, the most polar of carotenoids, are unique to this family because of their functional hydroxyl groups.

Lutein is commonly found in fruits and vegetables. The richest source of lutein is leafy green vegetables but also can be found in significant amounts in broccoli, corn and peas [137,138]. Although levels are not high, lutein is also found in egg yolk, which is considered to be a highly bioavailable source of lutein [139]. There is no established Dietary Recommended Intake (DRI) for lutein, but 6 mg is associated with a reduced risk of cataracts and age-related macular degeneration [140,141,142]. Most Americans only get 1 to 2 mg/day [143,144,145,146].

Lutein has a well-established role in the eye health, acting as an antioxidant and absorbing blue light. Lutein also has an established presence in epidermal and dermal compartments of the skin and contributes to skin color [97].