Flavonoids and Skin Health

Summary

  • Due to first-pass metabolism in the digestive tract and liver, dietary flavonoids are extensively modified before reaching the skin. (More information)
  • Topical application of flavonoids is a successful way to achieve pharmacological levels of parent compounds in the skin; however, chemical composition of topical formulations greatly influences stability and bioavailability. (More information)
  • Green tea polyphenols exert photoprotective effects when obtained from both dietary and topical sources. (More information)
  • Animal and in vitro experiments suggest that topically applied genistein exerts photoprotective effects. (More information)
  • Some flavonoids may protect the skin by absorbing UVB and thus functioning as sunscreen. (More information)
  • Various flavonoids inhibit enzymes involved in the inflammatory response and may counteract UV-induced inflammation in the skin. (More information)
  • Flavonoids can influence endogenous defense mechanisms in the skin, potentially modulating the response to environmental agents, such as UVR and procarcinogens. (More information)
  • Flavonoids may influence wound healing and blood vessel health, but further research in humans is necessary before clinical efficacy can be determined. (More information)

Overview

Flavonoids are dietary factors that belong to the general class of compounds known as phytochemicals, or plant chemicals. More than 5,000 varieties of flavonoids have been identified, and hundreds of flavonoids can exist in a single food item (1). Flavonoids consist of a basic polyphenolic ring structure (see Figure 1 in the article on Flavonoids) with different side chains attached, thus imparting different properties to the compound (see Table 1 in the article on Flavonoids). Although often touted for their antioxidant properties, the ability of flavonoids to absorb ultraviolet (UV) light and modulate signaling pathways that influence cellular function appears to underlie their beneficial effects in skin health.

Content and availability

Dietary flavonoids are subjected to first-pass metabolism by the gastrointestinal tract and liver, which results in extensive modification of the ingested compound (see the article on Flavonoids) (2, 3). The biological actions of flavonoid metabolites likely differ from the parent compound; thus, the flavonoid that reaches the skin may have different effects when obtained from ingested versus topical sources (see Topical application).

Human epidermal keratinocytes express specific members of the organic anion transporting polypeptides (OATP) family, transporters responsible for the uptake of a variety of xenobiotics, drugs, and large amphipathic molecules (4). It is postulated that flavonoids enter epidermal cells via this route. Once inside the cell, flavonoids can bind catalytic ATP-binding sites on a diversity of proteins, thus exerting influence on a wide range of cellular processes (5, 6). For example, genistein and quercetin are known to inhibit tyrosine kinase and PI3 kinase, respectively (6). Specific interactions between certain flavonoids and cellular proteins also occur. Soy isoflavones for example bind to estrogen receptor-β (ER-β), the ER isoform expressed in skin cells and the cardiovascular system (7, 8).

Topical application

Topically applied flavonoids are not subjected to first-pass metabolism. Pharmacological doses can be achieved with topical delivery, although solubility, stability, and permeation issues are all concerns. Some specific flavonoid formulations have been evaluated in in vitro experiments for their ability to permeate excised human skin samples. Penetration enhancers reversibly modify skin barrier properties in order to influence the diffusion of topical agents through the skin. When dissolved in acetone, the flavanones naringenin and hesperitin successfully permeated excised human skin and pretreatment with penetration enhancers (D-limonene and lecithin) increased their permeation (9). The flavonol quercetin, on the other hand, had very low skin permeation under all experimental conditions. In a small sampling of human volunteers (six men and women, aged 25 to 35 years old), Saija et. al. (9) confirmed that topical application of naringenin and hesperitin in the presence of penetration enhancers protected against UVB-induced erythema.

The absorption and permeability of epigallocatechin-3-gallate (EGCG) in a hydrophilic ointment was tested in excised human skin (10). Firstly, EGCG in hydrophilic ointment was highly unstable unless stored at low temperature or supplemented with the antioxidant BHT. Secondly, EGCG in hydrophilic ointment successfully permeated, but did not exit, the human dermis, suggesting minimal accessibility to the systemic circulation. Another in vitro study used excised human skin to evaluate the penetration of EGCG and quercetin from a cosmetic formulation (11). After 24 hours, topical EGCG was retained in the stratum corneum, epidermis, and dermis but did not leave the skin sample; quercetin accumulated in the epidermis and stratum corneum but was not detected in the dermis.

Several additional in vitro experiments have evaluated the solubility and permeability of flavonoids from a variety of formulations (12-15). Although there is potential for flavonoids as topical photoprotective agents, suitable delivery vehicle, chemical additives, and pH significantly influence the permeation of bioactive product. The efficacy of various topical formulations requires further testing in humans.

Deficiency

Flavonoids are not considered essential nutrients; therefore, there are no established dietary reference intakes (DRIs) or clinical markers of deficiency. The potential health benefits of consuming a flavonoid-rich diet are discussed more extensively in the article on Flavonoids.

Functions in Healthy Skin

Photoprotection

Exposure to UV-radiation (UVR) has many negative effects on skin, including erythema, edema, sunburned cells, hyperplasia, inflammation, immunosuppression, photoaging, and photocarcinogenesis (16). Studies performed in cell culture, animals, and humans demonstrate that treatment with certain flavonoids can minimize adverse skin reactions caused by UVR.

Green tea polyphenols

Heinrich et.al. (17) conducted a 12-week, placebo-controlled trial in 60 healthy women (40-65 years of age) to evaluate the effect of dietary green tea polyphenol consumption on skin photoprotection, structure, and function. Subjects consumed 1L of beverage throughout the day, containing 1,402 mg of green tea catechins or inert ingredients matched for additives and flavor. Erythema formation in response to 1.25X MED, skin elasticity and structure (roughness, scaling, volume, and wrinkles), transepidermal water loss (TEWL), cutaneous blood flow, and serum flavonoid concentration were measured at 0, 6, and 12 weeks of treatment. Serum levels of the green tea polyphenols EGCG, ECG, and epicatechin significantly increased in the treatment group at both six and 12 weeks of intake. Additionally, all skin variables measured were significantly improved in those consuming green tea beverage compared to placebo at both time points (17).

Recognizing the challenges of consuming 1L of beverage over the course of a day, Heinrich et.al. performed a small dosing study to assess the effects of green tea extract ingested in capsule form (17). Fifteen healthy women received placebo or 0.5, 1, or 2 g of encapsulated green tea extract. Serum flavonoid content and capillary blood flow to the dermis were measured over the course of four hours in order to assess the short-term effects of a single dose of encapsulated green tea extract. Dermal microcirculation was measured since increased cutaneous blood flow may contribute to enhanced delivery of oxygen and nutrients to the skin, a proposed impact of flavonoids on skin health.

There was an equivalent quick and brief increase in dermal microcirculation (15-30 minutes) at all doses of green tea extract ingested compared to placebo. Serum epicatechin levels increased in a dose-dependent manner, with a maximum concentration two hours post-ingestion.

Ingestion of high-flavanol cocoa powder, rich in epicatechin and catechin, for 12 weeks also improved photoprotection and skin structure in healthy female subjects (18). In this double-blind intervention, 24 female volunteers (18-25 years of age) were randomly assigned to ingest a high (326 mg) or low (27 mg) flavanol-containing cocoa beverage daily for 12 weeks. As with green tea beverage, high-flavanol cocoa powder diminished UV-induced erythema formation, increased microcirculation, improved skin structure (as roughness, scaling, volume, and wrinkles), and reduced TEWL; none of these parameters changed in the low-flavanol group. Additionally, a single dose of high-flavanol (329 mg) cocoa beverage quickly and transiently increased plasma epicatechin levels and dermal microcirculation compared to low-flavanol cocoa beverage (19). The effects of catechins on skin structure, texture, and water homeostasis may be due to their ability to increase cutaneous blood flow (17-19). Vasodilatory mechanisms, which have also been shown for coca polyphenols in non-skin vessels, may underlie the vascular benefits associated with flavanols (20, 21). For more information on chocolate and cardiovascular health, see the article in the Spring/Summer 2012 LPI Research Newsletter.

Katiyar et al. studied the effects of topically applied green tea extract on several UV-mediated skin responses in humans (22-24). In each study, four to six volunteers (both male and female, aged 25 to 55 years old) received a topical application of purified green tea extract (1 mg/cm2 dissolved in acetone to a sun-protected skin) containing a mixture of the four major polyphenols in green tea: epigallocatechin-3-gallate (EGCG), epicatechin (EC), epigallocatechin (EGC), and epicatechin-3-gallate (ECG). Twenty or 30 minutes after topical application, skin sites were exposed to UVB (4X MED). Twenty-four or 48 hours later, punch biopsies (i.e., both epidermis and dermis) were collected and various endpoints measured. In each case, pretreatment with purified green tea polyphenols inhibited UV-induced inflammation (23), DNA damage (24), and formation of reactive oxygen species (ROS) (22) compared to vehicle-treated sites on the same individual.

In a similar study design, Elmets et. al. (25) also observed a protective effect of topically applied purified green tea extract on UV-induced photodamage, assessed as erythema formation, presence of sunburn cells, DNA damage, and number of Langerhans cells, a marker of immunosuppression. A 5% solution that contained a mixture of the four major green tea polyphenols (0.5 g of purified extract dissolved in ethanol/water) was the most effective at minimizing UV-damage compared to vehicle-treated sites in the same subjects. EGCG and ECG were also protective, although to a lesser extent than the mixed extract.

Camouse et. al. (26) performed a double-blind treatment in ten volunteers to compare topical green tea and white tea extracts as photoprotective agents. Pretreatment with either tea extract (2.5 mg/cm2 in organic solvent) protected against depletion of Langherhans cells and oxidative DNA damage caused by UVB exposure (2X MED) compared to vehicle-treated sites on the same individual.

UV damages DNA by causing strand breaks or creating cyclobutane pyrimidine dimers (CPDs), a photoproduct formed when energy derived from UVR is absorbed by DNA, forming an unwanted covalent bond between pyrimidine bases. A cell can either repair the damage or sacrifice itself (apoptosis) as a way to protect the organism from mutations and malignant transformation. The mechanism by which green tea polyphenols combat UV-induced cellular damage appears to be due primarily to their induction of DNA repair pathways in the skin (24, 25, 27) and influence on certain immune mediators known as cytokines (23, 28-31). Because DNA damage initiates immunosuppression, a risk factor for skin carcinogenesis, green tea polyphenols appear to function early in the UV-damage response in the skin.

Genistein

The photoprotective effect of genistein has been investigated in animals and in in vitro models of human skin. Pretreatment with topical genistein (5 µM, 60 minutes prior to UV exposure) reduced skin roughness and wrinkling and epidermal hyperproliferation in hairless mice that were exposed to daily doses of acute and chronic UVB irradiation (32). As observed with EGCG, the photoprotective effects of genistein may result from its impact on UV-induced DNA damage as topical genistein decreased CPD formation and restored proliferating cell nuclear antigen (PCNA) expression, a marker of proliferation and DNA repair (32). The authors performed a small study in six men to extend their observations to humans: topical genistein (5 μM/cm2) applied 30 minutes before UVB exposure (1X MED) blocked erythema formation as evaluated photographically 24 hours after treatment (32). Moreover, pretreatment with topical genistein dose-dependently reduced CPD formation and increased PCNA expression in human reconstituted skin samples (33).

Other flavonoids

Silymarin is a special type of flavonoid classified as a flavonolignan, part flavonoid and part lignan. Silymarin is present in the seeds of milk thistle (Silybum marianum), and its major bioactive flavonoid is called silibinin. Like green tea polyphenols, topical silymarin minimizes UV-induced photodamage and photocarcinogenesis in animal studies (34). Experiments using primary cultures of normal human epidermal keratinocytes (NHEKs) and transgenic mice indicate that topical silymarin inhibits UV-induced apoptosis and reduces CPD formation in the skin (35). By using cells and animals deficient in nucleotide excision repair, the authors further demonstrated that topical silymarin contributes to photoprotection by upregulating DNA repair processes.

Sunscreen effect

Topical application of certain flavonoids may protect skin by absorbing UVR before it can interact with and damage cellular components, thereby providing a sunscreen effect. Major epidermal chromophores (molecules that absorb UV light) include melanin, urocanic acid, amino acids, and nucleic acids (36). Likewise, topically applied flavonoids may protect skin by absorbing UV light and blocking UV penetration. Pycnogenol® (a registered mixture of naturally occurring mono- and oligomeric procyanidins) and honeybush extract (containing the flavanone hesperidin and xanthone magniferin) absorb light in the UVB range (37, 38). Thus, topical application of these flavonoids would function as sunscreens when applied prior to UV exposure.

Prevention versus suppression

The timing of flavonoid administration dictates if the intervention is being used as a preventive or treatment strategy. The majority of information reports on flavonoid administration prior to UV exposure, as a means to prevent UV-induced photodamage. However, flavonoid administration following UV exposure has been evaluated for several flavonoids. Genistein or EGCG dissolved in acetone was applied to hairless mouse skin one or four hours post-irradiation (2X MED), and 24 hours later, epidermal sections were collected and analyzed (39). Both flavonoids decreased the number of sunburn cells, epidermal hyperplasia, and immune suppression even when applied subsequent to UV exposure. Widyarini et al. applied isoflavone extracts (20 μM) from red clover (Trifolium pretense) to the skin of hairless mice immediately following UV exposure in order to evaluate their ability to protect against acute effects induced by UVR (40). Genistein and the isoflavone metabolites equol, isoequol, and dehydroequol significantly reduced inflammation, edema, and immunosuppression caused by UV exposure. In a randomized, double-blind, placebo-controlled trial, Casetti et. al. (41) compared a luteolin-rich Reseda extract (RE) to hydrocortisone, a standard anti-inflammatory agent, for its efficacy following UV exposure. Forty healthy volunteers (both sexes, 18 years of age and older) were exposed to UVB (1.5X MED) followed by immediate application of a topical nanoparticle formulation of RE (2.5%), hydrocortisone (0.1%), or vehicle (glycerol). Compared to vehicle, both RE and hydrocortisone significantly reduced UVB-induced erythema to a similar extent (41).

The benefit of suppressing the sunburn response in order to minimize skin damage is a subject of debate. Preventing sun damage in the first place is advised as primary protection against the damaging effects of UVR.

Photoaging

Green tea polyphenols

The long-term influence of oral supplementation with green tea polyphenols on clinical and histological signs of photoaging was evaluated in a two-year, double-blind, placebo-controlled trial (42). Fifty-six healthy female volunteers (aged 25-75 years old) received either 250 mg green tea polyphenols or placebo twice daily for two years. Photodamaged facial skin appearance and histology were evaluated by a dermatologist at 0, 6, 12, and 24 months for wrinkling, hyperpigmentation, depigmentation, lentigines (liver spots), pore size, roughness, erythema, telangiectasias (permanent dilation of superficial blood vessels), and overall solar damage. Although some skin parameters were improved in green tea over placebo at 12 months, no significant differences were observed between the groups after 24 months of treatment, with both groups showing improvements in overall solar damage and elastosis (abnormal accumulation of elastin) (42).

A small double-blind, placebo-controlled pilot study evaluated the impact of combined oral and topical treatment with green tea extract on skin appearance and histology in female subjects with moderate photoaging (43). Forty healthy women were randomly assigned to green tea treatment (10% green tea extract cream applied to the face and arms plus 300 mg green tea in an oral supplement) or placebo cream and supplement, both received twice daily for eight weeks. Self-reported grading of wrinkles and roughness were the same in placebo and treatment groups, while several patients in the green tea group complained of irritation, drying, and sun sensitivity at the site of application. Physician assessment of skin appearance found no significant differences between treatment and placebo groups. Histological examination revealed an improvement only in elastic tissue content in the green tea group compared to placebo (43).

Genistein. Because estrogen has a significant effect on skin aging (7), the isoflavone genistein has been investigated for its potential to counteract signs of photoaging in postmenopausal women. In a pilot study, 30 postmenopausal women who ingested a concentrated soy-extract (100 mg daily for six months) showed a significant increase in skin thickness, elastic fiber content, collagen fiber content, and vasculature in a gluteal skin biopsy after six months of treatment compared to baseline (44). Moraes et. al. performed a randomized, double-blind estrogen-controlled trial to evaluate the effect of topical isoflavones on morphological parameters in postmenopausal facial skin (45). Forty subjects applied either estrogen (0.01% 17-β-estradiol) or isoflavone (4% genistein) gel to their facial skin daily for 24 weeks. Topical estrogen significantly improved all parameters measured compared to baseline and to isoflavone treatment. Isoflavones significantly improved epidermal thickness and blood vessel number after 24 weeks of treatment, though to a lesser extent than that of estrogen treatment.

Xenobiotic metabolism

Skin is both a physical and biochemical barrier (46). Inactivation of potentially harmful compounds via xenobiotic metabolism in the skin serves as a second line of defense against substances that penetrate the skin surface (46-48). Xenobiotic metabolism involves a series of enzymatic reactions that convert a foreign chemical compound into an inert substance that can be safely excreted from the body (49, 50). In phase I, also referred to as activation, oxygen is used to form a reactive site on the xenobiotic compound; members of the cytochrome P450 (CYP) family of enzymes participate in phase I metabolism. Phase II, or conjugation, involves the addition of a water-soluble functional group to the reactive site of the phase I metabolite. And finally, in phase III, the solubilized compound is expelled from the cell.

Monoinduction of phase I enzymes without the concomitant induction of phase II enzymes can lead to the production of “activated” compounds that may cause cellular damage. Epidermal CYP 1A1 and 1B1 are induced in response to UVB exposure in a time- and dose-dependent manner (51). CYP 1A1 and 1B1 activate numerous compounds from exogenous substrates, including polycyclic aromatic hydrocarbons (PAH) a well-known class of procarcinogens (52). Thus, through its induction of phase I enzymes, UVB could enhance the activation of environmental pollutants, further increasing the mutagenic load in the epidermis (53). Flavonoid modulation of enzymes involved in xenobiotic metabolism may thus represent another mechanism for counteracting UV-induced photodamage.

Different flavonoids have variable effects on xenobiotic metabolism in the skin by targeting phase I or phase II components of the cellular detoxification pathway. The flavonols myricetin and quercetin can inhibit aryl hydrocarbon hydrolase (a phase I enzyme) activity when applied topically to mouse skin, potentially preventing the metabolic activation of procarcinogens (54) and the formation of DNA adducts (55). On the other hand, flavonoids that induce phase II enzymes could facilitate the inactivation of CYP-generated metabolites. Oral administration of silibinin, the active component of silymarin, for 15 days significantly induced phase II enzyme activity (glutathione S-transferase and quinone reductase) in mouse skin compared to vehicle-treated control mice (56).

Wound healing

Onion extract, rich in the flavonoids quercetin and kaempferol, has been used to reduce scar formation, particularly keloid scars. Cho et. al. (57) demonstrated that onion extract and quercetin induce matrix metalloproteinase-1 (MMP-1) expression in cultured human skin fibroblasts and hairless mouse skin. MMPs are enzymes secreted by epidermal keratinocytes and dermal fibroblasts in response to various stimuli, including UVR, oxidative stress, and inflammatory cytokines. UVR induces three MMPs: MMP-1 (collagenase), MMP-3, (stomelysin), and MMP-9 (gelatinase) that cleave and degrade skin collagen and contribute to photoaging (58). In the case of wound healing, a balance between MMP-1 and tissue inhibitor matrix metalloproteinase-1 (TIMP-1) enzymatic activity affects the amount of extracellular matrix (including collagen) formed at the wound site. Thus, quercetin may influence extracellular matrix deposition during wound healing in order to reduce hypertrophic scarring.

Other functions

Blood vessel health

Flavonoids, especially rutin and its derivatives, can benefit skin by influencing blood vessel permeability and fragility (5). Their protective effect on blood vessels may reduce the formation of telengiactasias (small dilated blood vessels near the surface of the skin) and petechiae (small red spots caused by broken capillaries or blood vessels). It appears that flavonoid binding of metals leads to inhibition of enzymes involved in blood clotting and inflammation, which in turn influence capillary permeability and platelet aggregation (5). However, clinical experimentation is lacking and more human studies are needed to conclusively establish a role for specific flavonoids on blood vessel health.

Conclusion

The majority of information on flavonoids and skin health relates to photoprotective effects of green tea polyphenols, catechins, and genistein. Both oral supplementation and topical administration of the flavanol subclass in particular have demonstrated photoprotective effects in humans. Experimentation with topically applied flavonoids typically test purified compounds or concentrated plant extracts dissolved in organic solvent; although they show promise as photoprotective agents, delivery is an issue that can influence how commercially available formulations penetrate and function in human skin. Flavonoids exert a wide range of influence due to their specific and nonspecific affinity for a diversity of proteins throughout the cell. The precise mechanisms by which flavonoids protect skin from the damaging effects of UVR are still being investigated, but there is evidence that flavonoids physically block UV penetration, influence DNA repair, reduce oxidative damage, attenuate the inflammatory response, preserve immune function, and induce cytoprotective pathways.


Authors and Reviewers

Written in June 2012 by:
Giana Angelo, Ph.D.
Linus Pauling Institute
Oregon State University

Reviewed in June 2012 by:
Wilhelm Stahl, Ph.D.
Institute of Biochemistry and Molecular Biology I
Heinrich-Heine-University Düsseldorf
Düsseldorf, Germany

This article was underwritten, in part, by a grant from Neutrogena Corporation, Los Angeles, California.

Copyright 2012-2015   Linus Pauling Institute


References

1.  Nijveldt RJ, van Nood E, van Hoorn DE, Boelens PG, van Norren K, van Leeuwen PA. Flavonoids: a review of probable mechanisms of action and potential applications. Am J Clin Nutr. 2001;74(4):418-425.  (PubMed)

2.  Kroon PA, Clifford MN, Crozier A, et al. How should we assess the effects of exposure to dietary polyphenols in vitro? Am J Clin Nutr. 2004;80(1):15-21.  (PubMed)

3.  Richelle M, Sabatier M, Steiling H, Williamson G. Skin bioavailability of dietary vitamin E, carotenoids, polyphenols, vitamin C, zinc and selenium. Br J Nutr. 2006;96(2):227-238.  (PubMed)

4.  Schiffer R, Neis M, Holler D, et al. Active influx transport is mediated by members of the organic anion transporting polypeptide family in human epidermal keratinocytes. J Invest Dermatol. 2003;120(2):285-291.  (PubMed)

5.  Arct J, Pytkowska K. Flavonoids as components of biologically active cosmeceuticals. Clin Dermatol. 2008;26(4):347-357.  (PubMed)

6.  Williams RJ, Spencer JP, Rice-Evans C. Flavonoids: antioxidants or signalling molecules? Free Radic Biol Med. 2004;36(7):838-849.  (PubMed)

7.  Jackson RL, Greiwe JS, Schwen RJ. Ageing skin: oestrogen receptor beta agonists offer an approach to change the outcome. Exp Dermatol. 2011;20(11):879-882.  (PubMed)

8.  Pelletier G, Ren L. Localization of sex steroid receptors in human skin. Histol Histopathol. 2004;19(2):629-636.  (PubMed)

9.  Saija A, Tomaino A, Trombetta D, Giacchi M, De Pasquale A, Bonina F. Influence of different penetration enhancers on in vitro skin permeation and in vivo photoprotective effect of flavonoids. Int J Pharm. 1998;175(1):85-94.

10.  Dvorakova K, Dorr RT, Valcic S, Timmermann B, Alberts DS. Pharmacokinetics of the green tea derivative, EGCG, by the topical route of administration in mouse and human skin. Cancer Chemother Pharmacol. 1999;43(4):331-335.  (PubMed)

11.  dal Belo SE, Gaspar LR, Maia Campos PM, Marty JP. Skin penetration of epigallocatechin-3-gallate and quercetin from green tea and Ginkgo biloba extracts vehiculated in cosmetic formulations. Skin Pharmacol Physiol. 2009;22(6):299-304.  (PubMed)

12.  Arct J, Oborska A, Mojski M, Binkowska A, Swidzikowska B. Common cosmetic hydrophilic ingredients as penetration modifiers of flavonoids. Int J Cosmet Sci. 2002;24(6):357-366.  (PubMed)

13.  Kitagawa S, Tanaka Y, Tanaka M, Endo K, Yoshii A. Enhanced skin delivery of quercetin by microemulsion. J Pharm Pharmacol. 2009;61(7):855-860.  (PubMed)

14.  Vicentini FT, Simi TR, Del Ciampo JO, et al. Quercetin in w/o microemulsion: in vitro and in vivo skin penetration and efficacy against UVB-induced skin damages evaluated in vivo. Eur J Pharm Biopharm. 2008;69(3):948-957.  (PubMed)

15.  Al Shaal L, Shegokar R, Muller RH. Production and characterization of antioxidant apigenin nanocrystals as a novel UV skin protective formulation. Int J Pharm. 2011;420(1):133-140.  (PubMed)

16.  Afaq F, Mukhtar H. Botanical antioxidants in the prevention of photocarcinogenesis and photoaging. Exp Dermatol. 2006;15(9):678-684.  (PubMed)

17.  Heinrich U, Moore CE, De Spirt S, Tronnier H, Stahl W. Green tea polyphenols provide photoprotection, increase microcirculation, and modulate skin properties of women. J Nutr. 2011;141(6):1202-1208.  (PubMed)

18.  Heinrich U, Neukam K, Tronnier H, Sies H, Stahl W. Long-term ingestion of high flavanol cocoa provides photoprotection against UV-induced erythema and improves skin condition in women. J Nutr. 2006;136(6):1565-1569.  (PubMed)

19.  Neukam K, Stahl W, Tronnier H, Sies H, Heinrich U. Consumption of flavanol-rich cocoa acutely increases microcirculation in human skin. Eur J Nutr. 2007;46(1):53-56.  (PubMed)

20.  Schroeter H, Heiss C, Balzer J, et al. (-)-Epicatechin mediates beneficial effects of flavanol-rich cocoa on vascular function in humans. Proc Natl Acad Sci U S A. 2006;103(4):1024-1029.  (PubMed)

21.  Katz DL, Doughty K, Ali A. Cocoa and chocolate in human health and disease. Antioxid Redox Signal. 2011;15(10):2779-2811.  (PubMed)

22.  Katiyar SK, Afaq F, Perez A, Mukhtar H. Green tea polyphenol (-)-epigallocatechin-3-gallate treatment of human skin inhibits ultraviolet radiation-induced oxidative stress. Carcinogenesis. 2001;22(2):287-294.  (PubMed)

23.  Katiyar SK, Matsui MS, Elmets CA, Mukhtar H. Polyphenolic antioxidant (-)-epigallocatechin-3-gallate from green tea reduces UVB-induced inflammatory responses and infiltration of leukocytes in human skin. Photochem Photobiol. 1999;69(2):148-153.  (PubMed)

24.  Katiyar SK, Perez A, Mukhtar H. Green tea polyphenol treatment to human skin prevents formation of ultraviolet light B-induced pyrimidine dimers in DNA. Clin Cancer Res. 2000;6(10):3864-3869.  (PubMed)

25.  Elmets CA, Singh D, Tubesing K, Matsui M, Katiyar S, Mukhtar H. Cutaneous photoprotection from ultraviolet injury by green tea polyphenols. J Am Acad Dermatol. 2001;44(3):425-432.  (PubMed)

26.  Camouse MM, Domingo DS, Swain FR, et al. Topical application of green and white tea extracts provides protection from solar-simulated ultraviolet light in human skin. Exp Dermatol. 2009;18(6):522-526.  (PubMed)

27.  Vayalil PK, Elmets CA, Katiyar SK. Treatment of green tea polyphenols in hydrophilic cream prevents UVB-induced oxidation of lipids and proteins, depletion of antioxidant enzymes and phosphorylation of MAPK proteins in SKH-1 hairless mouse skin. Carcinogenesis. 2003;24(5):927-936.  (PubMed)

28.  Meeran SM, Akhtar S, Katiyar SK. Inhibition of UVB-induced skin tumor development by drinking green tea polyphenols is mediated through DNA repair and subsequent inhibition of inflammation. J Invest Dermatol. 2009;129(5):1258-1270.  (PubMed)

29.  Meeran SM, Mantena SK, Elmets CA, Katiyar SK. (-)-Epigallocatechin-3-gallate prevents photocarcinogenesis in mice through interleukin-12-dependent DNA repair. Cancer Res. 2006;66(10):5512-5520.  (PubMed)

30.  Meeran SM, Mantena SK, Katiyar SK. Prevention of ultraviolet radiation-induced immunosuppression by (-)-epigallocatechin-3-gallate in mice is mediated through interleukin 12-dependent DNA repair. Clin Cancer Res. 2006;12(7 Pt 1):2272-2280.  (PubMed)

31.  Schwarz A, Maeda A, Gan D, Mammone T, Matsui MS, Schwarz T. Green tea phenol extracts reduce UVB-induced DNA damage in human cells via interleukin-12. Photochem Photobiol. 2008;84(2):350-355.  (PubMed)

32.  Wei H, Saladi R, Lu Y, et al. Isoflavone genistein: photoprotection and clinical implications in dermatology. J Nutr. 2003;133(11 Suppl 1):3811S-3819S.  (PubMed)

33.  Moore JO, Wang Y, Stebbins WG, et al. Photoprotective effect of isoflavone genistein on ultraviolet B-induced pyrimidine dimer formation and PCNA expression in human reconstituted skin and its implications in dermatology and prevention of cutaneous carcinogenesis. Carcinogenesis. 2006;27(8):1627-1635.  (PubMed)

34.  Katiyar SK, Korman NJ, Mukhtar H, Agarwal R. Protective effects of silymarin against photocarcinogenesis in a mouse skin model. J Natl Cancer Inst. 1997;89(8):556-566.  (PubMed)

35.  Katiyar SK, Mantena SK, Meeran SM. Silymarin protects epidermal keratinocytes from ultraviolet radiation-induced apoptosis and DNA damage by nucleotide excision repair mechanism. PLoS One. 2011;6(6):e21410.  (PubMed)

36.  Hruza LL, Pentland AP. Mechanisms of UV-induced inflammation. J Invest Dermatol. 1993;100(1):35S-41S.  (PubMed)

37.  Petrova A, Davids LM, Rautenbach F, Marnewick JL. Photoprotection by honeybush extracts, hesperidin and mangiferin against UVB-induced skin damage in SKH-1 mice. J Photochem Photobiol B. 2011;103(2):126-139.  (PubMed)

38.  Sime S, Reeve VE. Protection from inflammation, immunosuppression and carcinogenesis induced by UV radiation in mice by topical Pycnogenol. Photochem Photobiol. 2004;79(2):193-198.  (PubMed)

39.  Brand RM, Jendrzejewski JL. Topical treatment with (-)-epigallocatechin-3-gallate and genistein after a single UV exposure can reduce skin damage. J Dermatol Sci. 2008;50(1):69-72.  (PubMed)

40.  Widyarini S, Spinks N, Husband AJ, Reeve VE. Isoflavonoid compounds from red clover (Trifolium pratense) protect from inflammation and immune suppression induced by UV radiation. Photochem Photobiol. 2001;74(3):465-470.  (PubMed)

41.  Casetti F, Jung W, Wolfle U, et al. Topical application of solubilized Reseda luteola extract reduces ultraviolet B-induced inflammation in vivo. J Photochem Photobiol B. 2009;96(3):260-265.  (PubMed)

42.  Janjua R, Munoz C, Gorell E, et al. A two-year, double-blind, randomized placebo-controlled trial of oral green tea polyphenols on the long-term clinical and histologic appearance of photoaging skin. Dermatol Surg. 2009;35(7):1057-1065.  (PubMed)

43.  Chiu AE, Chan JL, Kern DG, Kohler S, Rehmus WE, Kimball AB. Double-blinded, placebo-controlled trial of green tea extracts in the clinical and histologic appearance of photoaging skin. Dermatol Surg. 2005;31(7 Pt 2):855-860; discussion 860.  (PubMed)

44.  Accorsi-Neto A, Haidar M, Simoes R, Simoes M, Soares-Jr J, Baracat E. Effects of isoflavones on the skin of postmenopausal women: a pilot study. Clinics (Sao Paulo). 2009;64(6):505-510.  (PubMed)

45.  Moraes AB, Haidar MA, Soares Junior JM, Simoes MJ, Baracat EC, Patriarca MT. The effects of topical isoflavones on postmenopausal skin: double-blind and randomized clinical trial of efficacy. Eur J Obstet Gynecol Reprod Biol. 2009;146(2):188-192.  (PubMed)

46.  Baron JM, Wiederholt T, Heise R, Merk HF, Bickers DR. Expression and function of cytochrome p450-dependent enzymes in human skin cells. Curr Med Chem. 2008;15(22):2258-2264.  (PubMed)

47.  Ahmad N, Mukhtar H. Cytochrome p450: a target for drug development for skin diseases. J Invest Dermatol. 2004;123(3):417-425.  (PubMed)

48.  Baron JM, Holler D, Schiffer R, et al. Expression of multiple cytochrome p450 enzymes and multidrug resistance-associated transport proteins in human skin keratinocytes. J Invest Dermatol. 2001;116(4):541-548.  (PubMed)

49.  Dinkova-Kostova AT, Talalay P. Direct and indirect antioxidant properties of inducers of cytoprotective proteins. Mol Nutr Food Res. 2008;52(Suppl 1):S128-S138.  (PubMed)

50.  Liska DJ. The detoxification enzyme systems. Altern Med Rev. 1998;3(3):187-198.  (PubMed)

51.  Katiyar SK, Matsui MS, Mukhtar H. Ultraviolet-B exposure of human skin induces cytochromes P450 1A1 and 1B1. J Invest Dermatol. 2000;114(2):328-33.  (PubMed)

52.  Afaq F, Mukhtar H. Effects of solar radiation on cutaneous detoxification pathways. J Photochem Photobiol B. 2001;63(1-3):61-69.  (PubMed)

53.  Villard PH, Sampol E, Elkaim JL, et al. Increase of CYP1B1 transcription in human keratinocytes and HaCaT cells after UV-B exposure. Toxicol Appl Pharmacol. 2002;178(3):137-143.  (PubMed)

54.  Das M, Mukhtar H, Bik DP, Bickers DR. Inhibition of epidermal xenobiotic metabolism in SENCAR mice by naturally occurring plant phenols. Cancer Res. 1987;47(3):760-766.  (PubMed)

55.  Das M, Khan WA, Asokan P, Bickers DR, Mukhtar H. Inhibition of polycyclic aromatic hydrocarbon-DNA adduct formation in epidermis and lungs of SENCAR mice by naturally occurring plant phenols. Cancer Res. 1987;47(3):767-773.  (PubMed)

56.  Zhao J, Agarwal R. Tissue distribution of silibinin, the major active constituent of silymarin, in mice and its association with enhancement of phase II enzymes: implications in cancer chemoprevention. Carcinogenesis. 1999;20(11):2101-2108.  (PubMed)

57.  Cho JW, Cho SY, Lee SR, Lee KS. Onion extract and quercetin induce matrix metalloproteinase-1 in vitro and in vivo. Int J Mol Med. 2010;25(3):347-352.  (PubMed)

58.  Fisher GJ, Kang S, Varani J, et al. Mechanisms of photoaging and chronological skin aging. Arch Dermatol. 2002;138(11):1462-1470.  (PubMed)