Arch Dermatol Res (2010) 302:71–83

DOI 10.1007/s00403-009-1001-3

MINI REVIEW

Skin photoprotection by natural polyphenols: anti-inflammatory,

antioxidant and DNA repair mechanisms
Joi A. Nichols • Santosh K. Katiyar

Received: 6 August 2009 / Revised: 15 October 2009 / Accepted: 21 October 2009 / Published online: 7 November 2009
Ó Springer-Verlag 2009

Abstract Epidemiological, clinical and laboratory stud- inflammation, oxidative stress and DNA damage, etc., with
ies have implicated solar ultraviolet (UV) radiation in a focus on mechanisms underlying the photoprotective
various skin diseases including, premature aging of the skin effects of these polyphenols. The laboratory studies con-
and melanoma and non-melanoma skin cancers. Chronic ducted in animal models suggest that these polyphenols
UV radiation exposure-induced skin diseases or skin have the ability to protect the skin from the adverse effects
disorders are caused by the excessive induction of of UV radiation, including the risk of skin cancers. It is
inflammation, oxidative stress and DNA damage, etc. The suggested that polyphenols may favorably supplement
use of chemopreventive agents, such as plant polyphenols, sunscreens protection, and may be useful for skin diseases
to inhibit these events in UV-exposed skin is gaining associated with solar UV radiation-induced inflammation,
attention. Chemoprevention refers to the use of agents that oxidative stress and DNA damage.
can inhibit, reverse or retard the process of these harmful
events in the UV-exposed skin. A wide variety of poly- Keywords Interleukin
DNA repair
Antioxidant

phenols or phytochemicals, most of which are dietary Anti-inflammation
Polyphenols
Ultraviolet radiation

supplements, have been reported to possess substantial skin Cyclooxygenase-2
photoprotective effects. This review article summarizes the
photoprotective effects of some selected polyphenols, such
Abbreviations
as green tea polyphenols, grape seed proanthocyanidins,
COX-2 Cyclooxygenase-2
resveratrol, silymarin and genistein, on UV-induced skin
EGCG Epigallocatechin-3-gallate
GSPs Grape seed proanthocyanidins
J. A. Nichols
S. K. Katiyar (&) GTPs Green tea polyphenols
Department of Dermatology, University of Alabama IL Interleukin
at Birmingham, 1670 University Boulevard, Volker Hall 557, NER Nucleotide excision repair
P.O. Box 202, Birmingham, AL 35294, USA
e-mail: [email protected] NFjB Nuclear factor-kappaB
UV Ultraviolet
S. K. Katiyar
Clinical Nutrition Research Center,
University of Alabama at Birmingham,
Birmingham, AL, USA
Introduction
S. K. Katiyar
Comprehensive Cancer Center,
University of Alabama at Birmingham, Polyphenols are a large family of naturally occurring plant
Birmingham, AL, USA products that are widely distributed in plant foods,
including fruits, vegetables, nuts, seeds, flowers and bark.
S. K. Katiyar
Birmingham Veterans Administration Medical Center, Important dietary sources of polyphenols are onions
Birmingham, AL 35294, USA (flavonols); cacao, grape seeds (proanthocyanidins); tea,

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apples and red wine (flavonols and catechins); citrus fruits including, hypopigmentation and hyperpigmentation, and
(flavanones); berries and cherries (anthocyanidins); and soy skin cancer [13, 28, 71].
(isoflavones) [56]. These polyphenols contribute to the Although many environmental and genetic factors con-
beneficial health effects of vegetables and fruits. A brief tribute to the development of various skin diseases, the
description of the important classes of polyphenols and most important factor is chronic exposure of the skin to
their sources is provided in Table 1. As we are concen- solar UV radiation. The solar UV spectrum can be divided
trating on the role of polyphenols in skin photoprotection, into three segments based on the wave lengths of the
we will briefly discuss the effects of solar ultraviolet (UV) radiation: short wave (UVC; 200–290 nm), mid wave
radiation on the skin, and the role of plant polyphenols in (UVB; 290–320 nm) and long wave (UVA; 320–400 nm).
skin photoprotection. Each spectrum has a characteristic limit of efficiency in
penetrating the epidermal and dermal layers of human and
Solar ultraviolet radiation and the skin murine skin. A brief detail is as follows:
1. UVC (200–280 nm) spectrum. UVC radiation is
The skin is the largest organ of the body and comprises a
largely absorbed by the atmospheric ozone layer and
surface area of approximately 1.5–2.0 m2 which protects
normally does not reach the surface of the earth. These
the internal organs of the body by acting as an effective
wavelengths have enormous energy and are mutagenic
barrier against the detrimental effects of environmental and
in nature. UVC radiation can penetrate the skin to a
xenobiotic agents. Exposure to solar UV radiation is the
depth of approximately 60–80 lm, and can damage
key factor in the initiation of several skin disorders, such as
DNA molecules.
wrinkling, scaling, dryness, mottled pigment abnormalities

Table 1 A brief description of various plant polyphenols and their sources

Classes of Source and description
polyphenols

Phenolic acids Phenolic acids are simple molecules such as caffeic acid, and coumaric acid. Phenolic acids form a diverse group that
includes the widely distributed hydroxybenzoic and hydroxycinnamic acids. Hydroxycinnamic acid compounds
(p-coumaric, caffeic acid, ferulic acid) occur most frequently as simple esters with hydroxy carboxylic acids or glucose,
while the hydroxybenzoic acid compounds (p-hydroxybenzoic, gallic acid, ellagic acid) are present mainly in the form of
glucosides. Ellagic acid is found in pomegranates. Coffee is particularly rich in bound phenolic acids, such as caffeic
acid, ferulic acid and p-coumaric acid. Phenolic acids found in blueberries include gallic acid, p-hydroxybenzoic acid,
caffeic acid, p-coumaric acid and vanillic acid
Flavonoids Flavonoids are a subclass of polyphenols and are widely distributed in nature. The polyphenolic structure of flavonoids and
tannins renders them quite sensitive to oxidative enzymes
Anthocyanins Anthocyanins and anthocyanidins are a large group of water-soluble pigments found in a large number of fruits, vegetables
and flowers, particularly grapes, grape seed extract and berries. Bilberry and other berries have a high concentration of
anthocyanins
Catechins or These are primarily found in tea leaves. Tea leaves and grape seeds have the monomeric flavan-3-ols catechin, epicatechin,
flavanols gallocatechin, epigallocatechin, epicatechingallate and epigallocatechin-3-gallate
Flavones Apigenin, luteolin. The herb chamomile has a good amount of apigenin
Flavonols Flavonols are found at high concentrations in onions, apples, red wine, broccoli, tea and Ginkgo-Biloba. The most common
flavonols are quercetin, kaempferol and myricetin. Flavonols also include fisetin, isoquercitrin and hyperoside
Flavanones Flavanones are hesperidin and naringin
Isoflavones Genistein and daidzein are found in soy
Lignans Lignans are found in nuts and whole grain cereals. Flaxseed has a high content of lignan
Proanthocyanidins These are found in grapes, red wine and pine bark. Pycnogenol is a pine bark extract. Grape seed extract provides a
concentrated source of polyphenols, many of which are proanthocyanidins. Red wine is rich in the complex polyphenols,
the proanthocyanidins. Proanthocyanidins share common properties with other polyphenols, in particular their reducing
capacity and ability to chelate metal ions
Procyanidins Oligomeric catechins are found at high concentrations in red wine, grapes and grape seeds, cocoa, cranberry, apples,
and some supplements such as pycnogenol. Apples contain many kinds of polyphenols, and the main components
are oligomeric procyanidins
Stilbenes Resveratrol is found in the skin of dark colored grapes
Tannins Tannins are found in red wine, tea and nuts. They are large molecules. Many flavonoids in foods also occur as large
molecules (tannins). These include condensed tannins (proanthocyanidins), derived tannins and hydrolysable tannins

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2. UVB (280–320 nm) spectrum. UVB radiation consti- living in regions of intense sun exposure experience an
tutes approximately 5% of the total solar UV radiation exceptionally high rate of skin cancer [48]. This observation is
and is mainly responsible for a variety of skin diseases consistent with the hypothesis that immune surveillance is an
including, non-melanoma and melanoma skin cancers. important mechanism designed to prevent the generation and
UVB radiation can penetrate the skin to a depth of maintenance of neoplastic cells. Further, the incidence of skin
approximately 160–180 lm. It can cross the whole cancers, especially squamous cell carcinoma, is also increased
epidermis layer and penetrate the dermis compartment among organ transplant recipients [12, 20, 72]. The increased
of human skin. UVB radiation can induce both direct frequencies of squamous cell carcinoma, especially in trans-
and indirect adverse biologic effects including the plant patients, are presumably attributable to a long-term
induction of oxidative stress, DNA damage, premature immunosuppressive therapy [15], however, non-immune
aging of the skin [13, 28, 71], and multiple effects on mechanisms may also play a role [24]. These studies provide
the immune system [51, and reviewed in 64, 74], evidence in support of the concept that UV-induced immune
which together play important roles in the generation suppression promotes skin cancer risk.
and maintenance of UV-induced neoplasms [25, 43,
85]. UVB can act as a tumor initiator [50], tumor Polyphenols and skin photoprotection
promoter [40] and co-carcinogen [17, 104]. Although
skin possesses an elaborate defense system consisting There has been considerable interest in the use of naturally
of enzymatic and non-enzymatic components to pro- occurring plant products, including polyphenols, for the
tect the skin from these adverse biological effects, prevention of UV-induced skin photodamage primarily
excessive exposure to UV radiation overwhelms and including the risk of skin cancer. Polyphenols, specifically
depletes the cutaneous defense system leading to the dietary, possessing anti-inflammatory, immunomodulatory
development of various skin disorders including skin and antioxidant properties are among the most promising
cancer [34, 40, 43, 66]. group of compounds that can be exploited as ideal che-
3. UVA (320–400 nm) spectrum. UVA comprises the mopreventive agents for a variety of skin disorders in
largest spectrum of solar UV radiation (90–95%) and is general and skin cancer in particular. Recent advances in
considered as the ‘‘aging ray’’. UVA penetrates deeper our understanding at the cellular and molecular levels of
into the epidermis and dermis of the skin. UVA can carcinogenesis have led to the development of promising
penetrate the skin to a depth of approximately strategies for the prevention of cancer or so-called ‘‘che-
1,000 lm. It has been shown that the extensive UVA moprevention’’ strategy. Chemoprevention is a means of
exposure can lead to benign tumor formation as well as cancer control that is based on the use of specific natural or
malignant cancers [5, and reviewed in 92]. The synthetic chemical substances that can suppress, retard or
exposure to UVA induces the generation of singlet reverse the process of carcinogenesis. In this respect,
oxygen and hydroxyl-free radicals, which can cause chemoprevention offers a realistic strategy for controlling
damage to cellular macromolecules, such as proteins, the risk of cancers. Furthermore, a chemopreventive
lipids and DNA [16]. In contrast to UVC or UVB, UVA approach appears to have practical implications in reducing
is barely able to excite the DNA molecule directly and skin cancer risk because, unlike the carcinogenic environ-
produces only a small number of pyrimidine dimers in mental factors that are difficult to control, individuals can
the skin; therefore, it is assumed that much of the modify their dietary habits and lifestyle in combination
mutagenic and carcinogenic action of UVA radiation is with a careful use of skin care products to prevent the
mediated through reactive oxygen species [14, 76]. photodamaging effects in the skin. Studies from our labo-
However, this is still a matter of debate. It has been ratory have shown the efficacy of naturally occurring
suggested that bipyrimidine photoproducts rather than polyphenols, such as green tea polyphenols (GTPs),
oxidative lesions are the main type of DNA damage silymarin from milk thistle and proanthocyanidins from
involved in the genotoxic effect of solar UVA radiation grape seeds (GSPs), against UV radiation-induced inflam-
[18]. UVA is a significant source of oxidative stress in mation, oxidative stress, DNA damage and suppression of
human skin, which causes photoaging in the form of immune responses. Here, we will briefly summarize and
skin sagging rather than wrinkling [53] and can suppress discuss the photoprotective potential of some polyphenols,
some immune functions [87]. such as polyphenols from green tea and grape seeds as
these polyphenols have been the object of extensive in vitro
There is ample clinical and experimental evidence to sug- and in vivo studies. The photoprotective role of other plant
gest that immune factors contribute to the pathogenesis of polyphenols such as silymarin, genistein and resveratrol
solar UV-induced skin cancer in mice and probably in humans also will be discussed. A summary of molecular targets or
as well [88, 101]. Chronically immunosuppressed patients mechanism of action of these selected polyphenols is given

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and their sources and molecular structures are described in tumor incidence (% mice with tumors), tumor multiplicity
Table 2 and Fig. 1. and tumor size [66]. Dietary GSPs also resulted in the
prevention of malignant progression of UVB-induced
Inhibition of photocarcinogenesis papillomas to carcinomas when compared with the malig-
nant progression observed in non-GSPs-treated UVB-
Non-melanoma skin cancers, including basal cell and exposed control mice [66]. Resveratrol is found in the skin
squamous cell carcinomas, represent the most common of colored grapes, peanuts, red wine and mulberries. Top-
malignant neoplasms in humans [65, 84, 88]. Epidemio- ical application of resveratrol inhibits UVB-induced skin
logical, clinical and biological studies have indicated that tumor initiation, promotion and progression [4, 29].
solar UV radiation is the major etiological agent in the Silymarin, a flavonoid obtained from milk thistle, also has
development of skin cancers [7, 65, 81, 84]. Various ani- been shown to have anti-photocarcinogenic activity in
mal models have been employed to examine the anti- laboratory animals. We [40] have shown that the topical
photocarcinogenic effects of phytochemicals, such as application of silymarin to SKH-1 hairless mice inhibited
polyphenols. Following the standard photocarcinogenesis UVB-induced skin tumor development in terms of tumor
protocols, it has been found that oral administration of incidence, tumor multiplicity and growth of the tumors.
GTPs (a mixture of GTPs or catechins) in drinking water of Silibinin, which is a major component of silymarin, has
mice resulted in significant protection against skin tumor- been shown to inhibit photocarcinogenesis in mice when
igenesis in terms of tumor incidence, tumor multiplicity applied topically or in the diet [21, 22]. As multiple in vivo
and tumor size per group compared with non-GTPs-treated animal studies suggest that plant polyphenols possess anti-
animals [reviewed in 36, 38, 44, 45, 99]. A water extract of photocarcinogenic activity, we will briefly summarize and
green tea leaves, which primarily contained a mixture of discuss the molecular targets or mechanisms of action of
polyphenolic ingredients, when provided as the sole source these selected polyphenols against photocarcinogenesis.
of drinking water to mice afforded protection against UVB
radiation-induced tumorigenesis [94], and also promoted
partial regression of established skin papillomas in mice Mechanism of action and molecular targets
[95]. Topical treatment of SKH-1 hairless mouse skin with of polyphenols
GTPs or (-)-epigallocatechin-3-gallate (EGCG) in a
hydrophilic ointment significantly inhibited UVB-induced Sunscreen effects
skin tumor development [67]. Dietary GSPs (0.2 and 0.5%,
w/w) supplementation of a control AIN76A diet inhibited Most of the natural polyphenols are pigments, typically yel-
photocarcinogenesis in SKH-1 hairless mice in terms of low, red or purple, and can absorb UV radiation. Therefore,

Table 2 A summary of molecular targets or mechanism of action of some selected polyphenols in skin photoprotection
Polyphenols Source Molecular targets/mechanisms Reference

Catechins Tea leaves and buds Inhibits H2O2, NO, iNOS, LPO, MPO [6, 19, 33–35, 38, 41, 43,
45, 47, 67, 90, 91]
Inflammation, COX-2, PGs, IL [19, 37, 39, 41, 43, 59]
NF-jB, IKKa, AP-1, MAPK proteins [6, 33]
Enhance antioxidant defense enzymes [36, 38, 44, 45, 99]
Inhibition of DNA damage [11, 46, 59, 61, 70, 96, 102]
DNA repair mechanism [61, 63]
Proanthocyanidins Grape seeds, nuts, bark Inflammation [6]
Inhibition of H2O2, iNOS, LPO, MPO [6, 66, 82]
NF-jB, IKKa, AP-1, MAPK proteins [57, 60, 82]
Antioxidant defense enzymes [57, 82]
Resveratrol Grape skin, peanuts, red wine Inhibition of inflammation, H2O2, LPO [1–3]
and mulberries COX-2, PGs [2]
NF-jB, IKKa, MAPK proteins [1, 2, 6]
Silymarin Milk thistle Inhibits H2O2, LPO, NO, iNOS, MPO [31, 32]
Inflammation, COX-2, PGs, PCNA [40]
NF-jB, IKKa, AP-1, MAPK proteins [21]
Cell cycle proteins [21]

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Fig. 1 Polyphenols: their

sources and molecular
structures

when applied topically, they can prevent penetration of the characteristic response of keratinocytes to acute or chronic
radiation into the skin. The radiation that polyphenols can exposure to UVB radiation. COX-2 is a rate-limiting
absorb includes the entire UVB spectrum of wavelengths and enzyme for the generation of PG metabolites from ara-
part of the UVC and UVA spectra. Thus, polyphenols may act chidonic acid [54], and COX-2 expression has been linked
as a sunscreen. This ability of natural polyphenols to act as to the pathophysiology of inflammation and cancer [10]. A
sunscreens can reduce inflammation, oxidative stress and number of studies have demonstrated overexpression of
DNA damaging effects of UV radiation in the skin and, thus, COX-2 in chronically UVB-irradiated skin, as well as in
on topical application the photoprotective effects of poly- UVB-induced premalignant lesions and squamous- and
phenols are due in part to this sunscreen effect. basal-cell carcinomas of the skin [8, 89]. Mechanistic
studies of photocarcinogenesis have revealed that the oral
Anti-inflammatory effects administration of GTPs (through addition to the drinking
water) to SKH-1 hairless mice resulted in significant
Ultraviolet radiation-induced erythema, edema and hyper- inhibition of UV radiation-induced cutaneous edema,
plastic epithelial responses are considered as inflammatory erythema and bi-fold skin thickness (a biomarker of
markers, and play crucial roles in skin tumor promotion inflammation). The treatment with GTPs also inhibits
[reviewed in 71]. UVB-induced cyclooxygenase-2 (COX- UVB-induced expression of COX-2 and its PG metabolites,
2) expression and a subsequent increase in the production which have been implicated in skin carcinogenesis and
of prostaglandin (PG) metabolites in the skin is a play a role in promoting tumors in the skin [59]. Topical

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treatment with GTPs prior to UV exposure reduced the UV-induced p53 expression and the number of apoptotic
UV-induced hyperplastic response, myeloperoxidase keratinocytes, suggesting that green tea extract may be a
activity and the numbers of infiltrating inflammatory leu- suitable everyday photochemopreventive agent. These in
kocytes in the skin [37, 39, 43]. The relevance of the vivo observations that have been generated using both
extensive in vitro and in vivo data that have been generated animal and human systems provide insights into the pos-
using animal models to the photoprotective effects of GTPs sible protective mechanisms involved in the anti-inflam-
in human skin is not yet clearly understood. However, we matory effects of GTPs.
have found that the topical application of GTPs prior to UV The in vivo effects of other polyphenols such as resve-
irradiation of the un-tanned backs of humans resulted in ratrol, GSPs and silymarin also have been examined using
significantly less development of erythema when compared animal models [reviewed in 6]. As was found for the GTPs
with the UV-irradiated skin that was not treated with GTPs and EGCG, topical treatment or dietary intake of the GSPs
[19, 41]. We also found that the topical treatment of human and/or silymarin inhibited UVB radiation-induced edema,
skin with GTPs or EGCG (\1 mg/cm2 skin area) prior to erythema, infiltration of inflammatory leukocytes and
UVB exposure significantly reduced UVB-induced infil- myeloperoxidase activity in the mouse skin [21, 22, 40, 66].
tration of inflammatory leukocytes and myeloperoxidase Silymarin has been shown to inhibit UVB-induced COX-2
activity [41], which is used as a marker of tissue infiltra- expression and subsequently the production of PG metabo-
tion. Topical application of EGCG also resulted in inhibi- lites, which are considered to be tumor promoters in the skin.
tion of UVB-induced production of PG metabolites, Silymarin also has been shown to inhibit the expression of
including PGE2, PGF2a and PGD2, which play a critical ornithine decarboxylase, an enzyme required for polyamine
role in inflammatory disorders and in proliferative skin biosynthesis, which has a role in tumor promotion in UVB-
diseases [41]. Exposure of the skin to UV radiation is exposed skin [40]. Topical application of resveratrol prior to
known to enhance the levels of proinflammatory cytokines. UVB irradiation resulted in significant inhibition of UVB-
As the elevated levels of proinflammatory cytokines, such induced increases in bi-fold skin thickness (a marker of
as tumor necrosis factor-a, interleukin (IL)-1b and IL-6, edema development), hyperplastic response, leukocyte
contribute to the tumor promotion process, this effect infiltration and COX-2 and ornithine decarboxylase activity
would be expected to result in an earlier occurrence of in SKH-1 hairless mouse skin [2, 3]. Collectively, the results
tumors and more rapid progression [reviewed in 71]. The concerning the inhibitory effects of these polyphenols on
administration of GTPs in the drinking water of mice sig- UVB-induced inflammatory responses revealed that anti-
nificantly reduced the levels of these proinflammatory photocarcinogenic effects of polyphenols are mediated in
cytokines in UVB-irradiated skin [59]. The GTPs also part through their anti-inflammatory effects.
reduced the levels of biomarkers of cellular proliferation in
the UV-irradiated skin, including proliferating cell nuclear Antioxidant effects
antigen (PCNA) and cyclin D1. The inhibitory effects of
GTPs on these biomarkers of inflammation in UV-exposed The skin possesses an elaborate antioxidant defense system
skin provide further mechanistic evidence of the anti-car- to deal with UV-induced oxidative stress; however,
cinogenic effects of GTPs. Jeon et al. have examined the excessive and chronic exposure to UV radiation can
effects of dietary EGCG (1,500 ppm in control diet) on overwhelm the cutaneous antioxidant capacity, leading to
UVB-induced inflammation in hairless mice [30]. They oxidative stress and oxidative damage which may result in
observed that the regular intake of EGCG strengthens the skin disorders, immunosuppression, premature aging of the
skin’s tolerance and appears to do so by increasing the skin and development of melanoma and non-melanoma
minimal dose of radiation required to induce erythema skin cancers. GTPs have been shown to inhibit photo-
thereby inhibiting the UV-induced perturbation of epider- enhanced lipid peroxidation [35]. Topical treatment of the
mal barrier function and skin damage. Zhao et al. [102] mouse and human skin with EGCG prior to UV exposure
demonstrated that the oral administration of green tea significantly reduced UVB-induced nitric oxide and
extract prior to and during multiple treatments with psor- hydrogen peroxide production, as well as leukocyte infil-
alen plus UVA reduced hyperplasia, hyperkeratosis, ery- tration [19, 41, 43]. It is well established that the infiltrating
thema and edema formation in murine skin. The treatment leukocytes are the major source of nitric oxide and
of EpiDerm, a reconstituted human skin equivalent, with a hydrogen peroxide production, which create the state of
green tea extract also has been shown to inhibit the oxidative stress. EGCG has been shown to have the ability
8-methoxypsoralen-DNA adduct formation and p53 protein to block UVB-induced leukocyte infiltration in mouse as
accumulation associated with exposure to psoralen plus well as in human skin, and thus may be able to inhibit
UVA irradiation [102]. Mnich et al. [68] found that topical UVB-induced production of reactive oxygen species by
treatment of human skin with green tea extract reduced these infiltrating leukocytes [34, 37, 41, 43]. Although

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reactive oxygen species help the host to destroy invading by GTPs or proanthocyanidins could result in a reduction
microorganisms [49], excessive and uncontrolled produc- in skin photo damage and, more specifically, may prevent
tion can also damage host tissues and predispose it to premature aging of the skin.
various disease states [23, 49]. Thus, the application of The treatment of normal human epidermal keratinocytes
EGCG may prove beneficial in ameliorating the harmful with EGCG in vitro was found to inhibit UVB-induced
effects caused by UVB radiation through its ability to intracellular release of hydrogen peroxide concomitantly
reduce the generation of reactive oxygen species. The with the inhibition of UVB-induced oxidative stress-med-
treatment with EGCG also has been shown to result in a iated phosphorylation of epidermal growth factor receptor
reduction in the numbers of hydrogen peroxide producing and mitogen-activated protein kinases (MAPK) signaling
and inducible nitric oxide synthase (iNOS) expressing pathways [33]. Similar effects also were observed when
cells, as well as a reduction in the production of hydrogen HaCaT cells were treated with (-)-epicatechin-3-gallate
peroxide and nitric oxide both in the epidermis and dermis (ECG) and exposed to UVB radiation. These in vitro
of UVB-irradiated skin sites [43]. Similar effects also have studies suggest that ECG can act as a free-radical scaven-
been observed in human skin when EGCG was applied ger when keratinocytes are photo damaged [26, 27]. The
topically before exposure to UVB (49 minimal erythema treatment of HaCaT cells with ECG also demonstrated its
dose) [34]. This EGCG treatment also inhibited UV- free-radical scavenging effects, when cells were irradiated
induced epidermal lipid peroxidation and protected the with UVA radiation. These observations indicate that
antioxidant defense enzymes in the UVB-exposed human EGCG could play an important role in the attenuation of
skin [34]. Based on the evidence of the photoprotective oxidative stress-mediated cellular signaling responses,
effects of GTPs/EGCG in animal and human systems, it which are essential factors in various skin diseases in
appears that both GTPs and EGCG can induce preventive humans. Topical cream-based formulations of EGCG or
effects by acting at different active sites within the cascade GTPs for human use have been developed, and their
of events that generates reactive oxygen species. Kim et al. photoprotective effects evaluated in vivo using an animal
[47] observed that EGCG treatment of the skin of guinea model. An exceptionally high-photoprotective effect of
pigs inhibits UVB-induced lipid peroxidation and the ery- EGCG or GTPs was observed against UV radiation-
thema response. They also found that EGCG treatment of induced oxidative stress in the mouse skin when evaluated
human fibroblasts in culture blocked the UV-induced in terms of lipid peroxidation, hydrogen peroxide produc-
increase in collagen secretion and collagenase mRNA tion and analysis of antioxidant defense enzymes [67, 90].
levels, and also inhibited the binding activities of the UV- Topical treatment of EGCG or oral administration of GTPs
induced nuclear transcription factors nuclear factor-kappaB in the drinking water of mice also has been shown to inhibit
(NF-jB) and activated protein (AP)-1 [47]. Wei et al. [98] UVB radiation-induced depletion of antioxidant defense
have demonstrated that aqueous extracts of green tea have enzymes, such as catalase, glutathione peroxidase, super-
potent scavenging effects on oxygen species and block UV- oxide dismutase and the levels of glutathione [90]. A study
induced oxidative DNA damage in the calf thymus, which has been conducted in an attempt to determine whether the
may, at least in part, explain the mechanisms by which sunscreen-containing green tea extracts protect human
green tea inhibits photocarcinogenesis. Collectively, these subjects from UV irradiation-induced photoaging and
data suggest that green tea may have the potential to reduce photoimmunosuppression [55]. The investigators reported
the risk of UV-induced oxidative stress-mediated skin that a sunscreen containing different concentrations of
diseases or disorders in humans, including premature aging green tea extracts conferred significant protection against
of the skin and development of cutaneous malignancies. biological events associated with photoaging matrix
Oxidation of some amino acid residues, such as lysine, metalloproteinase (MMP-2, MMP-9) and photoimmunol-
arginine and proline, leads to the formation of carbonyl ogy (CD1a? Langerhans cells). Similar to green tea, che-
derivatives that affect the nature and function of the pro- mopreventive effects also were noted when mice were
teins [83]. The presence of carbonyl groups in proteins has given a GSPs-supplemented AIN76A diet. The provision of
become a widely accepted measure of oxidative damage of dietary GSPs (0.2 and 0.5%, w/w) to mice exposed to either
proteins under conditions of oxidative stress. Multiple acute or chronic UVB irradiation was found to inhibit
exposures of the skin to UV radiation results in a several depletion of glutathione peroxidase, catalase and glutathi-
fold increase in the levels of protein carbonyls in com- one, and to inhibit UVB-induced hydrogen peroxide, lipid
parison to non-UV-exposed skin. In separate experiments, peroxidation, protein oxidation and nitric oxide, in mouse
it has been shown that the topical treatment with EGCG, skin [82]. As UVB-induced oxidative stress mediates
GTPs or GSPs significantly inhibits acute or chronic UV activation of MAPK and NF-jB signaling pathways, the
irradiation-induced protein oxidation in the skin of mice effects of GSPs in vivo in the same animal model on these
[82, 91]. The inhibition of UVB-induced protein oxidation pathways also were examined. It was observed that the

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treatment with GSPs inhibited UVB-induced phosphory- the skin [3]. Inhibition of these critical events by resvera-
lation of extracellular signal-regulated kinase 1/2 (ERK1/ trol may have contributed to the prevention of UV radia-
2), c-Jun-N-terminal-kinase and p38 proteins of the MAPK tion-induced skin cancer in these mice. Park and Lee [73]
family, which seemed to be mediated through reactivation have demonstrated that the treatment of HaCaT cells with
of MAPK phosphatases [82]. It has been shown that the resveratrol before UVB irradiation resulted in an increase
GSPs can inhibit the UVB-induced activation of NF-jB in cell survival of UVB-irradiated cells which was asso-
through inhibition of degradation of IjBa and activation of ciated with the reduction in reactive oxygen species pro-
IjB kinase a. Using an identical mouse model, it has been duction. In addition, the activation of caspase-3 and -8 was
further demonstrated that the dietary administration of partially reduced in the resveratrol-pretreated HaCaT cells,
GSPs resulted in the inhibition of the expression of PCNA, implying that the attenuation of caspase-3 and -8 activation
cyclin D1, iNOS and COX-2 in the skin, which are NF-jB- is involved in cell survival after UVB irradiation. Soybeans
targeted proteins. Similar studies were conducted in vitro are a rich source of the isoflavones, genistein and daidzein,
using normal human epidermal keratinocytes with and and are photoprotective [reviewed in 97]. Studies using
without treatment with GSPs and UVB irradiation. The SENCAR mice have shown that topical genistein treatment
results were identical to those obtained in the mouse reduced UV radiation-induced activation of c-fos and c-jun
model, which suggests that the results generated in this in a dose-dependent manner [93]. Genistein also has been
animal model of the photoprotective effects of GSPs can be shown to reduce UV radiation-induced oxidative and
extrapolated to the human system [57] and study also has photodynamic DNA damage [69]. Treatment of the human
been conducted to determine the effects of oligomeric keratinocyte cell line NCTC 2544 with genistein prevented
proanthocyanidins on UV-induced melanogenesis of UV-induced enhancement of the DNA-binding activity of
human melanocytes in vitro. The results of this study the signal transducer and activator of transcription-1 by
suggested that oligomeric proanthocyanidins have potential acting as a tyrosine kinase inhibitor, thus, limiting lipid
photoprotective effects on human melanocytes including peroxidation and increases in reactive oxygen species
scavenging of intracellular reactive oxygen species and generation [58].
adjustment of cell-cycle check points [103]. In an in vitro To further illustrate the role of polyphenols in derma-
cell culture model, treatment of human epidermoid carci- tologic conditions, as well as in skin photoprotection, we
noma A431 cells with GSPs resulted in inhibition of cell are providing an in-depth review of the studies on the
proliferation and induction of apoptotic cell death. This effects of polyphenols from green tea.
effect of GSPs was associated with the inhibition of con-
stitutive expression of NF-jB/p65 and its targeted genes, Green tea polyphenols rapidly remove or repair
such as COX-2, iNOS, PCNA, cyclin D1 and MMP-9 [60]. UVB-induced DNA damage
These observations provide a molecular basis for the
photoprotective effects of GSPs and GTPs in an in vivo Ultraviolet-induced DNA damage in skin cells is an
model. Studies conducted by the authors have shown that important initiator of signaling pathways. The DNA
the topical treatment of SKH-1 hairless mouse skin with photoproducts generated by UV-induced DNA damage are
silymarin resulted in inhibition of UVB-induced intracel- altered DNA structures that activate a cascade of responses,
lular production of H2O2 in both the epidermis and dermis beginning with the initiation of cell-cycle arrest and acti-
when analyzed by immunohistochemistry and biochemical vation of DNA repair mechanisms. The biologically
analytical procedures and compared with the results harmful effects associated with UV radiation exposure are
obtained using non-silymarin-treated control mice [31]. In largely the result of errors in DNA repair, which can lead to
these experiments, it was found that the significant inhi- oncogenic mutations [reviewed in 86]. UV-induced DNA
bition of the UVB-induced oxidative stress was associated damage in the form of cyclobutane pyrimidine dimers
with significant inhibition of UV-induced infiltration of (CPD) is considered as a molecular trigger for the induc-
activated macrophages and neutrophils. The treatment with tion of immunosuppression and initiation of photocarci-
silymarin also inhibits UVB-induced expression of iNOS nogenesis [52, 100]. Several studies have documented that
and subsequently nitric oxide production [31], and the exposure of the skin to UV radiation results in imme-
reviewed in 32]. Resveratrol is also a potential polyphe- diate formation of CPDs in skin cells [42]. Most of the
nolic antioxidant. Pretreatment of human epidermal kerat- UVB-induced CPDs were found in the epidermis, but some
inocytes with resveratrol inhibited UVB-mediated were detected in the dermis. The location of the damage
activation of the NF-jB pathway [1, 2]. In SKH-1 hairless depends on the ability of the UV radiation to penetrate the
mice, topical application of resveratrol inhibited UVB- skin [42]. It has been found that UV exposure of less than
induced inflammatory responses and hydrogen peroxide one minimal erythema dose is sufficient to cause damage
production, which is a stable source of oxidative stress, in DNA in target cells of human skin [42].

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Arch Dermatol Res (2010) 302:71–83 79

UVB-induced CPDs are formed immediately after the mediated through the induction of IL-12. Collectively,
interaction of photons with the DNA molecule. In an in these data suggest that the difference in the GTPs-associ-
vitro study using cultured human cells (lung fibroblasts, ated DNA repair capacity between IL-12 knockout mice
skin fibroblasts and epidermal keratinocytes), EGCG and their wild-type counterparts may be due to the absence
resulted in a dose-dependent reduction in UV-induced of IL-12 in the IL-12 knockout mice. The mechanisms by
DNA damage in all three cell types [70]. When applied which GTPs repaired CPDs were identical to the mecha-
topically to the mouse skin, GTPs (a mixture of GTPs) nisms by which EGCG repaired CPDs.
significantly inhibited UVB-induced DNA damage as Wei et al. [96] have shown that an aqueous extract of
assessed using a 32P-postlabelling technique [11]. Topical green tea scavenges H2O2 and inhibits UV-induced oxi-
treatment of human skin with GTPs prior to UV exposure dative DNA damage in an in vitro system. Zhao et al. [102]
resulted in a dose-dependent inhibition of formation of demonstrated that application of green tea extract to Epi-
CPDs [46]. Camouse et al. [9] found that topical applica- derm, a reconstituted human skin equivalent, also inhibited
tion of green tea or white tea extracts provided human skin psoralen-UVA-induced formation of 8-methoxypsoralen-
protection from solar-simulated UV light. These tea DNA adducts [102]. Treatment of skin with a 5% green tea
extracts were shown to provide protection against the extract significantly inhibited DNA damage induced by
detrimental effects of UV light on cutaneous immunity. solar simulator radiation when assessed using a 32P-post-
The investigators concluded that these protective effects labeling technique [11]. These observations demonstrate
were not due to direct UV absorption or sunscreen effects, the potential chemopreventive effects of GTPs against
as both products had a sun protection factor of 1. UVB-induced DNA damage.
Extensive studies of the effects of polyphenols, partic-
ularly GTPs, on the repair kinetics and repair mechanisms Repair of UV-induced DNA damage by green tea
of UV-induced CPDs have been carried out in the labora- polyphenols is mediated through nucleotide excision
tory of Dr Katiyar. One of these studies showed that topical repair mechanism
treatment of skin with EGCG does not prevent UVB-
induced formation of CPDs immediately after UVB irra- Further studies have been conducted to verify the GTP-
diation, which indicated that EGCG does not have a sig- associated DNA repair mechanisms in UVB-irradiated
nificant filtering effect on the UVB radiation. However; in skin. Meeran et al. postulated that a nucleotide excision
skin samples obtained at 24 or 48 h after UVB exposure, a repair (NER) mechanism is involved in the repair of photo
number of CPD-positive cells were significantly reduced damaged DNA by GTPs, and that IL-12 has a role in this
(or repaired) in the EGCG-treated C3H/HeN mouse skin process [61, 63]. To determine whether the NER mecha-
when compared with the control group of mice which were nism is required for the EGCG-induced IL-12-mediated
not treated with EGCG [61]. Studies of the DNA repair repair of UVB-induced CPDs, NER-deficient fibroblasts
mechanisms suggested that the rapid repair of UV-induced from xeroderma pigmentosum complementation group A
CPDs by EGCG was mediated through stimulation of a (XPA) patients and NER-proficient fibroblasts from a
cytokine (IL-12) on application of the EGCG onto the healthy person (XPA-proficient) were exposed to UVB with
mouse skin [61]. IL-12 has been shown to have the or without prior treatment with EGCG. The CPD-positive
capacity to induce DNA repair [62, 79, 80] and this con- cells were detected by immunostaining at different time
cept was confirmed by testing the effect of EGCG on points after UVB exposure of the cells. It was observed that
UV-induced CPD formation in IL-12 knockout mice. the numbers of CPD-positive cells were significantly lower
EGCG does not remove or repair UV-induced CPDs in the at 24 h after UVB exposure in the XPA-proficient cells, but
skin of IL-12 knockout mice, further confirming the role of that treatment with EGCG did not significantly remove or
IL-12 in rapid repair of DNA damage by this polyphenol repair UVB-induced CPDs in NER-deficient cells. This
[61]. Studies of the effects of oral administration of GTPs observation indicated that EGCG-induced DNA repair is
in the drinking water of mice on UVB-induced DNA mediated through a functional NER mechanism.
damage also were carried out and it was found that
UV-induced DNA damage (CPDs) was resolved rapidly in Repair of UVB-induced DNA damage by green tea
the GTPs-treated mice when compared with GTPs- polyphenols leads to a reduction in UVB-induced
untreated mice [59]. This DNA repairing effect of GTPs inflammation in the skin
was less pronounced in IL-12 knockout mice, as was
observed in the case of EGCG treatment. Schwarz et al. Exposure of the skin to UV radiation induces inflammation,
[78] observed that the treatment of normal human kerati- and there is increasing evidence that chronic inflammation
nocytes and ‘‘human skin equivalent’’ with GTPs reduced promotes the initiation of various skin diseases, including
UVB-induced DNA damage and that this effect was the development of skin cancers [16, and reviewed in 71].

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80 Arch Dermatol Res (2010) 302:71–83

Both UV-induced inflammatory responses and UV-induced gut. Detection of proanthocyanidin dimers B1 and B2 in
skin tumorigenesis are causally related to UV-induced human plasma indicated that the absorption of these dimers
DNA damage. Therefore, it was of interest to explore the was *100-fold lower than that of the monomeric flava-
effects of GTPs on DNA repair and their relationship with nols. In the case of topical delivery of the polyphenols, the
inflammatory effects. CPDs are formed immediately after penetration of polyphenols into the skin is limited and
the exposure of the skin to UV radiation, and inflammation successful delivery of plant polyphenols requires cream-
develops thereafter. Following the UV exposure, it was based, organic solvent-based or lipid soluble topical for-
observed that UV-induced DNA damage in the form of mulations that can enhance the penetration of the
CPDs was repaired or removed more rapidly in the skin polyphenols.
of mice that had been treated either with topical application
of EGCG or orally administered GTPs. Subsequently, the
levels of UVB-induced inflammation was lower in the Conclusion
treated mice than the non-treated mice with the levels of
inflammation in the mouse skin from the different treat- The polyphenols discussed in this review article show
ment groups being assessed through analysis of biomarkers significant anti-inflammatory, antioxidant and anti-DNA
of inflammation, such as COX-2 expression, PGE2 pro- damaging effects. These protective effects of polyphenols
duction and the levels of pro-inflammatory cytokines. may contribute to their anti-photocarcinogenic effects and
Interestingly, this effect of EGCG or GTPs was not act to abrogate the various biochemical processes induced
observed in IL-12-deficient or knockout mice. This may be or mediated by solar UV radiation. Based on the epide-
due to the fact that the treatment with EGCG or GTPs was miological evidence and laboratory studies conducted
not able to repair UV-induced DNA damage significantly using in vitro and in vivo systems, it is suggested that
in the IL-12 knockout mice, as detailed [59]. This new routine consumption or topical treatment of these poly-
information supports the concept that UV-induced DNA phenols may provide efficient protection against the
damage and inflammatory responses are causally related harmful effects of solar UV radiation in humans. For
with the increased risk of photocarcinogenesis. This in vivo appropriate conversion of drug or chemopreventive agent
experimental evidence indicates that the prevention of doses from animal studies to human studies, the body
UVB-induced skin cancer by GTPs or EGCG is mediated surface area normalization method has been prescribed
through inhibition of UVB-induced inflammation, which in [reviewed in 75]. Based on this reference, the human
turn is mediated, at least in part, through rapid repair of equivalent dose (HED) of any chemopreventive agent can
damaged DNA. The outcome of this study, therefore, sug- be calculated using the following formula:
gests that regular consumption of green tea or GTPs may be Animal Km factor
considered as an effective strategy to prevent inflammation- HED ðmg=kgÞ ¼ Animal dose ðmg=kgÞ 
Human Km factor
associated skin diseases including skin cancers.
(Km factor for mouse = 3; Km factor for adult
Bioavailability and metabolism of polyphenols human = 37).
Further, the use of polyphenols in combination with
The bioavailability and metabolism of polyphenols may sunscreens or skin care lotions may provide an effective
influence their effectiveness. The considerable structural strategy for mitigating the effects of UV radiation that will
diversity among the polyphenols can influence the bio- lead to the protection of the skin from various skin diseases
availability of the individual components. Small molecules, caused by excessive sun exposures.
such as catechin monomers, can be easily absorbed through
the gut barrier, whereas the large molecular weight poly- Acknowledgments The work reported from Dr Katiyar’s laboratory
phenols, such as proanthocyanidins and even (-)-epi- was supported by the funds from National Institutes of Health
(CA104428, AT002536) and Veteran Affairs Merit Review Award
gallocatechin-3-gallate, are poorly absorbed. Once (S.K. Katiyar). The content of this article does not necessarily reflect
absorbed, polyphenols are conjugated to glucuronide, sul- the views or policies of the funding sources. Grateful thanks are also
fate and methyl groups in the gut mucosa and inner tissues. due to our former and current colleagues and postdoctoral fellows for
Non-conjugated polyphenols are virtually absent in plasma. their outstanding contributions.
Such reactions facilitate their excretion and limit their
potential toxicity, if any [77]. During digestion in the
References
intestine, the large polyphenolic molecules break into
multiple small molecules or metabolites and these may 1. Adhami VM, Afaq F, Ahmad N (2003) Suppression of ultravi-
systemically induce beneficial effects in the body. Poly- olet B exposure-mediated activation of NF-kappaB in normal
meric proanthocyanidins are not absorbed as such in the human keratinocytes by resveratrol. Neoplasia 5:74–82

123
Arch Dermatol Res (2010) 302:71–83 81

2. Afaq F, Adhami VM, Ahmad N (2003) Prevention of short-term 23. Halliwell B, Gutteridge JMC, Cross CE (1992) Free radicals,
ultraviolet B radiation-mediated damages by resveratrol in SKH- antioxidants, and human disease: where are we now? J Lab Clin
1 hairless mice. Toxicol Appl Pharmacol 186:28–37 Med 119:598–620
3. Aziz MH, Afaq F, Ahmad N (2005) Prevention of ultraviolet B 24. Hojo M, Morimoto T, Maluccio M (1999) Cyclosporin induces
radiation—damage by resveratrol in mouse skin is mediated via cancer progression by a cell-autonomous mechanism. Nature
modulation in Survivin. Photochem Photobiol 81:25–31 (Lond) 397:530–534
4. Aziz MH, Kumar R, Ahmad N (2003) Cancer chemoprevention 25. Hruza LL, Pentland AP (1993) Mechanisms of UV-induced
by resveratrol: in vitro and in vivo studies and the underlying inflammation. J Invest Dermatol 100:35S–41S
mechanisms (review). Int J Oncol 23:17–28 26. Huang CC, Fang JY, Wu WB et al (2005) Protective effects of
5. Bachelor MA, Bowden GT (2004) UVA-mediated activation of (-)-epicatechin-3-gallate on UVA-induced damage in HaCaT
signaling pathways involved in skin tumor promotion and pro- keratinocytes. Arch Dermatol Res 296:473–481
gression. Semin Cancer Biol 14:131–138 27. Huang CC, Wu WB, Fang JY, Chiang HS, Chen SK, Chen BH,
6. Baliga MS, Katiyar SK (2006) Chemoprevention of photocar- Chen YT, Hung CF (2007) (-)-Epicatechin-3-gallate, a green
cinogenesis by selected dietary botanicals. Photochem Photobiol tea polyphenol is a potent agent against UVB-induced damage
Sci 5:243–253 in HaCaT keratinocytes. Molecules 12:1845–1858
7. Brash DE, Rudolph JA, Simon JA et al (1991) A role for sun- 28. Ichihashi M, Ueda M, Budiyanto A (2003) UV-induced skin
light in skin cancer: UV-induced p53 mutations in squamous damage. Toxicology 189:21–39
cell carcinoma. Proc Natl Acad Sci USA 88:10124–10128 29. Jang M, Cai L, Udeani GO et al (1997) Cancer chemopreventive
8. Buckman SY, Gresham A, Hale P et al (1998) COX-2 expres- activity of resveratrol, a natural product derived from grapes.
sion is induced by UVB exposure in human skin: implications Science 275:218–220
for the development of skin cancer. Carcinogenesis 19:723–729 30. Jeon HY, Kim JK, Kim WG et al (2009) Effects of oral epi-
9. Camouse MM, Domingo DS, Swain FR et al (2009) Topical gallocatechin gallate supplementation on the minimal erythema
application of green and white tea extracts provides protection dose and UV-induced skin damage. Skin Pharmacol Physiol
from solar-simulated ultraviolet light in human skin. Exp Der- 22:137–14131
matol 18:522–526 31. Katiyar SK (2002) Treatment of silymarin, a plant flavonoid,
10. Chapple KS, Cartwright EJ, Hawcroft G et al (2000) Localiza- prevents ultraviolet light-induced immune suppression and
tion of cyclooxygenase-2 in human sporadic colorectal adeno- oxidative stress in mouse skin. Int J Oncol 21:1213–1222
mas. Am J Pathol 156:545–553 32. Katiyar SK (2005) Silymarin and skin cancer prevention: anti-
11. Chatterjee ML, Agarwal R, Mukhtar H (1996) Ultraviolet B inflammatory, antioxidant and immunomodulatory effects. Int J
radiation-induced DNA lesions in mouse epidermis: an assess- Oncol 26(1):169–176
ment using a novel 32P-postlabelling technique. Biochem Bio- 33. Katiyar SK, Afaq F, Azizuddin K et al (2001) Inhibition of UVB-
phys Res Commun 229:590–595 induced oxidative stress-mediated phosphorylation of mitogen-
12. Cowen EW, Billingsley EM (1999) Awareness of skin cancer by activated protein kinase signaling pathways in cultured human
kidney transplant patients. J Am Acad Dermatol 40:697–701 epidermal keratinocytes by green tea polyphenol (-)-epigallo-
13. de Gruijl FR, van der Leun JC (1994) Estimate of the wave- catechin-3-gallate. Toxicol Appl Pharmacol 176:107–110
length dependency of ultraviolet carcinogenesis in humans and 34. Katiyar SK, Afaq F, Perez A et al (2001) Green tea polyphenol
its relevance to the risk assessment of stratospheric ozone (-)-epigallocatechin-3-gallate treatment of human skin inhibits
depletion. Health Phys 67:319–325 ultraviolet radiation-induced oxidative stress. Carcinogenesis
14. de Gruijl FR (2000) Photocarcinogenesis: UVA vs UVB. Singlet 22:287–294
oxygen, UVA, and ozone. Methods Enzymol 319:359–366 35. Katiyar SK, Agarwal R, Mukhtar H (1994) Inhibition of spon-
15. DiGiovanna JJ (1998) Posttransplantation skin cancer: scope of taneous and photo-enhanced lipid peroxidation in mouse epi-
the problem, management and role for systemic retinoid che- dermal microsomes by epicatechin derivatives from green tea.
moprevention. Transplant Proc 30:2771–2775 Cancer Lett 79:61–66
16. DiGiovanni J (1992) Multistage carcinogenesis in mouse skin. 36. Katiyar SK, Ahmad N, Mukhtar H (2000) Green tea and skin.
Pharmacol Ther 54:63–128 Arch Dermatol 136:989–994
17. Donawho CK, Kripke ML (1991) Evidence that the local effect 37. Katiyar SK, Challa A, McCormick TS et al (1999) Prevention of
of ultraviolet radiation on the growth of murine melanomas is UVB-induced immunosuppression in mice by green tea poly-
immunologically mediated. Cancer Res 51:4176–4181 phenol (-)-epigallocatechin-3-gallate may be associated with
18. Douki T, Reynaud-Angelin A, Cadet J et al (2003) Bipyrimidine alterations in IL-10 and IL-12 production. Carcinogenesis
photoproducts rather than oxidative lesions are the main type of 20:2117–2124
DNA damage involved in the genotoxic effect of solar UVA 38. Katiyar SK, Elmets CA (2001) Green tea polyphenolic antiox-
radiation. Biochemistry 42:9221–9226 idants and skin photoprotection. Int J Oncol 18:1307–1313
19. Elmets CA, Singh D, Tubesing K et al (2001) Cutaneous 39. Katiyar SK, Elmets CA, Agarwal R et al (1995) Protection
photoprotection from ultraviolet injury by green tea polyphe- against ultraviolet-B radiation-induced local and systemic sup-
nols. J Am Acad Dermatol 44:425–432 pression of contact hypersensitivity and edema responses in
20. Fortina AB, Caforio AL, Piaserico S (2000) Skin cancer in heart C3H/HeN mice by green tea polyphenols. Photochem Photobiol
transplant recipients: frequency and risk factor analysis. J Heart 62:855–861
Lung Transplant 19:249–255 40. Katiyar SK, Korman NJ, Mukhtar H et al (1997) Protective
21. Gu M, Dhanalakshmi S, Singh RP et al (2004) Silibinin protects effects of silymarin against photocarcinogenesis in a mouse skin
against photocarcinogenesis via modulation of cell cycle regu- model. J Natl Cancer Inst 89:556–566
lators, mitogen-activated protein kinases, and Akt signaling. 41. Katiyar SK, Matsui MS, Elmets CA et al (1999) Polyphenolic
Cancer Res 64:6349–6356 antioxidant (-)-epigallocatechin-3-gallate from green tea redu-
22. Gu M, Dhanalakshmi S, Singh RP et al (2005) Dietary feeding ces UVB-induced inflammatory responses and infiltration of
of silibinin prevents early biomarkers of UVB radiation-induced leukocytes in human skin. Photochem Photobiol 69:148–153
carcinogenesis in SKH-1 hairless mouse epidermis. Cancer 42. Katiyar SK, Matsui MS, Mukhtar H (2000) Kinetics of UV
Epidemiol Biomarkers Prev 14:1344–1349 light-induced cyclobutane pyrimidine dimers in human skin in

123
82 Arch Dermatol Res (2010) 302:71–83

vivo: an immunohistochemical analysis of both epidermis and 63. Meeran SM, Mantena SK, Katiyar SK (2006) Prevention of
dermis. Photochem Photobiol 72:788–793 ultraviolet radiation-induced immunosuppression by (-)-epi-
43. Katiyar SK, Mukhtar H (2001) Green tea polyphenol (-)-epi- gallocatechin-3-gallate in mice is mediated through interleukin
gallocatechin-3-gallate treatment to mouse skin prevents UVB- 12-dependent DNA repair. Clin Cancer Res 12:2272–2280
induced infiltration of leukocytes, depletion of antigen present- 64. Meunier L, Raison-Peyron N, Meynadier J (1998) UV-induced
ing cells and oxidative stress. J Leukoc Biol 69:719–726 immunosuppression and skin cancers. Rev Med Interne 19:247–
44. Katiyar SK, Bergamo BM, Vayalil PK, Elmets CA (2001) Green 254
tea polyphenols: DNA photodamage and photoimmunology. 65. Miller DL, Weinstock MA (1994) Nonmelanoma skin cancer in
J Photochem Photobiol B 65:109–114 the United States: incidence. J Am Acad Dermatol 30:774–778
45. Katiyar SK, Mukhtar H (1997) Tea antioxidants in cancer che- 66. Mittal A, Elmets CA, Katiyar SK (2003) Dietary feeding of
moprevention. J Cell Biochem Suppl 27:59–67 proanthocyanidins from grape seeds prevents photocarcinogen-
46. Katiyar SK, Perez A, Mukhtar H (2000) Green tea polyphenol esis in SKH-1 hairless mice: relationship to decreased fat and
treatment to human skin prevents formation of ultraviolet light lipid peroxidation. Carcinogenesis 24:1379–1388
B-induced pyrimidine dimers in DNA. Clinical Cancer Res 67. Mittal A, Piyathilake C, Hara Y et al (2003) Exceptionally high
6:3864–3869 protection of photocarcinogenesis by topical application of (-)-
47. Kim J, Hwang J-S, Cho Y-K et al (2001) Protective effects of epigallocatechin-3-gallate in hydrophilic cream in SKH-1 hair-
(-)-epigallocatechin-3-gallate on UVA- and UVB-induced skin less mouse model: relationship to inhibition of UVB-induced
damage. Skin Pharmacol Appl Skin Physiol 14:11–19 global DNA hypomethylation. Neoplasia 5:555–565
48. Kinlen L, Sheil A, Peta J (1979) Collaborative United King- 68. Mnich CD, Hoek KS, Virkki LV et al (2009) Green tea extract
dom–Australia study of cancer in patients treated with immu- reduces induction of p53 and apoptosis in UVB-irradiated
nosuppressive drugs. Br Med J 1461–1466 human skin independent of transcriptional controls. Exp Der-
49. Klebanoff SJ (1988) In: Gallin JI, Goldstein IM, Snyderman R matol 18:69–77
(eds) Inflammation: basic principles and clinical correlates. 69. Moore JO, Wang Y, Stebbins WG et al (2006) Photoprotective
Raven Press, New York, pp. 391–444 effect of isoflavone genistein on ultraviolet B induced pyrimi-
50. Kligman LH, Akin FJ, Kligman AM (1980) Sunscreens prevent dine dimer formation and PCNA expression in human recon-
ultraviolet photocarcinogenesis. J Am Acad Dermatol 3:30–35 stituted skin and its implications in dermatology and prevention
51. Kripke ML (1990) Photoimmunology. Photochem Photobiol of cutaneous carcinogenesis. Carcinogenesis 27:1627–1635
52:919–924 70. Morley N, Clifford T, Salter L et al (2005) The green tea poly-
52. Kripke ML, Cox PA, Alas LG et al (1992) Pyrimidine dimers in phenol (-)-epigallocatechin gallate and green tea can protect
DNA initiated systemic immunosuppression in UV-irradiated human cellular DNA from ultraviolet and visible radiation-induced
mice. Proc Natl Acad Sci USA 89:7516–7520 damage. Photodermatol Photoimmunol Photomed 21:15–22
53. Krutmann J (2001) The role of UVA rays in skin aging. Eur 71. Mukhtar H, Elmets CA (1996) Photocarcinogenesis: mecha-
J Dermatol 11:170–171 nisms, models and human health implications. Photochem
54. Langenbach R, Loftin CD, Lee C et al (1999) Cyclooxygenase- Photobiol 63:355–447
deficient mice. A summary of their characteristics and suscep- 72. Otley CC, Pittelkow MR (2000) Skin cancer in liver transplant
tibilities to inflammation and carcinogenesis. Ann N Y Acad Sci recipients. Liver Transpl 6:253–262
889:52–61 73. Park K, Lee JH (2008) Protective effects of resveratrol on UVB-
55. Li YH, Wu Y, Wei HC et al (2009) Protective effects of green irradiated HaCaT cells through attenuation of the caspase
tea extracts on photoaging and photoimmunosuppression. Skin pathway. Oncol Rep 19:413–417
Res Technol 15:338–345 74. Parrish JA (1983) Photoimmunology. Adv Exp Med Biol
56. Manach C, Scalbert A, Morand C et al (2004) Polyphenols: food 160:91–108
sources and bioavailability. Am J Clin Nutr 79:727–747 75. Reagan-Shaw S, Nihal M, Ahmad N (2007) Dose translation
57. Mantena SK, Katiyar SK (2006) Grape seed proanthocyanidins from animal to human studies revisited. FASEB J 22:659–661
inhibit UV radiation-induced oxidative stress and activation of 76. Runger TM (1999) Role of UVA in the pathogenesis of mela-
MAPK and NF-jB signaling in human epidermal keratinocytes. noma and non-melanoma skin cancer. A short review. Photo-
Free Radic Biol Med 40:1603–1614 dermatol Photoimmunol Photomed 15:212–216
58. Maziere C, Dantin F, Dubois F et al (2000) Biphasic effect of 77. Scalbert A, Morand C, Manach C et al (2002) Absorption and
UVA radiation on STAT1 activity and tyrosine phosphorylation metabolism of polyphenols in the gut and impact on health.
in cultured human keratinocytes. Free Radic Biol Med 28:1430– Biomed Pharmacother 56:276–282
1437 78. Schwarz A, Maeda A, Gan D et al (2008) Green tea phenol
59. Meeran SM, Akhtar S, Katiyar SK (2009) Inhibition of extracts reduce UVB-induced DNA damage in human cells via
UVB-induced skin tumor development by drinking green tea interleukin-12. Photochem Photobiol 84:350–355
polyphenols is mediated through DNA repair and subsequent 79. Schwarz A, Maeda A, Kernebeck K et al (2005) Prevention of
inhibition of inflammation. J Invest Dermatol 129:1258–1270 UV radiation-induced immunosuppression by IL-12 is depen-
60. Meeran SM, Katiyar SK (2008) Proanthocyanidins inhibit dent on DNA repair. J Exp Med 201:173–179
mitogenic and survival-signaling in vitro and tumor growth in 80. Schwarz A, Stander S, Berneburg M et al (2002) Interleukin-12
vivo. Front Biosci 13:887–897 suppresses ultraviolet radiation-induced apoptosis by inducing
61. Meeran SM, Mantena SK, Elmets CA et al (2006) (-)-Epi- DNA repair. Nat Cell Biol 4:26–31
gallocatechin-3-gallate prevents photocarcinogenesis in mice 81. Scotto J, Fears TR (1978) Skin cancer epidemiology: research
through interleukin-12-dependent DNA repair. Cancer Res needs. Natl Cancer Inst Monogr 50:169–177
66:5512–5520 82. Sharma SD, Meeran SM, Katiyar SK (2007) Dietary grape seed
62. Meeran SM, Mantena SK, Meleth S et al (2006) Interleukin-12- proanthocyanidins inhibit UVB-induced oxidative stress and
deficient mice are at greater risk of ultraviolet radiation-induced activation of mitogen-activated protein kinases and nuclear
skin tumors and malignant transformation of papillomas to factor-jB signaling in in vivo SKH-1 hairless mice. Mol Cancer
carcinomas. Mol Cancer Ther 5:825–832 Ther 6:995–1005

123
Arch Dermatol Res (2010) 302:71–83 83

83. Stadtman ER (2001) Protein oxidation in aging and age-related light and 12-O-tetradecanoylphorbol-13-acetate in the skin of
diseases. Ann N Y Acad Sci 928:22–38 SKH-1 mice. Cancer Res 52:1162–1170
84. Strom S (1996) In: Weber R, Miller M, Goepfert H (eds) Basal 95. Wang ZY, Huang MT, Ho CT et al (1992) Inhibitory effect of
and squamous cell skin cancers of the head and neck, Williams green tea on the growth of established skin papillomas in mice.
and Wilkins, Baltimore, pp 1–7 Cancer Res 52:6657–6665
85. Taylor CR, Stern RS, Leyden JJ et al (1990) Gilchrest, photo- 96. Wei H, Ca Q, Rahn R et al (1998) DNA structural integrity and
aging/photodamage and photoprotection. J Am Acad Dermatol base composition affect ultraviolet light-induced oxidative DNA
22:1–15 damage. Biochemistry 37(18):6485–6490
86. Timares L, Katiyar SK, Elmets CA (2008) DNA damage, 97. Wei H, Saladi R, Lu Y et al (2003) Isoflavone genistein:
apoptosis and Langerhans cells-activators of UV-induced photoprotection and clinical implications in dermatology. J Nutr
immune tolerance. Photochem Photobiol 84:422–436 133(11 Suppl 1):3811S–3819S
87. Ullrich SE (1995) Potential for immunotoxicity due to envi- 98. Wei H, Zhang X, Zhao JF et al (1999) Scavenging of hydrogen
ronmental exposure to ultraviolet radiation. Hum Exp Toxicol peroxide and inhibition of ultraviolet light-induced oxidative
14:89–91 DNA damage by aqueous extracts from green and black teas.
88. Urbach F (1991) Incidences of nonmelanoma skin cancer. Free Radic Biol Med 26:1427–1435
Dermatol Clin 9:751–755 99. Yang CS, Wang ZY (1993) Tea and cancer. J Natl Cancer Inst
89. Vanderveen EE, Grekin RC, Swanson NA et al (1986) Arachi- 85:1038–1049
donic acid metabolites in cutaneous carcinomas. Arch Dermatol 100. Yarosh D, Alas LG, Yee V et al (1992) Pyrimidine dimer
122:407–412 removal enhanced by DNA repair liposomes reduces the inci-
90. Vayalil PK, Elmets CA, Katiyar SK (2003) Treatment of green dence of UV skin cancer in mice. Cancer Res 52:4227–4231
tea polyphenols in hydrophilic cream prevents UVB-induced 101. Yoshikawa T, Rae V, Bruins-Slot W (1990) Susceptibility to
oxidation of lipids and proteins, depletion of antioxidant effects of UVB radiation on induction of contact hypersensi-
enzymes and phosphorylation of MAPK proteins in SKH-1 tivity as a risk factor for skin cancer in humans. J Invest Der-
hairless mouse skin. Carcinogenesis 24:927–936 matol 95:530–536
91. Vayalil PK, Mittal A, Hara Y et al (2004) Green tea polyphenols 102. Zhao JF, Zhang YJ, Jin XH et al (1999) Green tea protects
prevent ultraviolet light-induced oxidative damage and matrix against psoralen plus ultraviolet A-induced photochemical
metalloproteinases expression in mouse skin. J Invest Dermatol damage to skin. J Invest Dermatol 113:1070–1075
122:1480–1487 103. Zi SX, Ma HJ, Li Y et al (2009) Oligomeric proanthocyanidins
92. Wang SQ, Setlow R, Berwick M (2001) Ultraviolet A and from grape seeds effectively inhibit ultraviolet-induced mela-
melanoma: a review. J Am Acad Dermatol 44:837–846 nogenesis of human melanocytes in vitro. Int J Mol Med
93. Wang Y, Zhang X, Lebwohl M et al (1998) Inhibition of ultra- 23:197–204
violet B (UVB)-induced c-fos and c-jun expression in vivo by a 104. Ziegler A, Jonason AS, Leffell DJ et al (1994) Sunburn and p53
tyrosine kinase inhibitor genistein. Carcinogenesis 19:649–654 in the onset of skin cancer. Nature 372:773–776
94. Wang ZY, Huang MT, Ferraro T et al (1992) Inhibitory effect of
green tea in the drinking water on tumorigenesis by ultraviolet

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