Hindawi Publishing Corporation
Oxidative Medicine and Cellular Longevity
Volume 2012, Article ID 560682, 8 pages
Protective Mechanismsof GreenTea PolyphenolsinSkin
PatriciaOyetakinWhite,1Heather Tribout,1and ElmaBaron1,2
1Department of Dermatology, University Hospitals Case Medical Center, Cleveland, OH 44106-5028, USA
2Department of Dermatology, Louis Stokes Cleveland Veterans Affairs Medical Center, Cleveland, OH 44106, USA
Correspondence should be addressed to Elma Baron, email@example.com
Received 9 February 2012; Accepted 25 April 2012
Academic Editor: Luciano Pirola
Copyright © 2012 Patricia OyetakinWhite et al.ThisisanopenaccessarticledistributedundertheCreativeCommonsAttribution
License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly
Skin is frequently exposed to a variety of environmental, chemical, and genotoxic agents that contribute to disease and
carcinogenesis. Ultraviolet light (UVR) is the main external stress that leads to immunosuppresion, oxidative stress, premature
aging, and tumor formation. Scientists and health professionals emphasize the importance of prevention strategies to circumvent
such unfavorable outcomes. Plant polyphenols are a promising approach to disease prevention and treatment. Green tea is an
abundant source of plant polyphenols that exhibit significant antioxidant, chemopreventive, and immunomodulatory effects in
protecting the skin.
Ultraviolet radiation (UVR) is a major environmental source
of damage to the skin. Its effect on the skin’s biology
and immune system plays a major role in photoaging,
inflammation and carcinogenesis . Approximately 3.5
million skin cancers are diagnosed annually in the United
dramatically from 1996 to 2006 . The morbidity and
economic burden of this malignancy is significant as the
estimated total direct costs for treatment of NMSC and
melanoma are $1.5 billion and $249 million, respectively [3,
4]. Sun avoidance, regular use of sunscreen, and protective
clothing are the recommended methods of preventing UVR-
4837 adult skiers and snowboarders about their sunscreen
use and reapplication. Only 4.4% of adults were compliant
with the recommended guidelines of applying sunscreen up
to 30 minutes before sun exposure and reapplication every
2 hours . Therefore there is a need to identify additional
photoprotection strategies to engage the community at-large
about the importance and benefits of sun protection.
In the last few decades there has been a dramatic increase
in the use of plant and herbal supplements as people are
seeking different methods of disease prevention . Green
tea consumption has become a popular trend in western
cultures as its beneficial effects in human disease have shown
promising results. Scientists searching for alternatives to
preventing and treating disease have recognized its powerful
beneficial effects in many organ systems. Green tea extracts
were found to be effective at suppressing environmentally
induced breast cancer , inhibiting T lymphocyte expan-
sion in autoimmune diseases , and suppressing inflam-
matory responses in coronary vessels in rodent experiments
. Favorable results have also been demonstrated in skin
disease and carcinogenesis. Recent in vitro and in vivo animal
and human skin studies also showed its anti-inflammatory,
antioxidant, photoprotective, and chemopreventative effects
after topical application and oral consumption [10–14]. This
review will discuss the chemical properties of green tea
that make it effective in skin biology and immunology and
how its mechanisms of action play a role in antioxidant,
photoprotective and chemopreventative functions in the
Polyphenols are naturally occurring chemicals derived from
plants, fruits, nuts, and vegetables. They have been proven to
2Oxidative Medicine and Cellular Longevity
(a) (−)-Epigallocatechin-3-gallate (EGCG)
(b) (−)-Epigallocatechin (EGC)
(c) (−)-Epicatechin (EC)
(d) (−)-Epicatechin-3-gallate (ECG)
Figure 1: Structure of green tea polyphenols.
have many beneficial health benefits. Being widely abundant
and relatively inexpensive, the use of polyphenols is highly
attractive to researchers as a strategy for a cost-effective
alternative to current pharmacologic therapeutics . Tea
is an important dietary source of plant polyphenols and next
to water it is the second most commonly consumed beverage
Camellia sinensis. The tea plant originated in Southeast Asia
over 4,000 years ago and is currently produced in over 35
countrieswithChina, India,SriLanka,andKenya generating
three-quarters of the world’s production. The six different
types of tea (white,yellow,green, oolong, black,and post fer-
mented teas) are categorized based on the wilting and enzy-
matic oxidization that takes place during processing .
There are three main types of polyphenols (flavonoids,
stilbenes, and lignans) that are classified by the num-
ber of phenol rings they contain and the binding
properties of the ring structures. The phenol rings
are comprised of phenyl and hydroxyl group struc-
tures that possess anti-inflammatory, immunomodulatory
and antioxidant properties . Each class of polyphe-
nols can be further subclassified by the interactions of
their respective phenyl rings to carbon, oxygen, and
organic acid molecules . This creates the huge diver-
sity of polyphenol compounds that can be found in
many naturally occurring food products. Flavonoids are
divided into 6 subclasses: flavonols, flavones, isoflavones,
flavanones, anthocyanidins, and flavanols. Majority of
the green tea polyphenols (GTPPs) are monomeric fla-
vanols called catechins. The four main catechin com-
pounds are (−)-epigallocatechin-3-gallate (EGCG), (−)-
epigallocatechin (EGC), (−)-epicatechin-3-gallate (ECG),
and (−)-epicatechin (EC) (Figure 1). EGCG is the most
abundant and extensively studied catechin with potent
therapeutic effects in skin.
3.SkinDamagingEffects of UltravioletLight
Sunlight is an important source of energy to sustain life.
However, except for vitamin D synthesis, it has several
harmful effects to the skin. Solar UVR can be divided into
three categories based on wavelength: UVA (320–400nm),
Oxidative Medicine and Cellular Longevity3
wavelength UVC (<280nm) and a portion of UVB (280–
295nm) are absorbed by the ozone layer and atmosphere;
therefore it does not reach the Earth’s surface where it is
capable of causing extreme damage to DNA and biomolec-
ular molecules . Longer wavelength UVB (295–320nm)
makes up only 5–10% of atmospheric UVR but it has been
implicated in a variety of skin diseases, nonmelanoma and
melanoma skin cancers. DNA is a chromophore for UVB
and this direct interaction produces cyclobutane pyrimidine
dimers (CPD) and pyrimidine-pyrimidone (6–4) mutagenic
photoproducts that lead to tumor initiation and tumor pro-
motion [20–22]. UVB also has indirect detrimental effects
on the skin’s immune system, oxidative stress responses, and
photoaging [22, 23].
UVA radiation is far more abundant (90%) and pene-
trates much deeper into the epidermis and dermis of the
skin. It is weakly absorbed by DNA but reacts with other
nonDNA chromophores that lead to the formation of ROS
which damage DNA, proteins, and lipids in the skin [24–
26]. Singlet molecular oxygen produced by UVA targets
DNA base guanine producing 8-oxo-7,8-dihydroguanine (8-
odHG) which is an important marker of oxidative stress [27,
28]. With the increased use of high-intensity UVA tanning
booths and UVB-absorbing sunscreens, human exposure
to UVA has become a public health concern . UVA-
induced mutagenesis is still an area of debate; however, it
is clear it plays a significant role in producing bipyrimidine
photoproducts that have genotoxic effects . In vivo
human studies have also demonstrated the immunosuppres-
sive effects of UVA and its increasing role in carcinogenesis
. In order to avoid potential mutations, UVR-induced
DNA lesions are repaired by nucleotide excision repair
(NER) and base excision repair (BER) mechanisms before
DNA replication occurs. Additionally, stress signals created
by UVR trigger protective signaling responses in the cell
membrane, nucleus, and mitochondria that lead to cell cycle
arrest or apoptosis [32–34]. Chronic and excessive UVR
exposure overwhelms and depletes these cutaneous defense
mechanisms. Therefore, compounds with antioxidant and
cell repair potential are promising additions to our sun
4.Oral Consumption andTopical
Human and animal studies using both topical and oral
preparations of GTPP have shown significant protective
effects against UV-induced skin damage and immunosup-
pression. As an external organ system, skin allows for direct
pharmacological intervention with topical products. This
mode of delivery also minimizes the potential for systemic
toxicity. Topical application of EGCG in a hydrophilic
ointment demonstrated better photoprotective properties
versus oral consumption in mice . In this in vivo study,
topical application provided significantly greater benefit
against UVB irradiation-induced depletion of antioxidant
enzymes and signaling protein phosphorylation. These pho-
toprotective functions of GTPP may be mediated through
interactions with inflammatory signaling molecules. Upon
UVR exposure Interleukin-12 (IL-12) is known to enhance
NER enzyme activity in keratinocytes . Meeran et al.
proposed an IL-12-dependent mechanism of DNA repair
by topically applied EGCG . In this study, UV-induced
suppression of CHS responses was maintained in IL-12
knockout mice in comparison to wild type mice. Subcuta-
neous injection with IL-12 three hours prior to UV exposure
in the IL-12 knockout mice diminished the amount of CPD
positive cells produced in contrast to the untreated group.
Earlier studies using topical and orally consumed GTPP in
mice decreased UVR-induced carcinogenesis, by inhibiting
the activity of chemical tumor initiators and promoters [38–
Recent studies by Katiyar et al. demonstrated a dose-
dependent decrease in UVR-induced immunosuppression
via contact hypersensitivity response (CHS) to 2, 4-
dinitrofluorobenzene in mice that were fed purified GTE
. This decrease in immunosuppression was persistent
4 weeks after resumption of a normal liquid diet in the
animals. The authors further demonstrated that GTPs in
drinking water of UV-irradiated mice reduced the migration
of CPD positive cells to lymph nodes and improved the
NER mechanisms. Similar results were seen in adult human
subjects that ingested 7.5mg of pure (commercially avail-
able) green tea brewed in 540mL of boiling water. There
was a significant decrease in UVR-induced DNA damage
of peripheral white blood cells [42, 43]. Human studies
using topically applied GTPP prior to exposure with 2-MED
of SSR demonstrated a decrease in SSR-induced erythema,
DNA damage, Langerhans cell damage, and production of 8-
OHdG in healthy human subjects [44, 45].
In general, GTPP has been shown to be well tolerated in
animal and human trials. Topical preparations have the
least harmful effects with minor irritation being the most
significant finding ; however, adverse effects of oral
study in fasting Beagle dogs, oral ingestion of green tea
extract capsules caused unexpected morbidity and mortality
(16 deaths out of 24 treated animals) in the treated versus
control group resulting in early termination of the study
group . Clinical signs of toxicity, weight loss were
observed as early by day 9 of this chronic study group
with fasting animals. Follow-up studies by the authors
demonstrated more favorable results when the green tea
capsules were administered in a fed state. Although the exact
mechanism of the toxicity was not determined, the authors
suggested gastrointestinal irritation, organ, and hematologic
evidence of immune-mediated hemolysis may have played a
role in the toxicity of ingesting a capsular form of the green
tea extracts. Studies by Isbrucker et al., where mice were fed
liquid and powered purified green tea extracts, did not show
any genotoxic effects .
In vitro culture experiments by Navarro-Peran et al.
showed that EGCG inhibits the activity of dihydrofo-
late reductase (DHFR) which is an important enzyme
4Oxidative Medicine and Cellular Longevity
in nucleotide biosynthesis . The authors suggested
that this effective inhibition provides evidence for EGCG’s
chemotherapeutic mechanism of action. Their results pro-
vide an interesting insight into the reported association of
maternal tea consumption and neural tube defects .
There are a limited number of published studies showing
this teratogenic effect especially given the large amount of
tea consumed globally. Experiments evaluating reproductive
and developmental toxicity of EGCG in rats did not show
teratogenic effects .
The skin has a complex defense system to deal with harmful
environmental and chemical substances but excessive or
chronic exposure can overwhelm the system leading to
oxidative stress and oxidative damage. In cells, reactive oxy-
gen species (ROS) are formed during the energy-producing
process of reducing molecular oxygen to water. These are
superoxide radicals (O2•−), hydrogen peroxide (H2O2), and
hydroxyl radical (•OH). An overproduction of ROS depletes
physiologic ROS-scavenging enzymes (superoxide dismu-
tase, and catalase) which cause damage to proteins, lipids,
and DNA  that contribute to skin diseases, immunosup-
pression, and development of skin cancer. GTPPs have been
their chemical structures can chelate metal ions and decrease
free radical damage to cellular structures [53, 54].
Photoaging is caused by chronic UV exposure. In vitro
GTPP showed a decrease in hydrogen peroxide (H2O2)-
induced ROS. In this study, the authors demonstrated
the ability of GTPP to improve fibroblast cell shape and
absolute cell numbers when compared to control groups
. To assess the effect of GTE on lipid peroxidation
(LPO), Jorge et al. conducted an in vitro assay using
liposomal phophatidylcholine structure. They demonstrated
a significant decrease in the concentration of hydroperoxides
after a 3-hour reaction with an oxidative compound .
The inhibitory effect of GTPP on hydrogen peroxide
formation and cell signaling is paramount to its antioxidant
properties. There are few in vivo human studies demonstrat-
ing this protective event. In 2001, Katiyar and colleagues
demonstrated this protective effect in adult human volun-
teers exposed to a single dose of (4xMED) UV irradiation
prior to topical EGCG administration . These authors
confirmed what is already known about EGCG inhibition
of UV-induced H2O2, NO and LPO production. They also
demonstrated blockage of UV-induced infiltration of ROS-
cells and restoration of epidermal
antioxidant enzymes reduced glutathione, catalase, and
7.Mechanismof Action of GTPP
Mitogen-activated protein kinases (MAPKs) are a group
of serine/threonine proteins that are involved in cellular
functions in the skin including cell growth, differentiation,
proliferation, and apoptosis . These proteins include
extracellular signal-regulated kinases (ERK), c-Jun NH2-
terminal kinases (JNK), and p38. MAPK signaling cascades
and downstream effectors are triggered in response to UVR-
induced oxidative and genotoxic stress. The activity of
GTPP is likely due to free radical scavenging activity that
prevents MAPK activation. Topical application of GTPP in
SKH-1 hairless mice showed inhibition of UVB-induced
phosphorylation of ERK1/2, JNK, and p38 expression .
These results were also seen in human dermal fibroblasts
where EGCG inhibited the UVB-induced activation of these
downstream effector pathways . Bae et al. also demon-
strated the attenuation of nuclear transcription factors c-
Jun, p53, and c-fos within 30mins of UVB irradiation
of the cultured cells. UVB-generated hydrogen peroxide
stimulates membrane epidermal growth factor receptors
(EGFRs) that activate ERK proteins which contribute to
cell proliferation and differentiation that may be involved
in tumor promotion . Pretreatment of normal human
epidermal keratinocytes (NHEKs) with EGCG prior to UVB
ERK1/2, JNK, and p38 proteins . Green tea extracts have
been implicated in immunoregulatory signaling functions.
Rodent experiments by Kim et al. demonstrated a dose-
dependent decrease in histamine production by peritoneal
these authors proposed that the altered histamine release was
due to a GTE-mediated decrease in cAMP and calcium levels
which led to a NFκB and p38 MAPK-dependent inhibition
of proinflammatory cytokines, TNF-α and IL-6. Table 1 lists
the major cellular and molecular targets of GTPP on normal
8.Role of GTPP inChemoprevention
Cancer remains the second leading cause of death in the
United States . Studies have shown that 30–40% of all
cases of cancers can be prevented by combining a healthy
diet, exercise, and maintaining a healthy body weight, and
more than 20% of all cases of cancer can be prevented
just by consuming an ample and varied amount of fruits
and vegetables [15, 63]. EGCG has been shown to inhibit
tumor invasion and angiogenesis thereby preventing tumor
growth and metastasis . Dermatologists are considerably
interested in green tea polyphenols (GTPP) as preventative
products for skin cancer, as their use have shown promising
Skin cancer is the most common of all cancers; however
it is very preventable and curable if diagnosed early. Chronic
exposure to UVR is the key factor in initiating skin cancer.
UVB radiation induces both direct and indirect biologic
effects, including multiple effects on the immune system,
inducing oxidative stress, and damaging DNA, all in which
play an important role in the generation and maintenance of
neoplasms .Invitro andinvivo systemshavebothshown
the protective effects from polyphenols on the biochemical
processes that are induced or mediated by UV radiation,
Oxidative Medicine and Cellular Longevity5
Table 1: Summary of effects of green tea polyphenols on skin.
GTPP protective effect Cellular and/molecular response
Inhibits UVB-induced MAPK activation and phosphorylation of ERK1/2, JNK
Attenuates nuclear transcription factors, c-Jun p53, and c-fos
Free radical scavenging activity
Inhibits NOS, H2O2production
Prevents UVB-induced depletion of antioxidant enzymes: catalase, glutathione
peroxidase, superoxide dismutase, and glutathione
Inhibits UVB-induced LPO and protein oxidation
Prevents UV-induced depletion of CD1a + LC and APC Inhibits UV-
induced infiltration of monocytes, macrophages, neutrophils
Protects UVB-induced immunosuppression via IL-12 production
↓ in histamine release by mast cells
Inhibits DNA damage.
Inhibits UV-induced CPD, 8-OHdG formation
DNA repair enzyme activation
Modulates transcriptions factors AP1, NFKB
Inhibits tumor growth, progression and angiogenesis
UV protection [51–54, 57]
[37, 45, 55, 57, 60]
Anticarcinogenesis[45, 48, 59, 60]
LC: langerhans cells; LPO: lipid peroxidase; MAPK: mitogen-activated protein kinase; NOS: nitric oxide synthase.
orally may provide effective protection against UV radiation
and ultimately skin cancer .
Polyphenols are shown to possess anti-inflammatory,
and green tea extract are non-toxic for humans and have a
wide range of target organs making it significantly different
than the standard form of preventative cancer drugs. Not
only is EGCG widely distributed throughout the body, but
studies also show that multiple oral administrations causes a
synergistic effect leading to higher concentrations of EGCG
in the cells. This effect was first seen in a study involving
mice, where 3H-EGCG was administered and measured in
the excretions. 24 hours after the intubation, radioactivity
was still found in multiple organs including the skin.
After multiple administrations of 3H-EGCG, radioactivity
increased 4–9 times in most organs, suggesting that routine
consumption or topical treatment may provide efficient
protection against UV radiation in humans. These results
at green tea consumption and the average age of cancer
onset. Cancer onset of male patients consuming more than
10 cups of green tea was approximately 3.2 years later than
male patients who consumed less than 10 cups of green
tea per day, and cancer onset for women drinking more
than 10 cups of green tea per day was 7.3 years later. These
results allowed researchers to determine the effective cancer
preventative amount to be approximately 10 Japanese-size
cups (120mL/cup) of green tea per day, which is equivalent
to about 2.5g of green tea extract . Another study
observed that regular intake of EGCG increased the minimal
dose of radiation required to induce erythema, suggesting
that the EGCG is able to strengthen the skin’s tolerance by
inhibiting the UV-induced skin damage from the radiation
. From these findings it can be seen that orally consumed
EGCG has two different mechanisms of action and can act
as both a chemopreventive and photochemopreventive drug;
it can protect the body by suppressing, slowing down, and
reversing the process of carcinogenesis, as well as protecting
the skin from damaging radiation caused by harmful UVB
As mentioned before, UVB radiation induces oxidative
stress and DNA damage, and also affects the immune system.
In separate experiments, it has been shown that topical
treatments containing EGCG significantly inhibits acute or
chronic UV irradiation-induced protein oxidation in the
skin of mice, suggesting that GTTP’s may be able to reduce
photo damage in the skin and prevent premature aging
[45, 65, 67]. Another study showed that the pretreatment of
mouse skin with EGCG inhibited UVB-induced infiltration
of leukocytes, specifically CD11b+cells in the skin which
mediate UV-induced immunosuppression. These infiltrating
leukocytes can be a potential source of H2O2and NO which
play important roles in initiating and promoting tumor cells.
Less damage to the epidermal structure of the mouse skin
was also observed with the topical application of EGCG
before being exposed to UVB light. The data collected
in this study demonstrated the potent preventative effects
of topical EGCG in mice against UV radiation-induced
infiltration of leukocytes, suggesting that GTTP’s may have
preventative effects against the development of skin cancer
in humans . Inflammatory responses are implicated in
skin disease, tumorigenesis, and tumor metastasis. EGCG
effectivelyinhibited human melanoma cellculturegrowth by
decreasing IL-1β secretion and NFκB activity .
As discussed in this paper, GTPPs have important antiox-
idant, immunomodulatory, and photoprotective functions.
6Oxidative Medicine and Cellular Longevity
Their ability to modulate critical biochemical functions
through topical and oral formulations makes GTPPs a
promising candidate for chemoprevention and treatment of
disease. Future collaborative studies are needed to clarify
optimum dosing amounts that will provide therapeutic
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The authors declare no conflict of interests.
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