solar radiation induced skin damage review of protective and preventive options

Solar radiation induced skin damage: Review of protective andpreventive options

ALENA SVOBODOVA & JITKA VOSTALOVA

Department of Medical Chemistry and Biochemistry, Faculty of Medicine and Dentistry, Palacky University, Hnevotınska 3,

Olomouc, Czech Republic

(Received 20 October 2009; Revised 10 June 2010; Accepted 14 June 2010)

AbstractPurpose: Solar energy has a number of short- and long-term detrimental effects on skin that can result in several skindisorders. The aim of this review is to summarise current knowledge on endogenous systems within the skin for protectionfrom solar radiation and present research findings to date, on the exogenous options for such skin photoprotection.Results: Endogenous systems for protection from solar radiation include melanin synthesis, epidermal thickening and anantioxidant network. Existing lesions are eliminated via repair mechanisms. Cells with irreparable damage undergoapoptosis. Excessive and chronic sun exposure however can overwhelm these mechanisms leading to photoaging and thedevelopment of cutaneous malignancies. Therefore exogenous means are a necessity. Exogenous protection includes sunavoidance, use of photoprotective clothing and sufficient application of broad-spectrum sunscreens as presently the best wayto protect the skin. However other strategies that may enhance currently used means of protection are being investigated.These are often based on the endogenous protective response to solar light such as compounds that stimulate pigmentation,antioxidant enzymes, DNA repair enzymes, non-enzymatic antioxidants.Conclusion: More research is needed to confirm the effectiveness of new alternatives to photoprotection such as use of DNArepair and antioxidant enzymes and plant polyphenols and to find an efficient way for their delivery to the skin. Newapproaches to the prevention of skin damage are important especially for specific groups of people such as (young) children,photosensitive people and patients on immunosuppressive therapy. Changes in public awareness on the subject too must bemade.

Keywords: skin, solar radiation, melanin synthesis, antioxidant system, DNA repair, exogenous protection

Introduction

Life on the earth is impossible without sunlight.

Plants utilise the energy in photosynthesis and many

vital functions in animals and humans are associated

with solar light. However, exposure to the sun rays is

becoming increasingly dangerous and is associated

with a number of acute and chronic detrimental

effects to the skin that may result in the development

of skin cancer. Studies in photodermatology have

focused mainly on ultraviolet (UV) radiation, the

frequency range recognised as the most abundant

potential carcinogen. However growing evidence

shows that visible and infrared (IR) light has

significant effects on the skin as well. In contrast to

the precise characterisation of the UV response, little

is known about the biological effects of visible and IR

radiation, although the skin is exposed to several

sources of visible and IR light such as sunlight and

sunbeds. Apart from deleterious effects, UV light has

beneficial health effects such as vitamin D3 formation

and the treatment of skin diseases such as psoriasis

and vitiligo. Similarly, visible and IR wavelengths

have therapeutic applications in several conditions

such as inflammation, malignancies and wound

healing.

In this review, we summarise approaches to skin

protection against UV radiation. The skin covers the

body and guards the organism against the deleterious

effects of the environment including sunlight. For

this reason it has defences against its harmful impact.

However, due to changed lifestyles, increasing

amounts of UV rays reaching the earth and the

limited potential of the skin’s defence, conscious

Correspondence: Dr Alena Svobodova, Department of Medical Chemistry and Biochemistry, Palacky University, Hnevotınska 3, 775 15 Olomouc, Czech

Republic. Tel: þ420 5856 32314. Fax: þ420 5856 32302. E-mail: [email protected]

Int. J. Radiat. Biol., Vol. 86, No. 12, December 2010, pp. 999–1030

ISSN 0955-3002 print/ISSN 1362-3095 online � 2010 Informa UK, Ltd.

DOI: 10.3109/09553002.2010.501842

protection is becoming necessary. Both endogenous

and exogenous skin protection are discussed here.

Skin anatomy

The skin covers the whole body surface and

represents the largest organ with a surface area and

thickness of approximately 1.5–2.0 m2 and 1–4 mm,

respectively. The skin is a complex, integrated,

dynamic tissue with many vital functions such as

metabolic, detoxication, immunological and thermo-

regulative. However, it is the main barrier protecting

the body from environmental attack including solar

radiation (Kanitakis 2002).

Anatomically, the skin is made up of three layers:

epidermis, dermis, and hypodermis (Junqueira et al.

1992). The epidermis consists of squamous kerati-

nised epithelium in which approximately 80% of the

cells are keratinocytes. Other cell types include

melanocytes (pigment synthesis), Langerhans cells

(immunological function), and Merkel cells (recep-

tor function). The human epidermis is formed of 4–5

layers, depending on body site. The most important

are the stratum basale (the innermost layer) and

stratum corneum (the outermost layer). The stratum

basale is a single layer of cuboidal to columnar

shaped cells that separate the epidermis from the

dermis. This layer serves as stem cells with the ability

to divide and produce new keratinocytes. After the

basal cells undergo mitosis, they migrate upward,

increase in size and produce numbers of differentia-

tion products. The basal layer is thus responsible for

continual keratinocyte replacement. The stratum

corneum consists of several layers of completely

keratinised dead cells devoid of nuclei and other

organelles. These cells, called corneocytes, are

constantly being shed (Monteiro-Riviere 2004).

The stratum corneum comprises a unique, highly

lipophilic 2-compartment system of structural cor-

neocytes embedded in a lipid-enriched intercellular

matrix, forming stacks of bilayers that are rich in

ceramides, cholesterol and free fatty acids. The lipid

composition and structure of the stratum corneum

play a key role in determining the barrier integrity

that is essential for skin desquamation (Thiele et al.

2001). Melanocytes are specialised epidermal cells

comprising approximately 1–2% of all epidermal

cells and are the second most abundant cell type in

the epidermis. They are derived from the neural crest

and migrate into the epidermis late in the first

trimester. Melanocytes reside in the basal cell layer in

contact with adjacent keratinocytes (Reedy et al.

1998, Yaar and Gilchrest 2001). Each basal layer

melanocyte is associated with about 30–40 keratino-

cytes and one Langerhans cell. This association

enables melanocytes to transport the skin photo-

protective pigment melanin which they produce, into

keratinocytes and in this way protect epidermal cells

against UV-induced damage (for more see Skin

pigmentation). Recent studies show that melanocytes

also have other functions in addition to melanin

synthesis. They secrete a wide range of signal

molecules such as cytokines (interleukin-1, -3,

-6 [IL-1, IL-3, IL-6], tumour necrosis factor-a[TNF-a]), catecholamines and nitric oxide (NO) in

response to a number of stimuli including UV

radiation. In this way they influence surrounding

keratinocytes, fibroblasts, Langerhans cell, lympho-

cytes, mast cells and endothelial cells (reviewed in

Tsatmali et al. 2002). Langerhans cells are mobile,

dendritic, antigen presenting cells. They are present

in all stratified epithelia. They originate from CD34þ

haemopoietic precursors of the bone marrow and are

capable of uptaking exogenous antigens deposited on

the skin (Kanitakis 2002).

The dermis and epidermis are interconnected by

epidermal and dermal papillae. The dermis consists

primarily of dense irregular connective tissue within

the matrix of collagen and elastin fibres that make it

compressible and elastic. Fibroblasts are the pre-

dominant cell type in the dermis. Other cell types

include mast cells, macrophages, adipocytes and

plasma cells. The tissue is interwoven with nerve

fibres, blood and lymphatic vessels that also feed the

epidermis (Junqueira et al. 1992). Fibroblasts are

spindle-shaped or stellate cells containing a well-

developed rough endoplasmic reticulum. They

synthesise all types of fibres and ground substances.

Fibrocytes are small, quiescent fibroblasts devoid of

obvious metabolic activity, and encountered in

mature connective tissue. The majority (4 90%) of

dermal fibres are made of interstitial collagen, mainly

of types I and III and are responsible for the

mechanical resistance of the skin. Other collagens

found in the dermis include type IV and VII

(Kanitakis 2002).

Sun radiation and biological damage

The sun emits a wide spectrum of electromagnetic

wavelengths classified into different spectral regions

as UV, visible and IR radiation (Figure 1). UV

wavelengths are studied most intensively and are still

recognised as the most aggressive towards cell

components although several studies, however, have

shown that other regions of solar radiation have

adverse biological effects as well.

UV radiation

UV makes up just 5% of solar rays that reach the

earth’s surface. Depending on the wavelength, UV

light (100–400 nm) is commonly divided into three

regions: UVA (315–400 nm), UVB (280–315 nm)

1000 A. Svobodova & J. Vostalova

and UVC (100–280 nm). UVA is further subdivided

into UVA1 (340–400 nm) and UVA2 (315–340 nm).

The most damaging and cytotoxic part of solar UV

light (100–295 nm) is absorbed in the stratospheric

ozone layer. The remaining incoming UV radiation,

a part of UVB (295–315 nm) and all UVA, is

responsible for manifold skin disorders (Ridley et al.

2009). The amount of UV rays reaching the ground

and ratio of UVA/UVB depend on several factors

such as latitude, season, cloud cover and time of day.

However, the sun is primarily a UVA source with an

approximate terrestrial UVB content of about 5%

(Young 2006). UVB is mostly absorbed by the

epidermis and as much as 70% is blocked by the

stratum corneum. 80% of UVA reaches the dermo-

epidermal junction and penetrates deeper into the

papillary dermis (Figure 2). Around 10% of UVA

even reaches even the hypodermis (Verschooten

et al. 2006).

UV damage occurs in two different ways. UVA

primarily initialises massive production of reactive

oxygen and reactive nitrogen species (ROS, RNS;

Table I) through interaction with endogenous

chromophores (photosensitisers) such as nucleic

acid bases, aromatic amino acids, NADH, NADPH,

heme, quinones, flavins, porphyrins, carotenoids,

7-dehydrocholesterol, eumelanin and urocanic acid.

ROS/RNS are capable of oxidising cellular mole-

cules leading to the formation of oxidised products

including lipid hydroperoxides and protein carbonyls

both of which have been implicated in skin disorders.

ROS/RNS have also been reported to induce various

types of oxidative DNA lesions such as single-strand

breaks, DNA-protein crosslinks but mainly, altered

DNA bases (Figure 3). Due to their low ionisation

potential, the guanine bases are the most susceptible

to oxidation and 8-hydroxyguanine (8-OH-G;

Figure 3) is a characteristic oxidative product.

Oxidative DNA lesions are thought to be important

in the initiating stage of carcinogenesis (Svobodova

et al. 2006).

In contrast, UVB is directly absorbed by DNA,

particularly by aromatic heterocyclic bases, strongly

absorbing chromophores with the absorption max-

imum between 260 and 280 nm. UVB absorption

leads to the formation of cyclobutane pyrimidine

dimers (CPD) and pyrimidine-(6–4)-pyrimidone

photoproducts (6-4PP) between adjacent pyrimidine

bases on the same strand (Figure 4) (Verschooten

et al. 2006). CPD are formed three times more often

than 6-4PP. On exposure to UVB/UVA light, 6-4PP

adducts are readily converted into Dewar valence

isomers (Figure 4). These are only moderately

photoactive but can undergo reversion to the 6-4PP

upon exposure to short-wavelength UV radiation

(Svobodova et al. 2006). Recently, CPD were found

to be produced in significant yield in whole human

skin exposed to UVA light as well. However, the

mechanisms of CPD formation on UVA and UVB

irradiation are different. CPD are predominantly

produced at thymine-thymine sites after UVA

irradiation. In addition, no other photoproducts

such as 6-4PP and Dewar valence isomers can be

detected in UVA exposed human skin. The distribu-

tion of dimeric photoproducts suggests that a

photosensitisation reaction involving a triplet energy

transfer mechanism rather than a direct excitation

process takes place on exposure of skin to UVA

(Mouret et al. 2006, 2010). Due to less pronounced

DNA protective response (expression of tumour

suppressor p53), the elimination of lesions is lower

and the UVA-caused lesions may have a more

mutagenic outcome (Kappes et al. 2006). Aromatic

amino acids of proteins, mainly tryptophane and

tyrosine, act as potent UVB radiation absorbers and

their UVB-caused modification may alter protein

function and cellular signalling (Verschooten et al.

2006). ROS/RNS as well as DNA lesions can affect

Figure 1. Solar radiation spectrum (modified according to Svobodova et al. 2006 and Ting et al. 2003).

Solar light protection: Review 1001

various cell pathways and gene expression. Altered

may be prostaglandin (PG) synthesis, expression of

inflammatory IL, TNF-a, nuclear factor-kappaB

(NFkB), matrix metalloproteinases (MMP), mito-

gen-activated protein kinases (MAPK), cyclin-

dependent kinases (CDK), tumour suppressor

p53, and pro- and anti-apoptotic pathway genes

(Svobodova et al. 2006). These signalling molecules

initiate the development of pathological changes in

skin tissue such as altered epidermal cell proliferation

and differentiation (cell cycle lengthening), decrease

in collagen (especially type I) synthesis, up-regula-

tion of collagen-degrading enzymes, accumulation of

amorphous elastin material and loss of vascular

network (Baumann 2007). Extensive and chronic

exposure to UV leads to accumulation of oxidatively

modified molecules and DNA lesions as well as

disruption of control mechanisms (see below) all of

which may result in skin inflammation, immunosup-

pression, premature skin aging (photoaging) and/or

carcinogenesis.

UV-induced inflammation is a complex process

that includes a cascade of interconnected events. UV

exposure enhances blood flow and infiltration of

inflammatory blood leucocytes (macrophages and

neutrophils) to the skin tissue. UV light also

stimulates activity of phospholipase and subsequent

arachidonic acid release and cyclooxygenase-2

(COX-2) induction that finally increases PG forma-

tion. Increased generation of PG and NO further

enhances leucocytes infiltration and lipid peroxida-

tion. The inflammatory response is also reinforced by

TNF-a, NFkB and cytokines (IL-1a, IL-1b, IL-6).

These multiply ROS/RNS production and increase

the oxidative stress contributing to inflammation

(Halliday 2005).

NO has a special role in skin physiology. It

critically influences cell behaviour within the cell

communication. NO is produced by NO synthase

(NOS; EC 1.14.13.39) from L-arginine. Constitu-

tive NOS isoforms generate permanently low con-

centrations of NO. However, inducible NOS,

stimulated by UV radiation via several cytokines,

growth factors and inflammatory stimuli, produces

high levels of NO. Most NO is produced by

inflammatory cells, notably macrophages though

fibroblasts, keratinocytes, melanocytes, Langerhans

and endothelial cells also contribute to NO genera-

tion (Witte and Barbul 2002). In general, the

Figure 2. Wavelength-dependent absorption of solar light by human skin (modified according to Ettler 2004, Schroeder et al. 2008, Timares

et al. 2008). The absorption of individual sunlight wavelength by the skin corresponds to the energy intensity of the solar radiation spectrum.

The energy intensity gradually increases in the UV range with increasing wavelength, reaches a peak in the range of visible wavelengths and

then decreases progressively in the IR range of wavelengths. Thus UVA, visible and IRA wavelengths reach the hypodermis and affect all

layers of the skin. The less penetrating UVB and IRB act mainly in the epidermis including cells of the basal layer. IRC is mostly absorbed in

the upper layers of the epidermis. UVC, completely eliminated by the atmospheric ozone layer, is absorbed by the stratum corneum (SC) in

laboratory experiments.

Table I. Reactive oxygen and nitrogen species produced in skin

cells by UV radiation.

ROS RNS

Hydroxyl radical OH. Nitrogen oxide NO

Superoxide radical O2.7 Nitrogen dioxide NO2

Singlet oxygen 1O2 Peroxinitrite anion OONO7

Hydrogen peroxyde H2O2

Ozone O3


presence of NO is associated with pathological

processes as NO in massive amounts participates in

the initiation of sunburn and erythema and in

augmentation of the inflammatory response. On the

other hand, NO has essential functions in the

regulation of skin homeostasis. It acts as messenger

in UV-induced skin melanogenesis and contributes

to skin healing as it stimulates keratinocyte prolifera-

tion, re-epithelisation and is a critical factor in

collagen synthesis. It also takes part in regulation of

apoptosis (reviewed in Frank et al. 2002, Witte and

Barbul 2002, Weller 2003).

Langerhans cells are the major antigen presenting

cell in the skin that play a key role in the development

of the immune response. UV exposure results in

their depletion possibly due to the emigration from

the skin to the draining lymph nodes. In addition,

UV photons impair the ability of Langerhans cells to

present antigens. The antigen presentation may also

be disturbed by the photoproduct cis-urocanic acid

and immunosuppressive cytokines, such as IL-10.

Both UVA and UVB have been found to suppress

the human immune system. UV exposure suppresses

a wide variety of other immune reactions, including

contact hypersensitivity to chemical haptens and

delayed-type hypersensitivity to viral, bacterial and

fungal antigens (reviewed in Katiyar 2007).

The other result of chronic exposure to solar UV

light is photoaging which includes a complex of

physiological processes that affect the different skin

layers with the major damage seen in the cognitive

tissue of the dermis. The clinical symptoms are

dryness, wrinkling, elastosis, telangiectasia and

anomalous pigmentation. Histologically, the

dermis is strikingly filled with an amorphous mass

of deranged elastic fibres. Collagen fibres are

disorganised. Blood vessels are dilated and

tortuous. Dermal inflammatory cells are increased.

Figure 3. The major products of oxidative damage to DNA (RNA) bases.


Keratinocytes are irregular with loss of polarity.

Melanocytes are abnormal and reduced in number.

UVA that penetrates deep into the dermis is

suspected to play a more substantial role in photoa-

ging than UVB. However, more likely is that both

wavebands participate in the process. UVA-induced

MMP are capable of degrading the skin collagen

framework at the same time as procollagen synthesis

is inhibited. MMP-1 cleaves collagen type I, MMP-2

degrades elastin as well as basement membrane

compounds including collagen types IV and VII

while MMP-3 reveals the broadest substrate speci-

ficity for proteins such as collagen type IV, proteo-

glycans, fibronectin, and laminin. In addition, UV-

activated NFkB stimulates neutrophil attraction

bringing neutrophil collagenase (MMP-8) to the

irradiation site to further aggravate matrix degrada-

tion. Oxidative stress can also increase elastin mRNA

levels in dermal fibroblasts providing a mechanism

for the elastolytic changes found in the photoaged

dermis (reviewed by Pinnell 2003).

Waveband dependency of sunlight-induced

responses

Over evolution, human skin has adapted to solar

radiation consisting of both UVA and UVB wave-

bands, among others. On UV exposure, skin cells

produce signalling molecules that are distributed to

other cells/tissues where they have effects. However,

the relative contribution of UVA and UVB light to

the skin response remains unclear. Experiments have

revealed that UVA and UVB may produce the same

effects but over different time periods. This is

probably associated with activation of different

signalling pathways (Halliday and Rana 2008).

Several trials have shown that UVA and UVB

affect the immune system. Earlier experiments

suggested that UVA light has a rather immunopro-

tective function in contrast to the immunosuppres-

sive potential of UVB. The mechanism of UVA

preventive effect was attributed to elimination of

UVB-caused cytokine imbalance, particularly up-

regulation of interferon-g and IL-12 and inhibition of

IL-10 release (Shen et al. 1999), and induction of

cutaneous heme oxygenase-1 (HO-1) (Reeve and

Tyrrell 1999). Subsequent studies showed that while

higher doses protect from immunosuppression, low-

er UVA doses are immunosuppressive (Byrne et al.

2002). Poon et al. demonstrated that UVA and UVB

immunosuppression in human skin is time-depen-

dent: while UVB triggered immunosuppressive

signals within 24 h, UVA did so after 48 h.

Immunosuppression induced by solar simulated

radiation was interestingly apparent after 72 h and

interaction between UVA and UVB made it much

more suppressive then either waveband indepen-

dently (Poon et al. 2005). Similarly molecular cross-

talk between UVA and UVB signalling has been also

shown in relation to MAPK activation. UVA (30 J/

Figure 4. Formation of cyclobutane pyrimidine dimer (CPD) from adjacent pyrimidine bases on the same strand (A), pyrimidine-(6–4)-

pyrimidone photoproduct (6–4PP) and Dewar isomer (B) after absorption of UVB light energy.


cm2) treatment resulted in modest activation of

extracellular signal-regulated kinases 1/2 (ERK1/2)

in human keratinocytes. In contrast UVB (100 mJ/

cm2) induced strong ERK1/2 activation in keratino-

cytes. Only minor activation of c-Jun N-terminal

kinases 1/2 (JNK1/2) and p38 was observed after

both UVA and UVB irradiation. On the other hand

sequential exposure to UVA and UVB or UVB and

UVA led to significant phosphorylation of JNK1/2

and p38, while ERK1/2 activation was minimal.

These results suggest interactive effects of both

wavebands (Schieke et al. 2005). Currently, there is

little knowledge about the exact mechanisms of UVA

and UVB interaction. Explanation of their cross-talk

may however, lead to new insights for skin photo-

protection.

Visible radiation

Visible light wavelengths range from 400–760 nm

and comprise approximately 45% of solar rays.

Visible light is the most penetrating and approxi-

mately 20% reaches the hypodermis (Figure 2).

Visible wavelengths are absorbed by several skin

chromophores (e.g., melanin, riboflavin, haemoglo-

bin and bilirubin). A recent report has confirmed

that visible light contributes to radical generation

(Zastrow et al. 2009). In this respect, unsaturated

fatty acids and nucleic acids are the main targets of

visible light action. Visible and near IR wavelengths

also induce changes in human skin pigmentation

(Mahmoud et al. 2008). Zhevago et al. (2006)

recently found that exposure of human body to

polychromatic visible and IR light stimulates periph-

eral blood T-lymphocyte proliferation in vitro and

in vivo. They also observed rapid changes in cytokine

level in peripheral blood (Zhevago et al. 2005). The

molecular mechanism of visible light action is not

exactly clear. However, as the division between UVA

and visible light is arbitrary, the photobiological

effects of UVA and visible wavelengths may be

similar and probably involve reactions and damage

mediated via ROS/RNS (reviewed in Mahmoud

et al. 2008).

Infrared radiation

IR radiation ranging from 760 nm to 1 mm is

subdivided into near IRA (760–1400 nm), middle

IRB (1400–3000 nm) and far IRC (3000 nm–

1 mm). While IRB and IRC do not penetrate deeply

into the skin and are mostly absorbed in the

epidermis, more than 65% of IRA reaches the

dermis and around 10%, the hypodermis (Figure

2). The actual IR dose reaching the skin is influenced

by the same factors as the UV dose (Schroeder et al.

2008). In contrast to photochemical reactions

induced by UV, IR light typically produces mole-

cular vibrations and rotations causing an increase in

temperature. Modification in these vibrations and

rotations may influence the photochemical reactions

induced by UV rays and thus may increase the

damaging effects of UV on human skin (Schieke

et al. 2003). A recent study also confirmed that IRA

contributes to ROS generation (Zastrow et al. 2009).

The precise molecular mechanism of IR is however

largely unknown. Several studies have described IR

effects on gene expression (e.g., MMP) via induction

of ROS generation in mitochondria (Schroeder et al.

2008). Like UV, chronic IR exposure seems to be

involved in photoaging and photocarcinogenesis.

Endogenous skin protection

Human skin is equipped with a complex defence

against the deleterious effects of solar UV radiation.

This includes production of skin pigment, skin

thickening and a network of enzymatic and non-

enzymatic antioxidants that eliminate hazardous and

toxic substances but however efficient, this defence

can be overwhelmed. For this reason, skin cells also

have the ability to repair or eliminate modified

biomolecules. The end point is cell death via

apoptosis or necrosis if the damage, particularly to

DNA, is irreparable. However, throughout life,

impaired molecules accumulate in skin leading

to both (photo)aging and possibly skin cancer

(Figure 5).

Skin pigmentation

One of the first events in response to UV radiation is

skin darkening. The skin turns brown (tans) via two

distinct mechanisms: Immediate pigment darkening

(IPD) and delayed tanning (DT). Both processes are

influenced by genetic factors and are more pro-

nounced in darker constitutive pigmentation. IPD

begins during irradiation as a greyish coloration that

gradually fades to a brown colour over a period of

minutes to days depending on UV dose and

individual complexion. These changes are not due

to new melanin synthesis but result from oxidation of

pre-existing melanin and redistribution of melano-

somes from perinuclear to peripheral dendritic

location in melanocytes. IPD is caused mainly

by UVA rays and is marginally photoprotective

(Routaboul et al. 1999). In contrast, UVB wave-

lengths induce DT as a result of new melanin

synthesis. Melanin is produced in specialised cells,

melanocytes where synthesis occurs in specific ovoid

organelles known as melanosomes. UVB radiation

increases the activity and dendricity of melanocytes,

melanin synthesis and its transfer via dendrites to

adjacent keratinocytes. The new melanin thus


protects the skin at subsequent UV exposures.

Moreover, repeated UVB exposures induce in-

creased melanocyte number. Melanogenesis is evi-

dent 3–4 days after UV exposure and can increase

over eight weeks (Whiteman et al. 1999). A number

of cytokines, growth factors and inflammatory

mediators, produced by keratinocytes and fibroblasts

in response to UV light, influence melanocytes and

contribute to the final tanning response (Sturm

1998). Within individual melanocytes or keratino-

cytes melanin, often accumulates as a nuclear ‘cap’

that is thought to shield DNA from UV rays

(Fitzpatrick and Breathnach 1963). Though DT

and IPD cannot be distinguished by the naked eye,

their UV protective potency is different. Darkening

due to UVB light, induces expansion of melanin as

far as the stratum corneum, while UVA wavelengths

induce pigmentation only in the stratum basale and

thus UVA light is less efficient (Ettler 2004).

Melanin and melanogenesis

Melanin is a complex of lighter red/yellow, alkali-

soluble sulphur-containing pheomelanin and darker

brown/black insoluble eumelanin (Thody et al.

1991). Pheomelanin is the major type in red hair

and also dominates in the epidermis of skin types I

and II (Fitzpatrick classification). Eumelanin is

present in large amount in individuals with dark hair

and skin and is considered to be more photoprotec-

tive than pheomelanin (Tsatmali et al. 2002). Studies

have clearly demonstrated that tanning is a response

Figure 5. Scheme of skin endogenous protective mechanisms.


to DNA damage and normal tanning is dependent

on p53 expression (reviewed in Ibrahim and Brown

2008). Synthesis of both types of melanin arises from

L-tyrosine and requires the enzyme tyrosinase.

Tyrosinase is a rate-limiting enzyme and catalyses

the conversion of L-tyrosine to L-dihydroxypheny-

lalanine (DOPA), the first step in a series of reactions

known as the Raper-Mason pathway (Figure 6) (Park

et al. 2009).

Tyrosinase level and activity are enhanced by

several factors including UV-induced DNA lesions

and/or their reparation. DNA damage leads to

accumulation of tumour suppressor protein p53 that

directly via a cascade of events, stimulates transcrip-

tion of the large keratinocyte-derived protein pro-

opiomelanocortin (POMC). The POMC, precursor

of polypeptide hormones, is proteolytically cleaved to

several peptides including a-melanocyte stimulating

hormone (a-MSH), a key physiological regulator of

melanin synthesis. a-MSH activates the melanocor-

tin-1 receptor on melanocytes that result in increased

mRNA, protein and activity of tyrosinase and

eumelanin synthesis (Tsatmali et al. 2002). Several

other biomolecules such as endothelin-1, stem cell

factor, inflammatory mediators (PG, leukotriens),

neutrophins, basic fibroblast growth factor, NO and

catecholamines increase tyrosinase activity as well as

melanocyte dendricity and/or melanin transfer to

keratinocytes (reviewed in Park et al. 2009).

Photoprotective activity of melanin

The shielding activity of melanin, mainly eumelanin,

is due to its ability to scatter UV rays and absorb

UVB, UVA, visible and IR radiation. Thus it reduces

the penetration of photons into the epidermis as well

as helps to transform this energy into heat (less toxic

form of energy) dispersing it between hairs and

capillary vessels (Kaidbey et al. 1979). A recent study

provides some evidence of the in vitro and in vivo

differences in melanin absorption of UV rays. In vivo

observation showed that melanin does not protect

against 290 nm UV threshold erythema, while still

affording protection against 310 nm UV-induced

threshold erythema in human skin volunteers of

phototype I–IV (Fitzpatrick classification) (Phan

et al. 2006). It also acts as a radical scavenger. The

sunscreen efficacy of melanin has been assumed

to be about 2–3 sun protective factor (SPF).

Yamaguchi et al. (2006) examined DNA damage in

the upper and lower epidermal layers in various types

of human skin (phototype I-VI) before and after

exposure to UV. The authors found that UV-

induced DNA damage in the lower epidermis

(including keratinocyte stem cells and melanocytes)

is more effectively prevented in darker skin, suggest-

ing that pigmented epidermis is an efficient UV filter.

They also noted that UV-induced apoptosis was

significantly greater in darker skin, which suggests

that UV-damaged cells may be removed more

efficiently in pigmented epidermis.

On the other hand, melanin, especially the red/

yellow pheomelanin, is known to act as a photo-

sensitiser because of the generation of ROS/RNS

which cause damage to cell molecules including

DNA. Irradiation of melanin in vivo in congenic

mice of black, yellow and albino coat colours

induced DNA lesions and apoptosis equally in all

three strains. However, UV-irradiated pheomelanin

photosensitised adjacent cells more than irradiated

Figure 6. Scheme of melanin synthesis. (DOPA – L-3,4-dihydroxyphenylalanine; DHCIA – 5,6-dihydroxyindole-2-carboxylic acid).


eumelanin (brown/black) (Takeuchi et al. 2004). UV

radiation, mainly UVA, also caused photosensitisa-

tion in cultured cells by generating ROS/RNS which

can indirectly induce oxidative base lesions and

DNA single-strand breaks (Wenczl et al. 1997,

Marrot et al. 1999). Several studies have also shown

that melanin precursors in the process of melanin

synthesis are inherently cytotoxic to melanocytes due

to their prooxidant capacity. For example, the

autooxidation of DOPA and the indolic precursors

may give rise to cytotoxic ROS. One of these

products, dihydroxyindol, being similar to the purine

bases, can react with DNA by inserting itself between

bases where it may act as a non-specific mutagen.

The other product, 5,6-dihydroxyindole-2-car-

boxylic acid (DHCIA; Figure 6) can also photo-

sensitise DNA cleavage after UV exposure but

appears to protect against the formation of UV-

induced CPD. Thus the protective action of melanin

may reverse when the antioxidant capacity of

melanocyte is overwhelmed (Sturm 1998).

Skin thickening

Repeated solar irradiation of the skin also results in

epidermal thickening. Both UVB and UVA exposure

induces mostly epidermal but also dermal mitotic

activity which is assessed as increased DNA, RNA

and protein synthesis. After an initial decrease in

synthetic activity (6 h after exposure), increased

synthesis follows for several days (Pearse et al.

1987, Ettler 2004). Increased cell proliferation and

differentiation, augment the thickness of the epider-

mis, more specifically the stratum corneum, resulting

in the formation of a compact protein barrier that

serves as a protective shield capable of reflecting and

absorbing sunlight photons. Consequently, there is a

decreased transmission of UV radiation to the

vulnerable cells of the basal and suprabasal layers

(Lee et al. 2002). Lavker et al. (1995) have found

that repeated UVA exposure at suberythemal dose

(0.5 minimal erythema dose [MED]) was more

effective than UVB and solar simulated radiation in

inducing stratum corneum thickening in human

volunteers. The effect of UVA after a single exposure

was dose-dependent. The thickening increased the

cutaneous protection on subsequent sun exposures.

This phenomenon has been confirmed in a human

volunteer trial. Repeated UV exposure also results in

increased tolerance to erythema (de Winter et al.

2001).

Antioxidant system

Skin cells are equipped with a large network of redox

regulating molecules. These protect against oxidative

damage as a result of excessive ROS/RNS generation

or eliminate potentially harmful molecules both

produced in response to environmental stresses such

as sunlight exposure. The redox regulating mole-

cules include enzymatic antioxidants like superoxide

dismutase (SOD), glutathione peroxidase (GPX),

glutathione reductase (GSR), glutathione S-transfer-

ase (GST), thioredoxin reductase (TRX-R) and

catalase (CAT), and non-enzymatic antioxidants.

Both groups of antioxidants work in synergy to

maintain redox status (Thiele et al. 1998).

Non-enzymatic antioxidants

The group of compounds called low molecular

weight antioxidants (LMWA) includes a large

number of endogenous molecules, such as glu-

tathione (GSH), ubiquinol/ubiquinone (coenzyme

Q), uric acid and lipoic acid and compounds present

in food, such as vitamin E and C (ascorbic acid),

carotenoids and phenolic compounds. According to

their properties they can be divided into lipophilic

substances that are present in cell membranes and

hydrophilic, localised mainly in cytoplasm. LMWA

are mutually interdependent; as a result of decreas-

ing reduction potentials they can reduce each other

and thus be restored to their active form (Podda and

Grundmann-Kollmann 2001). LMWA are capable

of direct (donation of electrons) and indirect (chela-

tion of transition metals) interaction with RON/RNS

(Kohen and Gati 2000). LMWA play a role in both

physiological and pathological processes such as

wound healing, ageing, modulation of the immune

system. Their physical/chemical properties also

increase protection against UV radiation (Podda

and Grundmann-Kollmann 2001).

Superoxide dismutase

SOD (EC 1.15.1.1) is a major antioxidant enzyme

that contributes to the homeostasis of oxygen

radicals in the stratum corneum and epidermis

(Sasaki et al. 1997). SOD catalyses the dismutation

of superoxide anions into oxygen and less reactive

hydrogen peroxide. It exists as isozymes that differ in

the redox-active metal in the catalytic site. CuZn-

SOD (32 kDa) is composed of two identical subunits

(homodimer) and is localised mainly in the cytosol

and nucleus, whereas MnSOD is a homotetramer

(96 kDa) and is found in mitochondria. The enzy-

matic activity in the epidermis is 2.3-times higher

than in the dermis (Shindo et al. 1994b). Several

in vitro studies have reported that UV light affects

SOD activity. UVB exposure of human keratinocytes

reduced both MnSOD and Cu/ZnSOD activities and

their protein levels, with subsequent recovery to basal

level within 24 h (Takahashi et al. 2000). According

to Sasaki et al. (1997), MnSOD and Cu/ZnSOD


protein levels changed in a different manner. The

Cu/ZnSOD decline began immediately after UV

exposure and further decreased while the MnSOD

level was reduced but recovered within 24 h.

Similarly irradiation (UVAþUVB) of human fibro-

blasts initially decreased MnSOD activity; however,

the activity and mRNA level was substantially

induced within five days (Leccia et al. 2001).

Another study showed a dose-dependent response

of MnSOD level to UVB exposure. While low doses

(up to 500 J�m72) stimulate the protein content in

keratinocytes, higher doses decreased SOD levels

and increased apoptosis (Wiswedel et al. 2007).

Single and repetitive exposures of human dermal

fibroblasts to low doses of UVA (200 kJ�m72)

resulted in time- and dose-dependent increase in

MnSOD, in both mRNA level and protein activity

12 h after irradiation. However, 24 h after UVA

exposure, MnSOD decreased to control level.

Repetitive UVA exposure resulted in a five-times

induction in MnSOD mRNA (Poswig et al. 1999).

Treatment of human dermal fibroblasts with media

collected from UVB irradiated epidermal keratino-

cytes (containing IL-1a, IL-1b and TNF-a) ampli-

fied fibroblast MnSOD activity (Naderi-Hachtroudi

et al. 2002). Acute UVB exposure (240 mJ�m72)

significantly reduced SOD activity in mouse skin

(Aricioglu et al. 2001) and remained depressed for

up to 72 h (Pence and Naylor 1990). Chronic UVB

irradiation of hairless mice increased SOD activity

which gradually returned to control levels. However,

UVA exposure did not affect SOD activity (Okada

et al. 1994). One human trial showed no significant

differences in SOD activity in the stratum corneum

between summer and winter (Hellemans et al. 2003).

Catalase

CAT (EC 1.11.1.6) is a tetrameric, heme-containing

redox enzyme. It catalyses the conversion of H2O2,

produced among others by SOD, into water and

molecular oxygen thus reducing the damaging effects

of H2O2. CAT is located within the mitochondria

and the peroxisomes. CAT has one of the highest

turnover rates of all enzymes: one molecule of CAT

can convert * 6 million molecules of hydrogen

peroxide each minute. The activity of CAT is about

8-times higher in the epidermis than the dermis.

Studies have shown that of antioxidant enzymes

CAT is the most affected by UVA and UVB

exposure of skin cells. The decrease is probably

due to irreversible oxidation of the enzyme (Shindo

et al. 1994b, Afaq and Mukhtar 2001). Both acute

and chronic exposure of hairless mice to UVB

diminished CAT activity (Vayalil et al. 2003, Sharma

et al. 2007). CAT activity in epidermis and dermis of

hairless mice exposed to a single dose of solar

simulated light (20–250 kJ�m72) decreased dramati-

cally at doses above 50 kJ�m72 (Shindo et al. 1994a).

In contrast, a single UV exposure of human skin to

46MED increased the CAT activity in epidermis

(Katiyar et al. 2001). The revitalisation ability of

CAT activity has also been demonstrated. In human

fibroblasts exposed to solar simulated radiation,

CAT activity was initially reduced, but returned to

pre-irradiation level within five days (Leccia et al.

2001). Shindo and Hashimoto obtained similar

results using several UVA doses (Shindo and

Hashimoto 1997). Hellemans et al. demonstrated

that sun exposure of human volunteers induces

seasonal variation in CAT activity in the stratum

corneum with low activities in summer and higher

ones in winter (Hellemans et al. 2003). UVA

irradiation of human skin resulted in a dose-

dependent deactivation of CAT activity in the

stratum corneum within 24 h, whereas UVB expo-

sure had no effect. Full recovery of CAT activity for

the dose of 150 kJ�m72 was found after 3–4 weeks

(Aricioglu et al. 2001).

Glutathione peroxidase

A recent investigation of human selenoproteome has

revealed five GPX (EC 1.11.1.9) (Brigelius-Flohe

2006). GPX are tetrameric proteins with selenocys-

teine at each of four active sites that catalyse the

conversion of H2O2 or organic peroxides (ROOH)

into water or alcohol, respectively, using GSH as a

co-substrate. In vitro and in vivo studies have shown

that GPX activity is not very strongly affected by UV

rays in comparison with other antioxidant enzymes

like CAT and SOD whose activity is decreased after

UV exposure (see above). Thus GPX is considered

to be the most important antioxidant defence system

in the skin (Afaq and Mukhtar 2001). UVA irradia-

tion (10–120 kJ�m72) of human skin fibroblasts

resulted in unchanged GPX activity immediately

after exposure and during the following five days

(Shindo and Hashimoto 1997). Low doses of solar

simulated light (up to 40 kJ�m72 UVAþ 200 J�m72

UVB) caused initial decrease in GPX activity in

human dermal fibroblasts but within five days

following irradiation the activity was slightly in-

creased (Leccia et al. 2001). The activity of GPX

in human fibroblasts was up-regulated, synchro-

nously with MnSOD activity, on repetitive low dose

of UVA. In a selenium-supplemented condition the

effect was significantly higher (Meewes et al. 2001).

Sharma et al. found that acute UVB exposure of

hairless mice resulted in a minor decrease in GPX

activity but chronic exposure led to significant

depletion (Sharma et al. 2007). In another study,

GPX activity in hairless mice irradiated with

different doses of solar simulated light was practically


unaffected in either dermis or epidermis (Shindo

et al. 1994a). GPX activity in UVAþUVB irradiated

murine dermis and epidermis was only slightly

reduced immediately after irradiation, recovered in

3 h and then increased in both the epidermis and the

dermis. GPX activity in the epidermis returned in

120 h but remained elevated in the dermis (Shindo

et al. 1994c). Single UV exposure of human skin to

46MED reduced the GPX activity in epidermis

after 24 h but it increased again after 48 h (Katiyar

et al. 2001).

Glutathione S-transferase

Proteins with GST (EC 2.5.1.13) activity include

two different supergene families: The soluble en-

zymes that comprise at least 16 genes and the

microsomal enzymes that comprise at least six genes.

Four major GST gene families expressed in mam-

mals are alpha, mi, theta and pi. GST enzymes are

believed to have a critical role in cell protection

against oxidative stress and xenobiotics (Hayes and

Strange 2000). They detoxify a variety of com-

pounds, potential carcinogens and mutagens, in-

cluding oxidised lipids, DNA and catechol products

which are generated via interaction of ROS/RNS

with intracellular molecules after sunlight exposure.

The general reaction of GST enzymes is the addition

of GSH to electrophilic compounds (Afaq and

Mukhtar 2001). A double-blind clinical trial showed

that heritable GST T1 deficiency might be a genetic

determinant of individual skin sensitivity to UV

irradiation (Kerb et al. 1997). Carless et al. examined

the role of GST M1, T1, P1, and Z1 gene

polymorphisms in susceptibility to solar keratosis in

human DNA samples. They found a significant

association between GST M1 genotypes and solar

keratosis development in null individuals having an

approximate two-times increase in risk for solar

keratosis development and a significantly higher

increase in risk in conjunction with high outdoor

exposure (Carless et al. 2002). A recent study

evaluated an association between GST M1 genotype

and DNA damage linked to sun exposure in human

skin specimens from melanoma patients. GST M1-

null individuals with a sunburn history showed

increased levels of both DNA fragmentation and

mtDNA deletions in comparison to GST M1 wild

type patients with little or no sunburn history.

Microarray analyses identified a number of genes

with up-regulated expression in cells from GST M1-

null patients or from individuals reporting sunburn

history. These genes encoded transporters, growth

factor/chemokine receptors, transcription factors and

tumour suppressors. Of 17 genes directly involved in

DNA repair, three DNA ligases were highly up-

regulated while the UV excision repair gene

(RAD23) and the growth arrest and DNA damage-

inducible gene (GADD45) were down-regulated

(Steinberg et al. 2009).

Glutathione reductase

GSR (EC 1.6.4.2) is a ubiquitous FAD-containing

enzyme belonging to the family of disulfide reduc-

tases, which also include TRX-R (Mustacich and

Powis 2000). The enzyme uses NADPH as a source

of reduction equivalents. The function of GSR is to

maintain high levels of reduced GSH in the cell and

low levels of its oxidised form (GSSG). Recent

publications report a value of about 300:1 for the

ratio [GSH]/[GSSG] (Akerboom et al. 1982). Only

minor influence of UV radiation on GSR activity has

been found. In human dermal fibroblasts irradiated

with various UVA doses (10–120 kJ�m72) the GSR

activity was almost unchanged immediately after

exposure and on the following five days (Shindo and

Hashimoto 1997). GSR activity in the dermis and

epidermis of hairless mice exposed to several doses of

solar simulated light was virtually unaffected im-

mediately after exposure up to the dose of

200 kJ�m72. A slight decrease was observed at the

dose of 250 kJ�m72 (Shindo et al. 1994a). A time-

dependent experiment showed that GSR activity in

murine epidermis and dermis, slightly reduced (80–

85% of control) immediately after irradiation (solar

simulator; 250 kJ�m72), recovered to 100% within

3 h and then increased. Values in the epidermis

returned within 120 h but remained elevated in the

dermis (Shindo et al. 1994c).

Glutathione

The tripeptide GSH is a major intracellular non-

enzymatic antioxidant. It is highly abundant in the

cytosol (1–11 mM), nuclei (3–15 mM), and mito-

chondria (5–11 mM) (Masella et al. 2005). GSH

plays a pivotal role in protection of skin cells from

oxidative damage by direct hydroxyl radical and

singlet oxygen scavenging as well as acting as co-

substrate in reactions catalysed by several detoxifying

enzymes such as GPX and GST (Afaq and Mukhtar

2001). GSH also participates in regeneration of other

important antioxidants, particularly vitamin C and E,

back to their active forms and elimination of

products of lipid peroxidation in the form of GSH-

conjugates (Masella et al. 2005). Studies have also

shown that GSH is involved in the DNA repair and

apoptosis (Hall 1999, Fonnum and Lock 2004).

Several reports describe the adverse effect of UVA

and UVB light on GSH level in vitro (Zhu and

Bowden 2004, Svobodova 2006) and in vivo (Katiyar

et al. 2001, Vayalil et al. 2003). Concerning the

mechanism of UVB-caused GSH depletion, Zhu and


Bowden (2004) found that decreased GSH level is

not related to GSH efflux from keratinocytes. UVB

radiation dramatically diminished cystine uptake

through inhibition of cystine transporter (Xc7) in

the cell membrane. This could be caused by

disruption of disulphide bonds between the subunits

of Xc7 or conformational changes after energy

absorption or interruption of Xc7 function by lipid

peroxidation products. The above authors also found

that UVB light induced a slight decrease in activity

of g-glutamate cysteine ligase, a rate-limiting en-

zyme in GSH synthesis. A clear relationship was

also found between UVA-induced cellular GSH

depletion and accumulation of both the constitutive

and oxidant-inducible HO-1 as a result of a direct

influence of GSH on signal transduction (Lautier

et al. 1992). UV-caused GSH depletion can also

alter the cellular redox status which results in

enhanced transactivation of redox-sensitive tran-

scription factors such as apoptosis protease-activat-

ing factor-1 protein (AP-1), NFkB, JNK and p38

that play essential roles in mediating the biological

effects of UV radiation (Wilhelm et al. 1997,

Rahman and MacNee 2000).

Thioredoxin/thioredoxin reductase system

TRX-R (EC 1.8.1.9) is a component of the

ubiquitous thioredoxin complex. This enzyme per-

tains to the family of selenium containing oxidor-

eductases. It is a homodimeric NADPH-dependent

flavoenzyme having a redox active disulphide and a

FAD in each subunit. There are two known isoforms

of the enzyme: TRX-R1 and TRX-R2. TRX-R

catalyses the reduction of redox proteins, known as

thioredoxin (TRX), as well as of other endogenous

and exogenous compounds (reviewed in Mustacich

and Powis 2000). TRX include ubiquitous, low

molecular weight (11–12 kDa) disulphide-contain-

ing proteins that have been shown to have several

intra- and extracellular functions. TRX is mainly

located in the cytoplasm and quickly translocates

into the nucleus in response to oxidative stress

(reviewed in Koharyova and Kolarova 2008). One

of its major functions is ROS/RNS scavenging

activity. TRX can reduce hydrogen peroxide, super-

oxide anion, and NO. It also reduces GSSG at pH

7.0 (Schallreuter and Wood 2001). TRX has been

found to modulate the DNA-binding activity of

several transcription factors, including NFkB and

heat shock factor, and to indirectly modulate AP-1

activity through the intranuclear redox factor (Didier

et al. 2001a). TRX-R and TRX expression is

induced by oxidative stress. The enzyme constitutes

5.2% of the basic protein cytosolic fraction of

proliferating keratinocytes (Schallreuter and Wood

1986). Schallreuter et al. (1987) showed that TRX-R

activity in human keratinocytes correlates with skin

photo types I–VI (Fitzpatrick classification) with

linear increase from fair to dark skin. TRX-R is

one of many transcriptional targets of p53 protein

and consequently its activity is affected by UV light

(Casso and Beach 1996). In response to UV

radiation, TRX-R is highly expressed on the surface

of human keratinocytes and melanocytes (Schallreu-

ter and Wood 1986). UVA radiation highly increased

synthesis of TRX in human skin fibroblasts (Didier

et al. 2001a). Reduced TRX has been also shown to

be an inhibitor of tyrosinase activity in epidermis,

whereas oxidised thioredoxin has no effect on this

enzyme activity (Schallreuter and Wood 1986). In

TRX-transfected fibroblasts, over-expression of

TRX was associated with the ability of the cells to

survive UV-induced cell death. TRX reduced the

level of ROS and prevented the loss of mitochondrial

membrane potential elicited by UVA (Didier et al.

2001a). Furthermore, TRX treatment as well as

TRX transfection of human skin fibroblasts strongly

reduced the number of DNA strand breaks or alkali-

labile sites in UVA-irradiated cells. TRX over-

expression plays a major role in preventing the

UVA-induced formation of 8-oxo-20-deoxyguano-

sine (8-oxo-dG) (Didier et al. 2001b). Rapid

translocation of TRX and its accumulation in the

nucleus has been found in UVB irradiated keratino-

cytes (Schallreuter and Wood 2001), UVA irradiated

fibroblasts (Hirota et al. 1999), as well as TRX-

transfected cells (Didier et al. 2001b) that suggest

TRX participation in maintaining of the integrity of

genetic information.

Heme oxygenase

HO (EC 1.14.99.3) is a redox-regulating enzyme

catalysing the degradation of heme. Three different

isoforms of HO have been identified, constitutive

HO-2 and HO-3 and inducible HO-1 (Schafer and

Werner 2008). HO-1 expression is a response to a

variety of oxidative stressors, including UVA radia-

tion and H2O2 (Allanson and Reeve 2005). UVB has

been reported to be only a weak HO-1 inducer

(Obermuller-Jevic et al. 2001). Both non-enzymatic

and enzymatic peroxidation of internal membrane

lipids, the integrity of the cytoplasmic membrane and

decrease in intracellular GSH are all important for

the UVA-mediated induction of HO-1 (Basu-Modak

et al. 1996). Free heme, released from microsomal

heme-containing proteins and generated in UVA

irradiated cells, also appears to be a critical inter-

mediate that can directly influence both the tran-

scriptional activation and repression of the HO-1

gene (Tyrrell 2004). A high degree of correlation has

been demonstrated between amount of released

heme and degree of subsequent induction of HO-1


transcription following UVA and H2O2 treatment

(Kvam et al. 1999).

Regulation of antioxidant gene expression

The expression of genes encoding antioxidant

proteins and phase 2 detoxifying enzymes is en-

hanced in response to various environmental stres-

ses. A number of recent studies have reported that

nuclear factor erythroid-2 related factor 2 (Nrf2), a

member of the ‘cap’ or ‘collar’ family of transcription

factors, is involved in the response to oxidative stress

and has an important function in several conditions

including chronic inflammatory disorders and can-

cer. Nrf2 is negatively regulated by the protein

Kelch-likeEch-associated-protein 1 (Keap 1). Nor-

mally Keap 1 binds to Nrf2 and facilitates its

ubiquitin-mediated proteasomal degradation in cy-

toplasm. Keap 1 is redox-sensitive due to the

presence of cysteine groups in its structure and can

be easily oxidised, thus decreasing its affinity for

Nrf2. Consequently under oxidative stress condi-

tions, Nrf2 is released from Keap 1 and then

translocates to the nucleus where it binds to the

antioxidant response element (ARE) and induces

expression of antioxidant proteins and phase 2

detoxifying enzymes such as nicotine adenine dinu-

cleotide phosphate quinone oxidoreductase-1

(NQO-1), some GST isoforms, g-glutamylcysteine

synthase, GSR, HO-1 and TRX. Activation of the

Keap 1/Nrf2/ARE pathway increases the capacity of

cells to detoxify reactive chemicals, to minimise

oxidative DNA damage and to restore cellular redox

homeostasis (reviewed in Wondrak 2007). Several

reports have confirmed the involvement of active

Nrf2 in the response of skin cells to UV light

exposure. Hirota et al. showed that UVA irradiation

but not UVB, causes nuclear translocation and

accumulation of Nrf2 in dermal fibroblasts (Hirota

et al. 2005). Exposure of normal human keratino-

cytes and melanocytes to solar UV (300–400 nm) or

to UVA alone (320–400 nm) results in activation of

the Nrf2 pathway, particularly significant stimulation

of NQO-1 expression. HO-1 induction was relatively

strong in melanocytes but generally absent in

keratinocytes. Interestingly, at doses where cell

growth reduction was comparable, UVA was gen-

erally more efficient than solar UV in inducing phase

2 genes (Marrot et al. 2007). A single UVB

irradiation that induced a sunburn reaction in

Nrf2-null mice indicates that the Nrf2-Keap1 path-

way plays an important role in protection of the skin

against acute UVB reactions, including skin cell

apoptosis and oxidative damage (Kawachi et al.

2008). The influence of UV on Nrf2 activity seems to

be related to the nature of the UV (UVA6UVB)

and the dose. Depending on the intensity of DNA

damage, cells either survive by activation of the Nrf2

pathway or trigger apoptosis via activating the p53

pathway (for more see Reparation mechanisms)

(Marrot et al. 2007). Beyer et al. (2007) reviewed

the role of endogenous Nrf2 in the control of gene

expression during cutaneous wound healing. Most

importantly, transient activation of Nrf2 in normal

skin protected it from UVB- and toxin-induced skin

cancer. However, the constitutive activation of Nrf2

in the epidermis is deleterious due to induction of

keratinocyte differentiation.

Repair mechanisms

In addition to protective components, skin cells have

specific strategies for recognising, repairing and

removing damaged molecules. Lipid peroxidation is

virtually an irreversible process that targets predomi-

nantly unsaturated fatty acids. It occurs mainly in

membranes and leads to the formation of several

reactive molecules including lipid alkoxyl radicals,

aldehydes, alkanes, lipid (hydro)peroxides and epoxides

and alcohols. These products are eliminated via

antioxidant systems e.g., GPX and GSR (Davies 2000).

Depending on the oxidising agent, protein oxida-

tion is reversible or irreversible. Both peptidic

backbone and amino acids side chains are targets

for oxidation. Sulphur-containing amino acids and

aromatic amino acids are the most susceptible.

Products of lipid peroxidation such as malondialde-

hyde and 4-hydroxy-2-nonenal are also capable of

protein modification. Irreversibly modified proteins

are eliminated through selective degradation by 20S

proteasome or lysosomal degradation, when protea-

some capacity is exceeded. Specific enzymatic

systems, GSH/GSR, GSH/GST and TRX/TRX-R,

are able to reverse oxidation of disulphide bridges,

cysteine sulphenic acids or methionine sulphoxide

(Petropoulos and Friguet 2006). Besides oxidation

damage, aromatic amino acids such as tryptophan

are directly affected by UVB light. It has been

demonstrated that tryptophan interaction with high

energetic photons leads to generation of several

derivatives. Of these 6-formylindolo[3,2-b]carbazole

(FICZ) has been recognised to have fundamental

importance. FICZ has extremely high binding

affinity to the aryl hydrocarbon receptor (AhR) that

up-regulates isoforms of cytochrome P450 (CYP),

CYP1A1 and CYP1B1 (Sindhu et al. 2003). These

enzymes participate in the detoxication and, para-

doxically, the formation of reactive intermediates of

thousands of chemicals that can damage DNA

(formation of DNA adducts). This suggests that

sunlight-induced activation of CYP may sensitise

cells to carcinogenesis (Nair et al. 2009). Antagonists

of AhR signalling are viewed as new possible agents

in the prevention of photocarcinogenesis.


Of targeted molecules, modified DNA chains are

the most hazardous as DNA lesions can disturb the

genomic integrity. For this reason, cells have devel-

oped a precise defence of genetic information. On

DNA damage, e.g., by UV radiation, transcription of

the tumour suppressor gene p53, called the guardian

of genome, is up-regulated and p53 protein is

activated by phosphorylation at multiple serine

residues (Matsumura and Ananthaswamy 2004).

Accumulation of p53 and its translocation into the

nucleus induces transcription of a number of genes

that play a role in cell cycle arrest, DNA repair or

apoptosis (Bartek and Lukas 2001) as well as

melanin synthesis that contribute to genome de-

fence.

DNA lesion elimination

Cycle arrest at the G1 phase allows cells time to

repair DNA lesions before DNA replication in S

phase. Enhanced expression of cell cycle regulatory

proteins such as cyclin-dependent kinases and

cyclins, and/or decreased expression of cyclin-de-

pendent kinases inhibitors are causally found after

UV radiation (Matsumura and Ananthaswamy 2004,

Melnikova and Ananthaswamy 2005).

Nucleotide excision repair (NER) is a major

defence against deleterious effects of CPD and 6-

4PP. The NER system includes at least 25 proteins

and has two distinct subpathways: slower global

genome repair (GGR) that probes lesions through-

out the complete genome for deformation of DNA

double helix, and very fast transcription-coupled

repair (TCR) that operates on lesions in the

transcribed strand of active genes (Balajee and Bohr

2000). Although the main proteins that participate in

each system are different, the lesions are removed in

similar steps by both NER and GGR. After

identification of a DNA lesion, in GGR by the

xeroderma pigmentosum group C (XPC) protein

and in TCR by blockade of RNA polymerase, NER

proteins are recruited and a multiprotein complex is

formed. Sequential action of helicases and endonu-

cleases then leads to disconnection of the DNA chain

on both sides of the lesion followed by excision of

damaged DNA fragment. Finally DNA polymerase

fills the remaining gap (Mullenders and Berneburg

2001). Zhao et al. (2008) has shown that the p38

facilitates NER through promoting both UV-induced

chromatin relaxation and UV-damaged DNA bind-

ing complex degradation. The speed with which the

damage is corrected depends on the location of

lesion, repair mechanism, and also on type of lesion.

6-4PP are fully repaired in 6 h, while the elimination

of more abundant CPD (5- to 10-times higher

amount) takes at least 24 h (Costa et al. 2003).

However, the NER system is not infallible and

residual lesions may remain in the DNA structure.

Therefore cells have additional preventive mechan-

isms for guarding the integrity of genetic informa-

tion. Cells have developed cell cycle checkpoints,

where DNA chains are controlled and if DNA

damage is detected cell proliferation is blocked until

the lesion is excised (Zhou and Elledge 2000).

D’Errico et al. (2003) have described a significant

diversity in DNA repair in UVB treated keratinocytes

and fibroblasts. While 6-4PP elimination was rapid

and similar in both cell types, CPD were repaired

significantly faster in keratinocytes than in fibro-

blasts. Moreover, in keratinocytes the CPD removal

was more efficient because only 20% residual CPD

were detected after 24 h. In fibroblasts 60% of the

lesions were still un-repaired after 24 h. Succesful

CPD removal was attributed to different p53

activation. In fibroblasts the p53 level significantly

increased after 12 h and accumulation continued to

24 h, in keratinocytes p53 protein reached a peak

after 6 h and decreased to basal level after 12 h.

However this finding does not imply a fundamental

hazard as most UVB photons are absorbed in the

epidermis.

The main routes for repair of oxidatively damaged

DNA are base excision repair (BER) and single

strand breaks repair (SSBR) pathways. These have a

number of steps and participating enzymes in

common (Ridley et al. 2009). 8-OH-G, the most

frequent DNA oxidation product, is repaired pre-

dominantly via BER pathway but other pathways,

such as NER may also play a role. BER of 8-oxo-dG

appears to primarily involve four enzymes: 8-oxo-dG

DNA glycosylase (OGG1), apurinic/apyrimidinic

endonuclease, DNA polymerase b and DNA ligase.

The removal of 8-oxo-dG is initiated by OGG1 that

first hydrolyses the glycosidic bond of 8-oxo-dG

then cleaves the phosphodiester bond leaving an

abasic site which is repaired by DNA polymerase

(Aburatani et al. 1997, Mistry and Herbert 2003).

Single-strand breaks arise either directly from sugar

damage induced by endogenous or exogenous agents

or indirectly from BER.

The mismatch repair (MMR) pathway is critical

for maintaining the genetic integrity. This includes

several proteins with a wide spectrum of functions.

These recognise and repair misincorporated bases

during DNA replication. However recent reports

have shown that enzymes of the MMR pathway may

contribute to defence against UV light caused

damage. Seifert et al. (2008) demonstrated that

human MSH2 (product of MMR genes) modulates

both UVB-induced cell cycle regulation and apop-

tosis in human melanocytes, most likely via inde-

pendent, uncoupled mechanisms. Pitsikas et al.

(2007) also showed a substantial involvement of

human MSH2 in the repair of UVA-induced


oxidative DNA damage. Mice defective in MSH2

gene manifested enhanced predisposition to UVB-

induced skin cancer. The predisposition was further

increased if the mice were also defective for the NER

pathway gene XPC (Meira et al. 2002). The other

MMR pathway product, PMS2 protein, was found

to play an important role in preventing UV- and

oxidative stress-induced tandem CC ! TT sub-

stitutions (Shin-Darlak et al. 2005).

Cell death

If UV-caused DNA damage is excessive or irrepar-

able, cells are eliminated by apoptosis to limit the

survival of defective cells (Kulms and Schwarz

2002). During apoptosis, the p53 protein plays an

important role as well. Protein p53 is activated by

phosphorylation at multiple serine residues, includ-

ing Ser15, Ser20, Ser33, Ser37, Ser46, and Ser392.

Various protein kinases such as ATM (ataxia-

telangiectasia-mutated), ATR (ATM-related), and

MAPK are involved in the phosphorylation of

various p53 serine residues in response to UV

radiation (Svobodova et al. 2006). Protein p53 can

up-regulate the expression of pro-apoptotic genes

such as Bax, Fas/Apo 1 or down-regulate the

expression of anti-apoptotic genes such as Bcl-2.

Protein p53 mediates cytoplasmic redistribution of

death receptor Fas to the cell surface. The Fas-Fas

ligand interaction results in cleavage of procaspase-8

and release of cytochrome c from mitochondria. The

subsequent reaction of cytochrome c with AP-1

results in the recruitment of procaspase-9, activation

of the apoptosomal complex, the processing of

caspase-3, and finally in apoptosis (Matsumura and

Ananthaswamy 2004, Melnikova and Ananthaswamy

2005). Kappes et al. (2006) found that UVA

exposure leads to less pronounced and more short-

lived p53 activation than UVB. The weaker UVA-

induced p53 activation increases the potential risk of

mutation. When mutations occur in the p53 gene,

cells lose their ability to undergo apoptosis (Melni-

kova and Ananthaswamy 2005). These potentially

dangerous cells stay in skin tissue and may be

transformed to precancerous and cancerous ones.

Cell survival and proliferation

At the same time as UV-induced DNA damage

activates cell cycle checkpoints and apoptosis, it also

stimulates pro-survival components that activate cell

surviving mechanisms and induces cell proliferation.

The main role is played by specific kinases.

The mammalian target of rapamycin (mTOR) and

Akt (also known as protein kinase B), serine/

threonine kinases, are members of the cellular

phosphatidylinositol 3-kinase (PI3K) pathway.

Activation of the PI3K/Akt signalling pathway

reduces apoptosis in many cell types and plays a

critical role in regulation of basic cellular functions

such as control of transcription and translation.

Upon phosphorylation, Akt modulates diverse down-

stream signalling pathways associated with cell

survival, proliferation, differentiation, migration and

apoptosis (Afaq et al. 2005b). mTOR has been

shown to be a key kinase acting downstream of the

activation of PI3K. Increasing evidence supports the

hypothesis that mTOR acts as a ‘master switch’ of

cellular catabolism and anabolism, signalling cells to

expand, grow and proliferate. In addition, mTOR

has recently been found to be important in the

regulation of apoptotic cell death, mainly expression

of p53, Bad, Bcl-2, p27 and c-Myc. The PI3K/Akt/

mTOR pathway is essential for the maintenance of

cell viability and proliferation and it is thought to be

activated in several types of cancers including

melanoma (Vignot et al. 2005).

AMP kinase (AMPK) is a heterotrimeric serine/

threonine kinase that originally senses depletion of

intracellular energy and activates catabolic pathways

that produce ATP together with inhibition of

anabolic pathways. As a result of its action, ATP is

refilled to maintain energetic homeostasis. AMPK

activation also triggers a phosphorylation cascade

that regulates the activity of various downstream

targets, including the mTOR pathway, p53 and p38.

Recently it has been confirmed that AMPK is

activated in UV exposed keratinocytes. ROS have

been found to be strong inducers of AMPK

activation although the precise mechanism of UV-

induced AMPK activation is still under investigation

(Cao and Wan 2009).

Besides participation in p53 phosphorylation,

MAPK play other essential roles in mediating the

biological effects of UV radiation. MAPK, proline/

threonine kinases, include ERK and the stress-

activated protein kinases (SAPK), which are divided

into JNK and the p38 kinases. ERK have been

described as activated in response to growth stimula-

tion. JNK and p38 are also activated in response to

growth factor signalling and also in response to

cellular stress (such as UV exposure and inflamma-

tory cytokines). MAPK have been shown to directly

phosphorylate proteins of the AP-1 complex, thereby

affecting AP-1 activity and also influence the

expression of individual AP-1 family members

(Melnikova and Ananthaswamy 2005). AP-1, a

member of the transcription factor proteins family,

regulates the expression and function of a number of

cell cycle regulatory proteins, such as cyclin D1, p53,

p21, p19, and p16. AP-1 is a protein dimer

consisting of either heterodimers between fos (c-fos,

fos B, Fra-1, Fra-2) and jun (c-jun, Jun B, Jun D)

family proteins or homodimer of the jun family


proteins. It has been suggested that c-fos expression

may play a key role in UVB induced AP-1 activation

in human keratinocytes. Proto-oncogene c-fos con-

trols cell proliferation and differentiation. It elim-

inates the UV-induced block of replication and thus

appears to play a decisive role in the cellular defence

against the genotoxic effects of UV radiation

(Svobodova et al. 2006).

Exogenous protection

Over the years, our lifestyle has changed. The

modern design of clothes uncovers a substantial part

of our skin especially in summer. Currently, people

generally spend much time outdoors but spasmodi-

cally. During leisure time and holidays, they pursue

various sports and stay in the sunlight for hours

without previous short exposures (adaptation) and

often without UV protection. People go to the coasts

at a time when in their homeland is winter or sunlight

is not so intense. Moreover, due to damage to the

protective ozone layer, an increased amount of

harmful UVB radiation is reaching the ground

(Svobodova et al. 2006). These changes demand

different approaches to skin protection and thus

people cannot rely only on the skin’s own protective

capacity. They have to consciously protect their

health. Several means for exogenous protection exist.

These differ in efficacy, applicability and safety.

Sun avoidance

Sun avoidance is obviously the most efficient way of

protection against solar light but not always practical

and sometimes not possible. At least limiting time

spent outdoors during the hours of the peak sun’s

intensity (10:00–16:00 h or at least 11:00–13:00 h) is

recommended, primarily in the case of young

children. However, the highest intensity refers only

to UVB because the intensity of UVA does not

substantially change during the day (Svobodova et al.

2006). Clouds do not possess UV protection as they

reduce UV rays by only about 15–30%. Moreover,

snow and sand can reflect up to 90 and 25% of UV.

Swimmers are exposed to potentially huge amounts

of UV because UV rays penetrate through water

(50% UV reaches a depth of 3 m). UVA wavelengths

also penetrate through standard window glass (Ettler

2004, Lautenschlanger et al. 2007).

Use of clothing

Wearing clothes is a usual and old-fashioned way for

protecting the body against climate and it is also an

easy and effective way of avoiding sunlight. Studies

have shown that reduction of UV exposure in early

life is essential in skin cancer prevention and thus the

importance of UV protective clothing for children is

evident. UV protective clothes are also a suitable

strategy for outdoor workers, photosensitive patients

as well as the general population. The UV protective

properties of threads, fabrics and thus clothes are

influenced by several factors such as material, colour,

fibre density and design of clothes (reviewed in Gies

2007). Hats are another clothing accessory essential

for sunlight protection. Their effectiveness depends

on size, particularly the brim size. A wide brim can

offer protection for the neck, nose as well as chin.

The advantages of clothing compared to sunscreens

are: No toxic or genotoxic risk, no photoallergic or

photosensitisation reactions and high UV protection

regardless of adequate application.

Standards for UV protective clothing

The first normative document dealing with sun-

protective clothing was published in Australia and

New Zealand in July 1996. This standard, called AS/

NZS 4399, defines the requirements for test methods

and labelling the ultraviolet protection factor (UPF)

of sun-protective fabrics and other items that are

worn in close proximity to the skin. According into

this standard, UPF are classified in three categories

(see Table II).

The lowest UPF value has to be larger than 40

(UPF 40þ). Furthermore, the average UVA trans-

mission has to be smaller than 5% and UV-protective

clothing has to be permanently marked with the

standard number, and UPF 40þ (see Figure 7)

(reviewed in Gambichler et al. 2006). A number of

other countries such as the USA, Canada, South

Africa, the UK and the European Union have

developed their own standards that originate from

AS/NZS 4399 (reviewed in Hoffmann et al. 2001).

Use of sunglasses

Although visible wavelengths are vital to vision, the

UV part of sunlight is implicated in many eye

diseases. Some damage is acute with immediate

signs and symptoms, while some of the injuries are

the result of cumulative or long-term UV exposure.

Short-wavelength UV light has great potential to

induce phototoxic damage to ocular cells. Pro-

longed eye exposure to UVB is known to cause the

ophthalmohelioses (sun-related eye conditions)

such as pterygium and cortical cataract, climatic

droplet keratopathy and photokeratitis (Coroneo

1993). Eye protection should involve a wearing of

wide-brimmed hat and well-designed sunglasses.

Sunglass effectiveness depends on size and shape

(shield the eye surrounding), UV blocking proper-

ties (less than 1% UVA and UVB transmittance)

and reflection of the back of the lens. Some clear


spectacles or contact lenses also provide good levels

of UV protection (reviewed in Sheedy and Edlich

2004).

Use of sunscreens

Sunscreens (UV filters), frequently called the ‘gold

standard’, are the commonest means of UV skin

protection. The first sunscreens on the market were

developed to protect predominantly against UVB, as

UVB rays were considered to be responsible for

adverse biological effects. Around 1990 compounds

with UVA-absorbing ability became available and

broad-spectrum sunscreens, effective against UVA

and UVB, were introduced. Generally sunscreens

come in two types: Physical (inorganic) and chemical

(organic).

Inorganic agents

Sunscreens contain insoluble, mineral-based materi-

als such as TiO2, ZnO, FeO, FeO2, and MgSiO2.

However, only ZnO and TiO2 are approved for sun

protective cosmetics (Table III). Depending on

particle size, they scatter, reflect or absorb solar

irradiation in the UV, visible and IR ranges

(Lautenschlanger et al. 2007). However, the use of

inorganic sunscreens in cosmetic products is un-

desirable: as they reflect visible light they are often

visible on the skin surface and therefore cosmetically

uninviting for many consumers. Modern pharma-

ceutical approaches result in better consumer accep-

tance of inorganic sunscreens. One of these is

micronisation that shifts the reflectance towards

shorter wavelengths and improves the transparency

of ZnO and TiO2 particles (Lautenschlanger et al.

2007). The surface of ZnO and TiO2 particles is

frequently covered with inert coating materials that

also improve their dispersion in sunscreen formula-

tions (Nohynek and Schaefer 2001).

The safety of ZnO and TiO2 is a subject of

discussion, especially possible penetration of nano-

particles. Recently, Nohynek et al. (2008) and

Schilling et al. (2010) reviewed the potential health

risk and concluded that ZnO and TiO2 micro- and

nanoparticles do not penetrate into or through living

skin and remain on the skin surface or the outer

layers of the stratum corneum. Zvyagin et al. (2008)

identically confirmed that in humans ZnO nanopar-

ticles stayed in the stratum corneum and accumu-

lated only into skin folds and/or hair follicle roots of

human skin. In vitro and in vivo studies have also

shown that the micro- and nanoparticles are not

cytotoxic, phototoxic or mutagenic and that the use

of ZnO and TiO2 in sunscreens is safe (reviewed in

Nohynek et al. 2008, Schilling et al. 2010). The

unquestionable advantage of TiO2 and ZnO is their

absorbing ability in both UVA and UVB regions

(300–400 nm) that is required in modern prepara-

tions. Sunscreens containing inorganic agents alone

are generally recommended for children (Lautens-

chlanger et al. 2007).

Organic agents

Organic sunscreens act by absorbing radiation.

Absorption of the energy of the photons changes

the distribution of electrons in a sunscreen molecule

and creates the excited state. In this state, the

molecule can emit fluorescence or lose the energy

as heat. Individual agents can absorb UVA, UVB or

both wavelengths. Throughout the 20th century,

numerous UV filters having unique characteristics

were developed. These included mainly amino-

benzoates (UVB), benzophenones (UVB and

UVA), cinnamates (UVB), salicylates (UVB), and

camphor derivatives (UVB and UVA) (Nash 2006).

About 55 UV filters are approved for use in sun

protective cosmetics globally. Of them only 10

compounds are approved uniformly worldwide

(Shaath 2010). EEC directive 76/768 (1999) listed

28 substances that are permitted in the European

Union. In the USA only 16 compounds are allowed

(US Food and Drug Administration Sunscreen

Monograph Final Rule 1999) (see Table III).

Adverse effects of sunscreens use

Controversy about sunscreen efficacy still remains.

In spite of the relatively long use of sunscreens,

several substances widely used in skin photoprotec-

tive preparations have been found to be questionable.

Adverse reactions include allergic and irritant con-

tact dermatitis, as well as phototoxic and photo-

allergic reactions. The overall incidence of harmful

effects of sunscreens in the general population is not

known but is considered to be low. For example

Table II. UPF rating scheme.

Protection category UPF range Rating

Excellent 40–50, 50þ 40, 45, 50, 50þVery good 25–39 25, 30, 35

Good 15–24 15, 20

*textiles with UPF lower than15 are not labeled.

Figure 7. Symbol marking UV-protective clothes.


oxybenzone, (Gambichler et al. 2006) butyl methoxy

dibenzoylmethane, methoxycinnamate and benzo-

phenone were found to cause photoallergic contact

dermatitis (Cook and Freeman 2001). p-Aminoben-

zoic acid can elicit photoallergic reactions. Benzo-

phenone-3 has been demonstrated to be a

photoallergen (Maier and Korting 2005). Avoben-

zone (Parsol 1789), a widely used UVA-absorbing

agent, has been found to inadequately protect human

keratinocytes from UVA damage (Armeni et al.

2004). It also suffers from extreme photo-instability

(Baron et al. 2008). Therefore sunscreen producers

usually combine avobenzone with other UV filters to

stabilise it (Shaath 2010). Paradoxically, some

randomised studies have found that sunscreen use

may lead to more frequent sunburns. This is

probably due to increased duration of sun exposure

at sun’s peak intensity (Autier et al. 2007).

Sunscreen efficacy is traditionally assessed using

SPF, which is defined as the ratio of the least amount

of UV energy required to produce minimal erythema

on the sunscreen protected skin to the amount of

energy required to produce the same erythema on

the unprotected skin (Diffey 2001). Therefore SPF is

based solely on a prevention of erythema (sunburn),

which is primarily caused by UVB. For this reason it

cannot be used as an indicator of the damage

induced by UVA irradiation. The users of the high

Table III. List of permited sunscreens (UV filters) in cosmetic products in the EU and USA.

No. Chemical name (INCI Names / synonyms)

1 4-Aminobenzoic acid (PABA) W * #

2 N,N,N-Trimethyl-4-(2-oxoborn-3-ylidenmethyl) anilinium methyl sulphate (Camphor benzalkonium

methosulfate)

*

3 3,3,5-Trimethylcyclohexyl-salicylate ((3,3,5-trimethylcyclohexyl) 2-hydroxybenzoate (Homosalate) W * #

4 2-Hydroxy-4-methoxybenzophenone (Benzophenone-3; Oxybenzone) W * #

5 2-Cyano-3,3-diphenyl acrylic acid, 2-ethylhexyl ester (Octocrylene) W * #

6 2-Phenylbenzimidazole-5-sulphonic acid (Phenylbenzimidazole sulfonic acid; Ensulizole) and its potassium,

sodium and triethanloamine salts

W * #

7 Ethoxylated ethyl-4-aminobenzoate (PEG-25 PABA) W *

8 2-Ethylhexyl salicylate (Octyl salicylate; Octisalate) W * #

9 2-Ethylhexyl-4-methoxycinnamate (Octyl methoxycinnamate; Octinoxate) W * #

10 Isopentyl-4-methoxycinnamate (Isoamyl p-methoxycinnamate; Isopentylp-methoxycinnamate) *

11 1-(4-tert-Butylphenyl)- 3-(4-methoxyphenyl) propane-1,3-dione (Butyl methoxydibenzoyl methane;

Avobenzone)

W * #

12 3,30-(1,4-Phenylenedimethylene) bis(7,7-dimethyl-2-oxo-bicyclo-[2,2,1]hept-1-yl-methanesulphonic acid and

its salts (Terephthalylidene dicamphor sulfonic acid; Ecamsule)

*

13 4-Dimethyl-aminobenzoate of ethyl-2-hexyl (Octyl dimethyl PABA; Octyl dimethyl-4-aminobenzoate; Padimate O) * #

14 2-Hydroxy-4-methoxybenzophenone-5-sulphonic acid (Benzophenone-4; Sulisobenzone) and its sodium salt

(Benzophenone-5; Sulisobenzone sodium)

* #

15 alpha-(2-Oxoborn-3-ylidene)-toluene-4-sulphonic acid and its salts (Benzylidene camphor sulfonic acid and

salts)

*

16 3-(40-Methylbenzylidene-d-1-camphor) (4-methylbenzylidene camphor; Enzacamene) *

17 3-Benzylidene camphor *

18 2,4,6-Trianilin-(p-carbo-20-ethylhexyl-r-oxy)-1,3,5-triazine (Octyl triazone; Ethylhexyl Triazone) *

19 Polymer of N-{(2 and 4)-[(2-oxoborn-3-ylidene)methyl]benzyl}acrylamide (Polyacrylamidomethyl benzilidene

camphor)

*

20 (1,3,5)-Triazine-2.4-bis((4-(2-ethylhexyloxy)- 2-hydroxy)phenyl)- 6-(4-methoxyphenyl)(Anisotriazine) *

21 2,20-Methylene-bis-6-(benzotriazol-2yl)- 4-(tetramethyl-butyl)-1,1,3,3,-phenol (Methylene bisbenzotriazolyl

tetramethyl butyl phenol)

*

22 Benzoicacid, 4,4-((6-(((1,1-dimethylethyl)amino)carbonyl)phenyl)amino)1,3,5-triazine-2,4diyl)

diimino)bis-,bis-(2-ethylhexyl)ester) (Dioctyl butami butamido triazone; Diethylhexyl Butamido Triazone)

*

23 Monosodium salt of 2,20-bis-(l,4phenylene)lH-benzimidazole-4,6-disulphonic acid) (Bisymidazylate) *

24 Phenol, 2-(2H-benzotriazol-2-yl)- 4-methyl-6-(2-methyl-3-(1,3,3,3-tetramethyl-1-

(trimethylsilyl)oxy)disiloxanyl)propyl) or 2-(2 H-benzotriazolyl)6{[3(1,1,1,3,5,5,5-heptamethyltrisiloxan-

3-yl]2-methylpropyl}4-methylfenol (Drometrizole trisiloxane)

*

25 Dimethicodiethylbenzal malonate (Polysilicone-15) *

26 2-(4-(Diethylamino)- 2-hydroxybenzoyl-hexylbenzoate (Diethylamino hydroxybenzoyl hexyl benzoate) *

27 Dioxybenzone (Benzophenone-8) #

28 Trolamine salicylate #

29 Menthyl anthranilate (Meradimate) #

30 2-Ethoxyethyl p-methoxycinnamate (Cinoxate) #

31 Titanium dioxie; micronized W * #

32 Zinc oxide; micronized * #

W approved worldwide; *permitted in EU; # permitted in USA.


SPF sunscreens usually have an artificial sense of

security, which leads to prolonged sunbathing. Due

to longer sunlight exposure without UVA protection,

they may be paradoxically more threatened with

increased skin cancer risk (Haywood et al. 2003).

Globally, there is no uniform standard for testing and

labelling sunscreens for UVA protection. Several

methods for evaluation of the skin UVA-photopro-

tection afforded by sunscreens exist. However, these

methods have not been validated and none is

universally accepted. The most frequently used

in vivo method is persistent pigment darkening

(PPD), in which irradiation of volunteers with a

pure UVA light source induces pigmentation (Her-

zog et al. 2004). Wang et al. (2008) recently

performed an in vitro study that assessed the degree

of UVA protection provided by 13 popular sunscreen

products commercially available in the USA. For

rating UVA protection of each product three in vitro

methods were used, Food and Drug Administration

Proposed Ruling (valid in the USA), European

Commission Recommendation (valid in the

European Union), and Boots Star Rating System

(valid in the UK). All of these are based on measure-

ment of UV transmittance through a sunscreen film.

The majority of the tested sunscreens offered a me-

dium degree of UVA protection. However, compared

with the sunscreens in the past, this study shows that

UVA protection in sunscreens has improved.

Moreover the SPF is assessed after phototesting

in vivo at an internationally agreed application dose

of 2.0 mg per cm2. However, a number of studies

have shown that consumers apply much less than

this, typically between 0.5 and 1.5 mg per cm2

(Diffey 2001). A recent trial on human volunteers

showed that the relation between SPF and sunscreen

quantity is exponential. Thus for example SPF 16

will be reduced to SPF 2 when applied in an amount

of 0.5 mg per cm2 (Faurschou and Wulf 2007). The

latter study confirmed that the amount of applied

sunscreen was critical for degree of photoprotection.

Some pharmaceutical companies caution consumers

on label that a UV protective preparation must be

used in an amount of 2.0 mg per cm2 to achieve the

claimed protection. However, there are also other

preconditions which should be respected to reach the

proper protection: Application of sunscreen 15–

30 min before sunlight exposure, the uniformity of

sunscreen application, application to all exposed skin

areas, number of applications per day, re-application

after swimming, towelling or friction with sand or

clothes (Lautenschlanger et al. 2007). It was

concluded that the regular homogeneous application

of a broad-spectrum sunscreen (SPF 15) to human

skin 30 min before UV exposure (26MED) effec-

tively prevented the CPD formation, a major form of

UV-induced DNA damage. Irregular and inadequate

use of sunscreen during exposure to solar radiation

results in CPD formation which may lead to

mutation and subsequent cancer development

(Mahroos et al. 2002).

Some handicaps of currently used UV filters might

by limited or eliminated by new generation of

sunscreens. Gallardo et al. (2010) have recently

introduced novel UV filters, termed progressive

sunscreens. They limit the dose of received radiation

rather than block a part of solar light on the skin

surface. The sunscreens action is based on the

photochemical transformation of suitable precursors

(e.g., pre-benzophenones, pre-avobenzone, and pre-

diethylamino hydroxybenzoyl hexyl benzoate) upon

sunlight exposure. Broadband sunscreens are thus

generated ‘on demand’, affording protection, when,

where and to the extent that it is needed, providing

higher protection to more exposed areas, and

increasing the UV blocking capacity. Encapsulation

in silica particles isolates the precursors and trans-

formation products that further improve the efficacy

and lower cytotoxic potential of the sunscreens.

Modern strategies

The possibility of strengthening the skin’s own

protective capacity is a potential strategy for UV

protection. This includes increase in pigmentation,

application of enzymatic or non-enzymatic antiox-

idants and delivery of DNA repair enzymes to the

skin. Further, the phytochemicals which plants use

for their own UV protection, are of interest to

researchers.

Enhancement of skin pigmentation

Skin darkening is one of the first skin responses to

sunlight exposure. Thus enhancing skin pigmenta-

tion before sun exposure may result in improved skin

protection. However, a large public misconception is

that artificial tans are safe. Synthetic melanins which

reflect and absorb UV light can be applied to the

skin. In humans, synthetic brown melanins provided

an SPF of about 6. Since topically applied melanins

penetrate up to 10 layers of the stratum corneum, it

is necessary to repeat the application once every 2–3

days for good colour retention. However, daily

treatment is recommended. Stimulation of the

tanning response may be achieved by application of

L-tyrosine or L-DOPA, the elementary substances in

melanin synthesis (reviewed in Brown 2001).

A promising strategy to stimulate tanning (mela-

nogenesis) is treatment with thymidine dinucleotides

(pTpT) or small single-strand DNA fragments. The

pTpT, a mimic of CPD, are structurally similar

to the small DNA fragments excised during

NER. pTpT have been shown to enhance repair of


UV-induced DNA damage in human skin fibroblasts

and keratinocytes by activation of p53 (Eller et al.

1997). Treatment of non-irradiated skin fibroblasts

with pTpT results in increased levels of p53 and p53-

regulated proteins involved in cellular growth arrest

and DNA repair (Goukassian et al. 1999). Applica-

tion of pTpT to non-irradiated melanocytes induced

a pigment response indistinguishable from UV-

induced reaction (Eller et al. 1996). In vitro, a

seven-times increase in melanin content and a two-

times increase in tyrosinase mRNA (the rate limiting

enzyme for melanin synthesis) was observed after

treatment with pTpT. Topical treatment of shaved

guinea pig skin with pTpT induced a visible tan

(Eller et al. 1994). pTpT represent original media-

tors signalling DNA damage. However, it was found

that larger oligomers containing pTpT are more

effective inducers of pigmentation and p53 expres-

sion (Hadshiew et al. 2001).

Self-tanning agents

A completely different way of tanning is the use of

self-tanning cosmetics. The primary purpose of self-

tanning agents is to obtain a ‘tanned’ skin rather than

to possess UV protection. The main browning

ingredient in commercial self-tanning preparations

is dihydroxyacetone (DHA). The pigment produc-

tion is based on the Mailard reaction, which includes

interaction of sugars, including DHA, with com-

pounds containing amino groups. DHA-induced

pigmentation is formed in the stratum corneum,

rather than in deeper epidermal layers. DHA-

induced pigments, called melanoidins, are much less

photoprotective than melanin (Jung et al. 2008a).

Moreover, recently Jung et al. (2008b) revealed that

DHA significantly increased ROS generation during

sun exposure. The detrimental effect of DHA during

sun exposure can be reduced by DHA encapsulation

into liposomes together with addition of antioxi-

dants.

Antioxidant enzymes

As mentioned above, CAT activity in the skin, in

comparison to GPX, GSR and SOD, is strongly

reduced after UVA and UVB exposure and thus its

delivery to UV exposed skin may strengthen the

antioxidant status. Lentiviral vector-mediated CAT

over-expression decreased UVB-induced DNA da-

mage, apoptosis and the late phase of ROS genera-

tion in normal human keratinocytes (Rezvani et al.

2006a). Vector-mediated CAT over-expression in

human reconstructed skin reduced UVA and UVB

alterations, particularly 8-OH-G formation, sunburn

cell production, caspase-3 activation and p53 accu-

mulation (Rezvani et al. 2006b). Pre-treatment with

the synthetic SOD/CAT mimetic molecule (EUK-

134) followed by a single dose of UVA reduced

the level of lipid peroxides at the surface of

UVA-exposed skin and baseline peroxide levels on

non-irradiated skin were also reduced in a dose-

dependent fashion (Declercq et al. 2004). Topically

administered SOD has been also shown to prevent

acute cutaneous toxicity in oncologic patient radio-

therapy (Manzanas Garcıa et al. 2008). These data

support the concept that topical antioxidant applica-

tion might be able to compensate for seasonal

deficiencies in antioxidant defence capacity at the

skin surface thereby contributing to optimal protec-

tion of the skin against the accumulation of oxidative

damage.

An increasing number of studies propose that the

treatment of skin with electrophilic Nrf2 activators

(e.g., broccoli isothiocyanate sulforaphane [Dinkova-

Kostova 2008], and ginger sesquiterpene zerumbone

[Nakamura et al. 2004]) that induce expression of

several Nrf2-Keap1-dependent antioxidant and

phase II enzyme genes, encoding g-glutamylcysteine

synthase, NQO-1, GST, GPX, and HO-1 are

promising novel topical agents for photoprotection

(Wondrak 2007).

Non-enzymatic antioxidant

ROS/RNS are well known consequence of UV

exposure. Thus, the use of compounds which

naturally participate in the elimination of ROS/

RNS in the skin especially vitamins, seems to be

appropriate alternative in skin photoprotection.

Several in vitro and in vivo studies dealing with

LMWA such as vitamin C, E, D and A (or b-

carotene) or their combinations have shown photo-

protective ability (Darr et al. 1992, 1996, Trevithick

et al. 1993, Bohm et al. 1998, Lopez-Torres et al.

1998, Steenvoorden et al. 1999, Krol et al. 2000,

Greul et al. 2002, Offord et al. 2002, Chiu and

Kimball 2003, Stahl et al. 2006, Baron et al. 2008).

On the other hand, there are publications indicating

no protective effect of vitamin supplementation in

humans (Werninghaus et al. 1994, Garmyn et al.

1995, McArdle et al. 2004). The safety of oral b-

carotene, a precursor of vitamin A, in photoprotec-

tion is controversial due to possible increase of risk in

lung cancer (Stahl et al. 2006). Moreover, the

effectiveness of vitamins in photoprotection is still

debated. While free but unstable forms are effective,

their more stable derivatives (esters) are less or not

effective in UV protection (F’guyer et al. 2003,

Pinnell 2003). For example, a stable derivative of

vitamin E, alpha-tocopherol acetate, was found to be

not converted to alpha-tocopherol in the skin and

this resulted in its ineffective protection against

DNA photoproduct formation (Baron et al. 2008).


Further, more stable vitamin derivatives may have

adverse effects on the skin. Gaspar and Campos

(2007) recently found that topical application of

vitamin derivatives (ascorbyl tetraisopalmitate, vita-

min E acetate and vitamin A palmitate) provoked

irritation of hairless mice skin and these compounds

cannot be considered safe. A combination of

vitamins with other antioxidants seems to be a more

suitable strategy for their stabilisation. Murray et al.

(2008) showed that topically applied vitamin C and

E solution stabilised by ferulic acid decreased DNA

damage and production of pro-inflammatory cyto-

kines in UV exposed skin. Regardless of experi-

mental data, vitamins A, C, E and b-carotene and/or

their (less effective) derivatives are used as active

components in UV protective preparations as well as

in after sun lotions.

Another promising low molecular compound is

GSH which is an important component of the

antioxidant network. However, systemic administra-

tion of a reduced form of GSH is understood to have

poor permeability into cells. In this regard GSH

derivatives (esters) have been prepared. Their

efficient delivery to the skin and protective potency

has been shown in vivo (Kobayashi et al. 1996,

Hanada et al. 1997, Steenvoorden et al. 1998a).

Several GSH precursors have also been tested in a

number of experiments (van der Broeke et al. 1995,

Deliconstantinos et al. 1997, Steenvoorden et al.

1998b, Morley et al. 2003, D’Agostiny et al. 2005,

Cotter et al. 2007).

Coenzyme Q10, a cellular antioxidant and a

component of mitochondrial electron transport

chain, is used in many skin care products to protect

the skin from free radical damage. Thus it is also an

interesting compound in photoprotection research.

Coenzyme Q10 has been reported to reduce ROS

production and DNA damage triggered by UVA

irradiation in human keratinocytes and UVA-in-

duced MMP in human dermal fibroblasts. Further-

more, coenzyme Q10 suppressed UVB-induced

inflammation in human dermal fibroblasts (Fuller

et al. 2006, Inui et al. 2008) that was amplified by

combination with carotenoids (Fuller et al. 2006).

Treatment of mice skin with coenzyme Q10 strongly

inhibits UVB-induced oxidative stress by modulation

of antioxidant enzymes (MnSOD, GPX) activities

(Kim et al. 2007).

An essential trace nutrient, selenium (Se), is an

important component of cellular anti-oxidant de-

fences and necessary for the normal function of the

immune system. Supplementation with low concen-

tration of inorganic or organic Se-containing com-

pounds (Leccia et al. 1993, Rafferty et al. 2002,

Burke et al. 2003) has been shown to prevent/reduce

UV light caused inflammation, oxidative DNA

damage, lipid peroxidation and apoptosis. Se in

combination with other antioxidants, vitamins E and

C, carotenoids and proanthocyanidins, was found to

inhibit erythema and expression of MMP in UV

irradiated human skin (Greul et al. 2002).

Studies have shown that the application of only

one antioxidant substance especially in high con-

centration may result in disruption of antioxidant cell

status and manifest oxidative injury. Furthermore,

antioxidants are known to work in synergism. Thus

antioxidants act more effectively in low concentra-

tion and in combination with others. For skin

photoprotection it seems to be more effective when

topical and systemic application is combined (re-

viewed in Darvin et al. 2006). Howsoever, vitamins

and other LMWA are promising but their appro-

priate stable form and delivery have to be found.

DNA repair enzymes

One of the most critical actions of UV rays is

formation of various types of DNA lesions and

breakage which by enhancing cellular DNA repair

capacity might reduce the degree of photodamage

and risk of carcinogenesis. The results of a recent

human trial indicate that topical treatment with a

moisturiser containing DNA repair enzymes signifi-

cantly prevents UV-induced immunesuppression

(Lucas et al. 2008). This approach is highlighted in

patients with genetically dependent defects in NER

associated genes which make them particularly

sensitive to UV radiation: Xeroderma pigmentosum

(XP) and Cockayne syndrome (de Boer and Hoeij-

makers 2000). XP patients are characterised by a

1,000-times increased susceptibility to sunlight-

induced skin cancer.

T4 endonuclease V (EC 3.1.25.2; T4N5) is a

16,500 molecular weight polypeptide produced by

bacteriophage T4 after infection of the host by

Escherichia coli. This is a DNA repair enzyme, which

especially recognises CPD, the main lesions induced

by UVB, in DNA and initiates excision repair by

cleaving CPD. The enzyme is well characterised and

is routinely used to analyse CPD repair in DNA

(Lloyd 2005). The T4N5 potential to support

elimination of DNA lesions has been documented

in several in vitro and in vivo studies. It was first

introduced into excision-repair-deficient XP cells to

enhance CPD removal more than 30 years ago

(Tanaka et al. 1975). Treatment of UVC-irradiated

human epidermal keratinocytes with T4N5 lipo-

somes (0.05, 0.1 or 0.2 mg per ml) decreased the

frequency of CPD in DNA (between 29% and 64%

for the used concentrations) (Yarosh et al. 1991).

T4N5 liposomes have been also demonstrated to

efficiently improve the removal of CPD in mouse

skin (Yarosh et al. 1989). Animal and human skin

explants studies established that the dosage of 1 mg


per ml of T4N5 liposomes saturates the repair

machinery (Yarosh et al. 1992). In laboratory

animals, such as the mouse, the epidermis is formed

from about 2–3 cell layers, whereas in humans from

about 8–15 cell layers. However, T4N5 into lipo-

somes has been shown to cross the stratum corneum

and reach the living cells in trials on human

volunteers. Treatment of DNA-repair-deficient XP

patients and skin cancer patients with T4N5

liposomes increased the rate of repair of UV-induced

DNA damage in the first few hours after treatment

(Yarosh et al. 1999). Yarosh et al. also demonstrated

that T4N5 liposome lotion lowered the rate of new

actinic keratoses and basal cell carcinomas by 68 and

36%, respectively, in XP patients during a one-year

treatment (Yarosh et al. 2001). Enhanced DNA

repair has also other profitable cellular effects. T4N5

liposomes applied to the skin of cancer patients

prevented UV-induced up-regulation of immuno-

suppressive cytokines TNF-a and IL-10 which are

considered to contribute to skin cancer risk, after 6 h

treatment (Wolf et al. 2000). Treatment of chroni-

cally irradiated mice with T4N5 liposome lotion after

each UV exposure delayed the accumulation of p53

in the skin and thus prolonged time for DNA

reparation (Bito et al. 1995).

Photolyases are monomeric proteins 45–66 kDa in

size that represents a class of DNA repair enzymes

produced by various plants, bacteria and animal

species. Mammals have lost DNA repair by photo-

lyases during evolution (Essen and Klar 2006). Two

different types of photolyases are now distinguished

depending on the type of DNA lesion they repair.

CPD photolyases recognise and specifically bind to

CPD (light-independent process), and if the photo-

lyase-dimer complex is exposed to photoreactivating

light (350–450 nm) the enzyme utilises the energy to

break up the CPD cyclobutane ring and converts the

dimeric pyrimidines to their monomeric form (Carell

et al. 2001, Essen and Klar 2006). In 1993 (6-4)

photolyases that repair 6-4PP were also discovered.

They are not well recognised and their mechanism is

still under investigation. However, it is assumed to

be similar to CPD photolyases (Carell et al. 2001).

Topical application of photolyase encapsulated into

liposomes to UV irradiated human skin reduced the

number of UV-induced CPD by 40–45%. Photo-

lyase-induced dimer repair completely prevented

UVB-induced immunosuppressive effects as well as

erythema and sunburn cell formation (Stege et al.

2000).

OGG1, an enzyme of the BER pathway, is highly

specific for the removal of the oxidatively damaged

guanine bases, 8-OH-G, from all regions of the

genome (Aburatani et al. 1997). First OGG1 was

identified in E. coli and later in yeast, humans and

plants. It was demonstrated that OGG1 isolated

from Arabidopsis thaliana is not only a structural but

also a functional eukaryotic OGG1 homologue

(Dany and Tissier 2001); therefore, plant OGG1

could be used for human treatment. In human cells,

the OGG1 gene encodes two forms of OGG1

protein, a-OGG1 protein has a nuclear localisation

whereas the b-OGG1 is targeted to the mitochon-

drion (Boiteux and Radicella 2000). Under severe

oxidative stresses, OGG1 mRNA and the amount of

OGG1 protein is not remarkably increased but the

activity of OGG1 protein is enhanced by an increase

in apurinic/apyrimidinic endonuclease 1/redox fac-

tor-1 in the cells (Saitoh et al. 2001). UVB light has

also been shown to directly inactivate the OGG1

repair enzyme thus allowing for an increase in

adducts (Van der Kemp et al. 2002). Sections of

human foreskin, adult buttock skin, and recon-

structed human skin samples showed the highest

expression of OGG1 in the superficial epidermal

layer (stratum granulosum). The level of OGG1

mRNA was the highest in the upper region of the

epidermis. This was not regulated by UV irradiation

but by the differentiation state of keratinocytes as

calcium-induced differentiation increased OGG1

gene expression. UVA-induced 8-OH-G was re-

paired more rapidly in the upper layer of human skin

compared to the lower layers. This indicates weaker

expression of the OGG1 in the basal cells of the

epidermis which may lead to a lack of DNA repair in

these cells and therefore accumulation of UVA-

induced oxidative DNA mutations (Javeri et al.

2008). SKH-1 mice exposed to UVB light and

immediately topically treated with liposome-encap-

sulated OGG1 enzyme for 25 weeks showed a

decrease in tumour size and dramatic reduction in

tumour progression; however tumour multiplicity

was not affected (Wulff et al. 2008). UVA-induced

mutant frequency, measured in Chinese hamster

ovary cells stably transfected to over-express OGG1,

was significantly decreased. Cells that over-expressed

OGG1 repaired DNA lesions three times faster than

non-transfected cells (Dahle et al. 2008).

Phytochemicals

Besides vitamins and non-enzymatic antioxidants,

application of plant secondary metabolites, in the

form of a pure compound or extract, has also been

investigated for the purpose of skin photoprotection.

Among these, the phenolics have gained a promi-

nence. The UV-absorbing characteristics of pheno-

lics have long been considered to be evidence for the

role of phenolics in UV protection. Indeed, phenolics

are often present in the epidermal cell layers of leaves

and in plant tissues that are susceptible to UV light

(Winkel-Shirley 2002, Jaakola et al. 2004). More-

over, phenolics exhibit a wide variety of beneficial


biological activities in mammals. Their UV protec-

tive effect particularly include: Direct absorption of

UV light, direct antioxidant activity (ROS/RNS

scavenging), indirect antioxidant activity (induction

of Keap 1/Nrf2/ARE pathway), modulation of

immunosuppression, inhibition of inflammation

and induction of apoptosis (Dinkova-Kostova

2008). On the other hand, natural compounds/

extracts, if used in UV protective dermatological

preparations, may have phototoxic effect depending

on their physical-chemical properties, metabolism in

skin and individual sensitivity (Korkina et al. 2008).

Furthermore, compounds that influence regulation

of genes expression (e.g., sulforaphane-rich extracts

of broccoli sprouts that activates Keap 1/Nrf2/ARE

pathway) should not be used continuously because

the constitutive activation of such genes may be

deleterious to skin cells due to disruption of their

normal functions (e.g., proliferation, differentiation)

(Beyer et al. 2007). Thus the safety of phytochem-

icals remains to be confirmed before human use.

Phenolic compounds or extracts rich in polyphe-

nols have been predominantly studied in the UVB

range, similarly as sunscreens. To date, green tea

(Camelia sinensis) (reviewed in Katiyar et al. 2007)

and its components epikatechin and epigalokatechin-

3-gallate (reviewed in Katiyar et al. 2007, Dinkova-

Kostova 2008) are the most intensively studied

phenolics followed by silymarin (a standardised

extract from the seeds of Silybum marianum)

(reviewed in Katiyar 2005, Deep and Agarwal

2007) and its main component silybin (reviewed in

Singh and Agarwal 2005, 2009), extract from Pinus

pinaster bark (Pycnogenol1) (Sime and Reeve 2004),

Polypodium leucotomos extract (reviewed in Gonzalez

et al. 2007), grape (Vitis vinifera) seeds proantho-

cyanidins (reviewed in Katiyar 2008, Nandakumar

et al. 2008), resveratrol (Aziz et al. 2005, Athar et al.

2007, Reagan-Shaw et al. 2008), pomegranate

(Punica granatum) polyphenols (Afaq et al. 2005a,

2009). In comparison to UVB light markedly, fewer

trials have involved UVA protection. Substances and

extracts that protect/suppress UVA-induced skin

cells damage include resveratrol (Chen et al. 2006),

quercetin (Erden et al. 2001), epikatechin (Basu-

Modak et al. 2003), epigallokatechin-3-gallate

(Song et al. 2004), rosmarinic acid (Sanchez-

Campillo et al. 2009), P. leucotomos extract (Alon-

so-Lebrero et al. 2003), pomegranate fruit extract

(Syed et al. 2006), silymarin (Svobodova et al. 2007)

and Prunella vulgaris extract (Psotova et al. 2006).

Most studies on UVA photoprotection have been

performed in vitro and require intensive investigation

and proof of UVA protective agents especially

in vivo.

In addition to phenolic compounds other groups

of compounds have been examined, e.g., alkaloids,

carotenoids, isothiocyanates, proteins (reviewed in

Adhami et al. 2008, Dinkova-Kostova 2008). The

listed compounds/extracts do not constitute an

absolute list of those studied in UVB and UVA

photoprotection and the effects of many others have

been published. However, photoprotective activities

of natural compounds/extracts have been of concern

to a large number of authors and reviews and thus

are not described in detail here.

Prevention

Perhaps the most important skin protection against

sunlight-induced damage is prevention. Neverthe-

less, inquiries indicate that the public is inadequately

informed about sun exposure risks and/or people

give this information insufficient relevance. For

example, El Sayed et al. (2006) performed a study

among nearly 1,000 teenagers, aged between 14 and

18, in 2004. The incidence of sunburn in teenagers

was high (85%) despite their awareness of the risks of

unprotected sun exposure (90%). The information

regarding sun damage seems to be insufficiently

delivered at school (33%) and by doctors (35%). The

main source of information was television (88%). It

was obvious that adolescents underestimated the

value of clothing to protect themselves. The use of

clothing, hats and sunglasses (40%) is the second to

sunscreens (60%). However, the application of

sunscreen seems to be inadequate. The other study

collected data in a four-year period (2002–2005) and

analysed nearly 4400 questionnaires. The results

showed that the knowledge about the harmful effects

was high (around 90%). However, 60% participants

sunbathe during the most danger hours of the day

(11:00–16:00 h), 30% get sunburn, 84% use sunsc-

reens, but 39% stop using them in the last days of

vacations to be more tanned. Only 33% protect

themselves by hats and sunglasses. Participants older

than 36 years are statistically more likely to follow

sun protection rules (Masnec et al. 2007). Thus

health organisations all around the world need to

alert people not to underestimate health risks

associated with sunbathing. People have to be aware

of that photoprotection is an everyday requisite not

only during holidays. Moreover, parents should be

very careful about UV protection for their children. It

is estimated that 80% of lifetime sun exposure occurs

before the age of 18. Epidemiological studies also

show a strong correlation between frequency of

sunburn in childhood and occurrence of skin cancer

in adulthood (Masnec et al. 2007).

Over the past 20 years, indoor tanning has hugely

increased, mainly in young female adults. Tanning

bed use is frequently associated with being attractive.

On average, 1 million people tan daily, and 70% are

Caucasian women aged 16–49 (reviewed in Ibrahim


and Brown 2008). Sunbed lamps emit a majority of

UVA, UVB wavelengths constitute only 1–5% (Ettler

2004). Thus the protective effect of UVB by

inducing new melanin synthesis, typical for sunbath-

ing, is not accomplished. In contrast, a powerful

tanning bed may have 10- to 15-times higher

intensity than the midday sun (Gerber et al. 2002)

and thus 20 min spent at a tanning salon may be

equivalent to 2–3 h natural noon sunlight (Ibrahim

and Brown 2008). Frequent sunbed tanning may

contribute to increased photoaging which is asso-

ciated with UVA rays (Yaar and Gilchrest 2007).

Moreover, experiments on human volunteers ex-

posed to UVA lamps used in sunbeds have revealed

induction of DNA lesions, p53 gene mutation by

oxidative damage and alterations to p53 protein

(Woollons et al. 1997, Persson et al. 2002), all of

which may increase the risk of carcinogenesis.

Moreover recent studies have shown that indoor

tanning can lead to dependency (reviewed in Nolan

et al. 2009). Visitors to tanning salons should be

informed about the health risks of sunbed use.

Early diagnosis of sunlight related skin cancers is

important for further prognosis and survival because

(skin) cancer is most curable when treated in an early

stage. To highlight the risk of skin cancer, the Euro-

Melanoma day has been established. The idea

originated in Belgium where the Euromelanoma

day took place for the first time under the leadership

of Dr Thomas Maselis in 1999. Currently annually

in May, dermatologists from 26 countries offer

public free examination of skin spots as well as

distribute educational materials about the risks

associated with sunlight and sunbeds exposure.

The need for photoprotection is also discussed in

the media (www.euromelanoma.org).

Conclusion

Sunlight UV radiation, a potent human carcinogen,

induces various acute and chronic reactions in

human skin. Fortunately, skin cells are equipped

with a variety of mechanisms that constantly monitor

and repair most of the UV-induced damage. How-

ever, excessive sun exposure can overwhelm these

mechanisms. For this reason, active photoprotection

is necessary. Changes in public awareness of the

effects of solar light must be made. People need to

know that ‘healthy tanning’ or ‘safe tanning’ does not

exist, even indoor tanning and that the use of shade,

clothing, well-designed sunglasses and wide-

brimmed hats are necessary to protect themselves

against sunlight. In situations where this is not

possible, UV protective dermatological preparations

containing both UVA and UVB sunscreens should

be used. The development of effective strategies that

support skin protective mechanisms is important as

well. Application of agents that induce melanin

synthesis is one way of reinforcing skin protection

(and maybe reduce the time spend in the sun in tan-

addicted people). Increasing evidence suggests that

treatment of the skin with compounds that influence

the Nrf2 signalling pathway and in this way increase

antioxidant enzymes expression, is a new possibility

for photoprotection. Delivery of antioxidant enzymes

in the form of liposomes is also a possibility as well.

In people at high risk for skin cancer development

(e.g., genetic susceptibility, patients on immunosup-

pressive therapy) topical formulations containing

DNA repair enzymes mainly T4 endonuclease V in

conjunction with other enzymes, e.g., OGG1, could

be benefitial. Skin supplementation with vitamins is

another promising strategy but the form of delivery

(stability vs. activity) has to be resolved. The most

studied plant polyphenols, silymarin and green

tea extract, have a proven wide spectrum of

protective biological activities helpful in the protec-

tion and treatment of UV light-caused damage.

Clinical trials are needed to validate the preventive

and therapeutic potential of these and other plant

derived agents.

Acknowledgements

We thank Prof. Daniela Walterova for helpful

comments on the manuscript. Because of space

limitation, this review could not discuss all effects of

solar UV light in details. This work was supported by

a grant of the Grant Agency of the Czech Republic

(303/07/P314) and Ministry of Education of the

Czech Republic (MSM 6198959216).

Declaration of interest: The authors report no

conflicts of interest. The authors alone are respon-

sible for the content and writing of the paper.

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