Ultraviolet Light Induced

Generation of Reactive Oxygen 2

Species

T.L. de Jager, A.E. Cockrell, and S.S. Du Plessis

Abstract
As ultraviolet (UV) radiation is naturally and ubiquitously emitted by the
sun, almost everyone is exposed to it on a daily basis, and it is necessary
for normal physiological function. Human exposure to solar UV radiation
thus has important health implications. The generation of reactive oxygen
species (ROS) by UV radiation is one of the mechanisms through which
UV light can manifest its possible detrimental effects on health. When an
imbalance develops due to ROS generation exceeding the body’s antioxi-
dant defence mechanisms, oxidative stress can develop. Oxidative stress
can lead to cellular damage (e.g. lipid peroxidation and DNA fragmenta-
tion), apoptosis and cell death. Broadly UV can induce ROS by affecting
the cellular components directly or by means of photosensitization mecha-
nisms. More specifically UV light can induce ROS by affecting the enzyme
catalase and up-regulating nitric oxide synthase (NOS) synthesis. It may
also cause a decrease in protein kinase C (PKC) expression leading to
increased ROS production. UVR is capable of modifying DNA and other
chromophores resulting in elevated ROS levels. The effects of raised ROS
levels can vary based on the intracellular oxidant status of the cell. It is
therefore important to protect yourself against the potentially harmful
effects of UV light as it can lead to pathological UV-induced ROS
production.

Keywords
Reactive oxygen species • Oxidant • Antioxidants • Catalase • Nitric oxide
• Protein kinase C

T.L. de Jager • A.E. Cockrell • S.S. Du Plessis (*)

Division of Medical Physiology, Faculty of Medicine
and Health Sciences, Stellenbosch University,
Tygerberg, South Africa
e-mail: [email protected]

© Springer International Publishing AG 2017 15

S. Ahmad (ed.), Ultraviolet Light in Human Health, Diseases and Environment, Advances in
Experimental Medicine and Biology 996, https://doi.org/10.1007/978-3-319-56017-5_2
16 T.L. de Jager et al.

2.1 Introduction 100 nm to 400 nm. Based on their wavelengths,

UV light can be subdivided into several catego-
As ultraviolet (UV) radiation is naturally emitted ries with three bands, namely UVA, UVB and
by the sun and thus regarded as ubiquitous, UVC [3, 15]. Environmental and dermatological
almost everyone is exposed to it on a daily basis. photobiologists commonly use slightly different
Human exposure to solar ultraviolet radiation has divisions, which are more closely associated
important health implications. Suitable amounts with the biological effect of the different wave-
of UV radiation exposure has beneficial effects, lengths [19].
however many studies have demonstrated evi-
dence in support of harm associated with overex- UVA 320–400 nm: The most commonly encoun-
posure to UV. Adequate exposure is vital for tered UV light as it passes through the atmo-
UV-induced vitamin D synthesis, while a number spheric ozone with little change. Initially
of health effects (e.g. skin cancer, malignant mel- UVA cause pigment darkening (tanning) fol-
anoma) have been identified as a result of excess lowed by sunburn when over exposed. UVA is
exposure. necessary for Vitamin D production in humans
The generation of reactive oxygen species but over exposure could result in epidermal
(ROS) by UV radiation is one of the mechanisms hardening, immune system suppression and
through which UV light can manifest its detri- formation of cataracts. UVA is vastly used in
mental effects on health. ROS are free radicals the cosmetic industry (sunbeds or tanning
and can be defined as an unstable chemical spe- booths).
cies possessing an unpaired electron. When an UVB 290–320 nm: UVB is the key factor in pho-
imbalance develops due to ROS generation tochemical damage to cellular DNA. UVB is
exceeding the body’s antioxidant defence mecha- also essential for production of Vitamin D in
nisms, oxidative stress can develop. Oxidative humans; however, over exposure may hold
stress can lead to cellular damage (e.g. lipid per- harmful effects to the human body. These
oxidation and DNA fragmentation), apoptosis harmful effects include sunburn, cataracts as
and cell death [22]. well as the initiation of the carcinogenic pro-
Due to industrialization there is a dramatic cess in the skin.
increase in chlorofluorocarbons (CFCs), with UVC 220–290 nm: UVC is almost completely
resulting loss of stratospheric ozone. This situa- absorbed by the atmospheric ozone and has
tion subsequently can lead to increased levels of little effect on human health. Germicidal
specially UVC radiation reaching the earth’s sur- lamps emit UVC in order to kill microbes.
face (which otherwise cannot) and therefore Humans get exposed to UVC accidentally
growing human exposure to UV radiation. The may cause corneal burns and snow blindness.
burden on human health is more noticeable with UVC is absorbed by the dead outer layer of
increased UV radiation induced pathologies and the dermis thus exposure may cause severe
thus the need to explore this phenomenon in pain but clears up within a few days [3, 15].
more detail. The chapter aims to provide a
detailed relationship between UV and ROS as
well as the associated burden. 2.2.1 T
 he Global Solar UV Index
(UVI)

2.2 Ultraviolet Light The global solar UV index [28] provides a

description of the level of solar UV radiation at
Ultraviolet (UV) light is part of the solar emis- the Earth’s surface [19]. The values are reported
sions spectrum which falls between the electro- as a number from zero upwards; the higher the
magnetic radiation spectrum of X-rays and number the greater the risk for UV induced dam-
visible light with wavelengths ranging from age. The UV index (UVI) can be used as a guide-
2  Ultraviolet Light Induced Generation of Reactive Oxygen Species 17

line and educational tool to ­determine the risk for small percentage to the total yearly exposure
potential UV damage to the skin and eye when [3].
exposed to solar UV radiation. This could be a
valuable tool to inform individuals of the
increased risk of skin cancers associated with 2.4 Tissue Exposure to UV
excessive UV radiation exposure, and to encour-
age individuals to adopt protective measures Vitamin D binds to steroid vitamin D receptors in
[19]. the body. These receptors are directly involved in
UVI is presented usually as the maximum UV proliferation and differentiation of cells. The
radiation levels on a given day, which occurs vitamin D dependent renewal process takes place
around solar noon. Geographical location plays a in the keratinocytes. Keratinocytes accounts for a
determining factor but none the less, solar noon large portion of the cells in the epidermis.
takes place between local noon and 2 pm [19]. Vitamin D is able to regulate the low resting
levels of cell signalling components such as ROS
by means of controlling the expression of these
2.3 Sources of UV Light components. Therefore, vitamin D is vital in the
replenishment of new cells for the skin surface.
Humans are exposed to UV radiation through Vitamin D production is dependent on the amount
outdoor sun exposure or due to artificial sources. of melanin in the skin [4, 5]. The amount of mela-
nin the skin produces depends how fair or dark
the skin colour is and the Vitamin D production is
2.3.1 Outdoor dependent on the amount of melanin in the skin.
Darker skins have more melanin which allows
Outdoor exposure by the sun is either through less UVB to enter the skin. Due to less UVB
deliberate activities (sun tanning) or as a result of entering the skin, less vitamin D is produced;
recreational or occupational activities. therefore dark skinned individuals require more
sun exposure.
These factors make it difficult to determine
2.3.2 Artificial Sources the amount of sun exposure time one requires in
order to get adequate vitamin D and avoid dam-
Exposure includes sources from medical and cos- age. A good rule of thumb for sun exposure is to
metic treatments. The following sources are expose your skin for half the time before it turns
major contributors to artificial UV exposure: pink. For fair skinned individuals it could be only
a few minutes, but darker skinned person requires
• Phototherapy/ sunbeds: They expose human a longer exposure time [9].
skin to UVA and some UVB radiation. Black A small amount of UV radiation is required
light, which is also referred to as a UV-A light, for the production of vitamin D in humans. The
is predominately used by tanning booths and amount of vitamin D one gets from exposing the
phototherapies bare skin to the sun depends on the intensity of
• Medical: Exposure will depend upon treat- the sun’s UV rays reaching the earth’s surface
ment type but, include a majority of diagnostic which is influenced by a number of different fac-
and treatment apparatus. tors [19]. Vitamin D’s role in cell proliferation
• Industrial/ commercial: Arc welding is a and differentiation could possibly have a protec-
potential source of UV exposure which can tive role against UV-induced ROS damage.
cause severe damage to the eyes and skin. Prolonged human exposure to solar UV radia-
• Lighting: Fluorescent lamps emit minor tion may result in acute and chronic health effects
amount of UV light which only contributes a on the skin, eye and immune system. Sunburn
18 T.L. de Jager et al.

and tanning are the best known acute effects of 2.5.1 W

 hat Are Reactive Oxygen
excessive UV radiation exposure; in the long Species?
term, UV radiation-induced degenerative changes
in cells, fibrous tissue and blood vessels lead to Free radicals are defined as molecules containing
premature skin ageing. UV radiation can also one or more unpaired electrons in their electron
cause inflammatory reactions of the eye, such as orbitals. Electrons are considered to be more sta-
photokeratitis [19]. ble when paired free radicals are generally more
reactive than non-radical species [13]. Radicals
can combine their unpaired electrons by forming
2.5  V Light Induced Reactive
U a covalent bond. Radical interactions with non-­
Oxygen Species radicals often involve the radical donating its
electron (a reducing action) or it could accept an
Human skin provides continuous protection electron from the non-radical molecule (an
against chemicals, radiation and infection. The oxidising action) or it could simply join onto a
skin is composed of different layers namely the non-radical [13]. This results in the non-radical
epidermis (composed of mainly dead cells), the becoming a radical and can have various physio-
dermis and subcutaneous tissue. The epidermis is logical repercussions.
constantly renewed and is separated from the der- ROS is the umbrella term used to describe
mis by a layer of continuously dividing cells oxygen derived free radicals as well as non-­
namely keratinocytes and melanocytes. Melanin radicals such as hydrogen peroxide. Organisms
pigment is produced by melanocytes, which is that are dependent on the reduction of oxygen for
the precursor of melanoma [17], and is trans- energy, aerobic organisms, are the most suscep-
ferred to the neighbouring keratinocytes. tible to the potentially damaging actions of ROS
Keratinocytes create a highly effective physical that are released during this process [6]
barrier; they accumulate melanin pigments as (Table 2.1).
they mature, and epidermal melanin functions to ROS is constitutively produced in the body
potently block UV penetration into the skin. A and sources of ROS can either be exogenous or
third cell type is the Langerhans cells which are endogenous.
present under the stratum corneum. They play a Endogenous ROS are predominantly pro-
role in immunological reactions of the skin and duced by the mitochondria in the cell, as this is
their actions are highly sensitive to UV. The der- where oxygen is reduced for ATP production by
mis contains collagen fibres which assists in the the addition of four electrons to produce water as
skins’ elasticity and provides supportive strength. the product. The largest portion of oxygen is
Collagen fibres are broken down by high levels of reduced in the electron transport chain (ETC). No
UV which leads to premature aging as skin loses remaining intermediates are produced. However
its elasticity [3, 12]. approximately 5% of oxygen is reduced by the
As the human skin is the largest organ and
covers the body’s whole surface area it is prone Table 2.1  Examples of ROS
to continuous UV light exposure [11]. Melanin Superoxide •
O2−
synthesis is stimulated by sun exposure [11], arti- Hydroxyl anion •
OH−
ficial sources [3] and inflammation. This results Hydrogen peroxide H2O2
in post inflammatory hyperpigmentation. Peroxyl ROO•−
Epidermal melanocytes are thus susceptible to Alkoxyl radicals RO•
ROS which is induced through excessive sun Radicals of nitric oxide •
NO
exposure [11]. If homeostasis is disrupted by the Peroxynitrite •
ONOO−
increased production of ROS this could possibly Ozone O3
drive the process of malignant transformation of Oxygen singlet O1O2
cells [11, 21]. Adapted from Ref. [6]
2  Ultraviolet Light Induced Generation of Reactive Oxygen Species 19

univalent pathway thereby leading to free radical peroxide via the reaction 2H2O2 2H2O + O2
production. ROS producing capabilities are often through a process known as catalytic activity.
dependent on the composition of the mitochon- The enzyme catalase is also capable of exhibiting
drial membrane, the species of animal and the peroxidatic activity when low concentrations of
age of the animal [6]. hydrogen peroxide (H2O2) are present. However,
Most reactions that take place in the mito- it was observed that UVB light caused a marked
chondrial ETC consist of redox reactions. These increase in ROS in keratinocytes, more so in glu-
reactions involve the exchange and movement of tathione depleted cells. Upon further experimen-
electrons, with the enzyme cytochrome oxidase tation it was found that the oxidant generating
being the only enzyme involved in a reaction that protein was catalase [14].
uses oxygen. It has been found that the redox This is thought to be a result of the ability of
reactions in the ETC ‘leak’ electrons and subse- the short wave UV (Likely UVC) light to alter the
quently generate superoxide (O2.-) with the H2O2 binding site on the catalase enzyme, thus
majority of the ROS formation taking place at allowing for water molecules to access the heme
complex III and to a lesser extent at complex iron. This essentially allows for the water mole-
I. ROS is also formed in the endoplasmic reticu- cules to act as a source for the generation of pro-
lum (ER) and peroxisomes of the cell. tons. These protons are then able to interact with
Extracellular or exogenous ROS sources are vast diatomic oxygen to generate ROS such as reactive
and are responsible for a large percentage of ROS peroxides. The activity of the charge relay net-
present in the body. Common air pollutants and work of the enzyme was also found to be of
industrial contaminants, exhaust fumes and the importance on the effect that UV light mediates
smoke generated by cigarettes have been impli- on catalase. The effects of UVB light on catalase
cated in ROS generated in the body. ROS gener- were found to be pH-sensitive and oxygen depen-
ated in this manner has been found to both dent, this and the intracellular oxidant status influ-
directly and indirectly cause O2.- formation and ences whether the catalase activity in response to
various types of nitric oxide derivatives, either by UV light is cytotoxic or protective [14].
direct contact with the skin or by inhalation.
Some drugs, narcotic substances and anesthetiz- 2.5.2.2 Nitric Oxide Synthase
ing gases are also thought to contribute to ROS UVB has also been implicated in the up-­
production. Certain food and alcohol consump- regulation of membrane-bound nitric oxide syn-
tion have also been implicated in ROS formation. thase (NOS) in human keratinocytes, thereby
Other environmental agents and non-genotoxic resulting in increased production of NO [10].
carcinogens such as gamma irradiation can also While UVA has been shown by [2] to generate
induce ROS formation [6]. increased superoxide levels at moderate UVR
levels in real time, O2.- is able to inactivate iron-­
sulphur proteins leading to release of the reduc-
2.5.2 UV – Light Induced ROS ing ferrous iron, thereby resulting in further
production of ROS [23]. The exact mechanisms
Even exposure to the ultraviolet light spectrum as to how UV causes these effects are not fully
can indirectly lead to the production of a variety elucidated, however the simultaneous production
of ROS including O2.-, singlet oxygen, hydroxyl of O2.- and NO within proximity of each other can
radicals and hydrogen peroxide through various lead to the spontaneous generation of peroxyni-
mechanisms [17] (Fig. 2.1). trite, a highly reactive free radical [10].

2.5.2.1 Catalase 2.5.2.3 Signalling Pathways

The first mechanism that will be discussed is the Various signaling pathways are activated by
UV induced ROS by the enzyme catalase. UV-mediated ROS generation, especially in the
Catalase is known to be able to degrade hydrogen pathophysiology of skin diseases. MAPKs have
20 T.L. de Jager et al.

Fig. 2.1  UV radiation is able to mediate damage to cel- in an excitation of the sensitizers to their triplicate states.
lular components in two ways: The first mechanism is by The excited photosensitizers exert their effects by two
the direct absorption of incident rays by the cell and its mechanisms. Type I photochemical reactions involve
components. This results in the formation of an excited electron transfer and the process of hydrogen abstraction
state of the components and subsequent chemical reac- to form free radicals. Type II photochemical reactions
tions. The second mechanisms are by means of photosen- involve the transfer of energy with O2 to yield reactive
sitization. Incident rays are absorbed by endogenous or state singlet oxygen (1O2) [20, 22]
exogenous photosensitizers such as bilirubin. This results

been shown to be a target of oxidative stress such cesses such as the cell cycle, proliferation and
the oxidative stress induced by solar UV radia- apoptosis [7].
tion, the UV radiation influences the pathways in
a manner that closely resembles ROS [7, 16]. The 2.5.2.4 Protein Kinase C
ROS produced lead to the activation of the UV irradiation was found to have an effect on
MAPKs such as ERK and JNK. These MAPKs protein kinase C (PKC) in murine fibroblasts.
play a pivotal role in the recruitment of factors Several different isoforms of this serine/threo-
that lead to the downstream activation of tran- nine kinase exist and have been implicated in
scription factor AP-1. The factor p38 and the UV-induced signal transduction pathways [8].
inhibitory kappa kinase activation are vital in the Low doses of UV exposure result in the adhesion
process of transcriptional activation of of cultured fibroblasts to the collagen matrices by
NF-kB. UVA irradiation of the fibroblast cells in means of PKC isoform activation and integrins.
the skin result in the release of labile iron, which PKC α has also been found to be irreversibly
is implicated in the activation of NF-kB [7, 24]. inhibited in UVA irradiated cells while PKC ε is
AP-1 and NF-kB play essential roles in the regu- known to act as an endogenous photosensitizer
lation of a diverse array of genes involved in pro- that plays a role in inducing UV-induced cutane-
2  Ultraviolet Light Induced Generation of Reactive Oxygen Species 21

ous damage. The accumulation of ROS associ- 2.5.3 B

 iochemical Actions of UV
ated with skin aging is thought to be linked to UV in the Skin
radiations effect on PKC. In a study done by
Bossi et al. [8] it was observed that UVA irradia- Chromophores absorb UV energy which allows
tion causes an increase in ROS levels and lipid for biochemical reactions in human skin [26].
peroxidation in both young and aging fibroblasts; They are molecules that absorb certain wave-
however basal ROS levels were much higher in lengths of visible light and transmit to others.
the aged cell population and they also exhibited a Chromophores could either be an exogenous
much slower response to UV irradiation. A agent or endogenous compound [1]. Cutaneous
decline in PKC δ expression in these fibroblasts chromophores include DNA, urocanic acid, aro-
was also observed to be closely linked to the matic amino acids, retinoids, carotenoids, biliru-
translocation of PKCδ to the nucleus due to the bin, flavins, haemoglobin, melanin and NAD(P)
exposure to UV light. At the same time it also H [26]. Chromophores may be damaged directly
resulted in an increase in ROS production. This or they can act as photosensitizers. This results in
observation is suggestive of the role that PKC δ the generation of ROS in the presence of molecu-
may have in regulating ROS production in ROS-­ lar oxygen [1].
induced states and lean towards the idea that loss If the epidermis is exposed to direct UV radi-
of PKC δ expression can cause the activation and ation from the sun it can lead to oxidative stress
elevation of ROS levels [8]. It was also found that through activating the enzyme NADPH oxidase
PKC α expression post UV irradiation is not or by promoting lipid peroxidation. When
linked to the elevation in ROS levels, regardless molecular oxygen is reduced to O2.- the produc-
of increased PKC α expression following UV tion of ROS is initiated. This process can be
irradiation. enzymatic through NADPH oxidase or xanthine
oxidase catalysed reactions or non-enzymatic.
2.5.2.5 DNA Damage Glutathione is recycled by glutathione reduc-
Exposure of cells to UVA, UVB or UVC is capa- tase to the detriment of NADPH, which is recy-
ble of causing 8-oxo-7-8-dihydro-2′- cled by glucose 6- phosphate dehydrogenase
deoxyguanosine (8-oxodGuo). This is an after glucose has been phosphorylated by hexo-
oxidatively modified DNA base that is often used kinase [26].
as a marker of possible oxidative DNA damage, UV radiation also causes oxidative stress in
both in vivo and in vitro in calf thymus DNA as the skin by inducing the release of mediators of
well as cultured cells [28]. Various ROS have inflammation. Leukocytes produce the radical
been implicated in the UV-induced oxidation of anion O2.-, catalysed by the enzyme NADPH oxi-
8-oxodGuo. Singlet oxygen (1O2) is proposed to dase. O2.- then undergoes dismutation to oxygen
be the only source of ROS involved in UVC-­ and H2O2, catalysed by superoxide dismutase.
induced production of 8-oxodGuo. While for Myeloperoxidase then converts H2O2 to hypo-
UVA and UVB 1O2 is a large source of the ROS chlorite. Another pathway for oxidative stress
involved. Both H2O2 and hydroxyl radicals (.OH) caused by UV is the removal of a proton and an
were also found to play a significant role as well. electron from lipid molecules which produces
Surprisingly it was observed that the O2.-, usually lipid radicals. Lipid radicals can interact with
a highly reactive free radical, was not involved in molecular oxygen giving rise to lipid peroxidase
UV-induced oxidative damage in these cells [28]. and new lipid molecules [26].
These observations were also noted in a study
conducted by Wei et al. [27] where they con-
firmed the role of 1O2 in oxidative DNA damage
induced by UV exposure.
22 T.L. de Jager et al.

2.6 UV, ROS epidermal layer. However, UVA passes the

and Pathophysiological Skin through the epidermal layer inducing damage
Effects which leads to damage in the deeper dermal tis-
sue [25].
The best known effect of excessive UV radiation
exposure is erythema, which is reddening of the
skin due to sunburn. Chronic exposure to UV 2.7 Conclusion
radiation can cause a series of degenerative skin
conditions. Humans are exposed to UV light on a daily basis,
Photoaging is a consequence of exposure to with the skin bearing the brunt of this exposure
UVA and UVB. Abnormal elastic fibres in the due to its large surface area. The constant UV
dermis and a decrease in collagen fibres are dis- radiation is imperative for normal physiological
tinct characteristics of photo aged skin. Photoaged function. However over-exposure to UV light is
skin displays an increased degradation of colla- known to have detrimental physiological effects.
gen and elastic fibres in the dermis which is It is believed that these effects are a result of an
caused by an increase in proteolytic activation increase in ROS in the cells. UV light can induce
and abnormal Extra Cellular Matrix (ECM) turn- ROS in various ways, such as affecting the enzyme
over. UV rays can also contribute to the genera- catalase and up-regulating NOS synthesis. UV
tion of ROS that stimulates the inflammatory radiation may also cause a decrease in PKC
process in the skin. This causes reduced levels of expression leading to increased ROS production.
natural enzymatic and non-enzymatic antioxi- It can also modify DNA and other chromophores
dant defence mechanisms of the photoaged skin resulting in elevated ROS levels. The effects of
as well as an increased neutrophil infiltration into raised ROS levels can vary based on the intracel-
skin and increased inflammation [3]. lular oxidant status of the cell. However, it is still
UVA mainly drives the production of important to protect yourself against the poten-
ROS. UVA has the ability to penetrate the deep tially harmful effects of UV light as it can lead to
dermal layer, inducing changes and driving the pathological UV-induced ROS production.
process and progression of photoaging. Once
UVA penetrates the skin it is absorbed by cellular
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