European Review for Medical and Pharmacological Sciences 2015; 19: 98-112

Photoprotection: facts and controversies

K. SKOTARCZAK1, A. OSMOLA-MAŃKOWSKA2, M. LODYGA2, A. POLAŃSKA3,
M. MAZUR2, Z. ADAMSKI
1
Faculty of Pharmacy, Specialisation Cosmetology, Poznan University of Medical Sciences, Poznan,
Poland
2
Department and Clinic of Dermatology, Poznan University of Medical Sciences, Poznan, Poland
3
Department of Dermatology and Venereology, Faculty of Health Sciences, Poznan University of
Medical Sciences, Poznan, Poland

Abstract. – Excessive exposure of the skin Thusly, radiation intensity increases by 4% for
to sunlight can lead to many negative effects, every 300 m. Snow reflects approximately 90%
such as sunburn, photoaging and skin cancer
development. Pollution and stratospheric ozone
of ultraviolet radiation, which is far more than
layer depletion are factors that increase expo- any other granular material, such as sand (ap-
sure to ultraviolet radiation. proximately 15-30%). The sun’s rays can pass
This work is an accurate summary of the cur- through water to a depth of approximately 1 m.
rent state of knowledge on broad-spectrum Water also strongly reflects UV rays. Another
photoprotection. Avoiding the sun, skin protec- physical factor that affects radiation intensity is
tion through the use of protective clothing and pollution. The air contamination compromises
protective filters are currently the most effec-
tive methods of sunscreen provided that they the ozone layer and consequences in the forma-
are suitably used. In addition, discussed are tion of the Ozone Hole, resulting in greater in-
controversial issues such as the toxicity of zinc coming radiation to earth and exposed skin.
used in sunscreen preparations and the poten- Ultraviolet radiation (UVR) is one of the most
tial for deficiency of vitamin D3 in relation with important environmental factors influencing the
the application of strict photoprotection. human body. Discovered in the early nineteenth
The study has also addressed issues con-
cerning the most recent lines of research in the
century by Johann Wilhelm Ritter, ultraviolet
exploration of modern methods of photoprotec- electromagnetic radiation is invisible to the hu-
tion both local and systemic, such as with the man eye, with a wavelength shorter than visible
use of photolyase or examination of various en- light (390-700 nm) and longer than x-rays (0.01-
zymes repairing damage after sun exposure, as 10 nm). Due to the different biological effects of
well as the promising future in photoprotection UVR, there is a division into three main areas:
technology.

Key Words: • UVA – wavelength range of 320 to 400 nm.

Photoprotection, Ultraviolet radiation, Infrared radi- • UVB – wavelength range of 280 to 320 nm.
ation. • UVC – wavelength range of 100 and 280 nm1.

The most dangerous ultraviolet radiation is

UVC, as it is nearly entirely absorbed by the
Introduction ozone layer. UVC has the shortest wavelength
and the highest energy of the three UVRs and
The earth is constantly exposed to radiation posses strong mutagenic properties and erythema
from the sun, which is essential for life. Such causation. Characterized by a bacteriostatic and
emitted radiation includes visible, infrared (IR), bactericidal action (particularly radiation having
and ultraviolet (UV) light. The strongest radia- a wavelength of 254 nm), UVC was applied in
tion reaches the earth in the summer months, be- medicine as germicidal lamps.
tween the hours of 10 am and 5 pm, when the UVB radiation, comprising approximately 5 to
rays fall perpendicularly. With greater elevation 10% of the entire spectrum of UV radiation
above sea level, the atmosphere becomes thinner reaching the earth’s surface, is characterized by a
and smaller amounts of UV rays are absorbed. relatively high energy and is a potent erythema

98 Corresponding Author: Agnieszka Osmola-Man´kowska, MD, Ph.D; e-mail: [email protected]

 Photoprotection: facts and controversies

inducer. Responsible for the most important bio- activity and activating the synthesis of vitamin
logical effects (e.g. sunburn, pigmentation, vita- D3, whilst, also demonstrating beneficial effects
min D3 synthesis, immunosuppression and car- on the course of various dermatological disor-
cinogenesis), UVB is absorbed in the stratum ders, such as atopic dermatitis or psoriasis 2.
corneum of the skin by chromophores. Effected Thus, providing the basis for the use of pho-
elements in the skin are melanin, cellular DNA, totherapy as a method of therapy.
urocanic acid, proteins, lipids and amino acids2.
UVB directly damages the DNA strand, resulting Negative Effects of UV Radiation
in the formation of pyrimidine dimers and distor-
tion of repair mechanisms, which lead to muta- Acute Adverse Reactions of UV Radiation
tions3. The reactions induced by UVB radiation Negative effects of UV radiation on the body
are immediate, resulting in the release of inflam- may be acute (immediate) in character and mani-
matory mediators (e.g. histamine, serotonin, and fest in the form of erythema. The sun can also
prostaglandins), which lead to dilation of capil- provoke immediate reactions in people suffering
laries and the development of erythema and ede- from photodermatoses. Photodermatoses are a
ma4. This range of rays easily penetrates through group of diseases, which aggravate hypersensitiv-
water and quartz glass. However, these rays are ity reactions to ultraviolet radiation. Increased
filtered through clouds and windowpanes. Great- frequencies of dermatoses induced by UV occur
est ray intensity is reached during the summer, in the spring when intensity of natural sunlight
between the hours of 10 am and 5 pm. increases. Polymorphic light eruption is the most
UVA radiation is divided into two ranges: common idiopathic acquired photodermatosis4.
UVA2 (wavelength range of 340-380 nm) and Phototoxic and photoallergic reactions are de-
UVA1 (wavelength range of 315-400 nm). UVA1 pendent on external factors. Reactions of photo-
is in the category of UV radiation with the lowest toxicity predominately occur under the influence
energy. However, it represents up to 95% of total of substances that increase the impact of UV rays
UVR emitted and is minimally attenuated by the on the skin, mainly UVA rays5. Such factors are
ozone layer. Rays reach the earth year-round and usually substances of vegetable origin, drugs, or
despite weak energy, UVA1 penetrates through chemicals administered either externally or oral-
clouds and windowpanes. Intensity is independent ly, i.e. psolarens, sulfonamides, tetracyclines, fu-
of time of day or year. Despite lesser induction of ranocoumarins or colorants6. In contrast to pho-
erythema, UVA1 stimulates production of pigment totoxic reactions, photoallergies are initiated by
to a much greater extent than other UVRs. It pene- specific immunological reactions caused by the
trates into the deeper layers of the dermis, impair- combination of ultraviolet rays and exogenous
ing the normal functioning of cells, affecting photosensitizing substances7. Reactions are not
blood vessels and collagen fibers. UVA rays have dose-dependent on either the photosensitizing
indirect effects on cellular DNA through genera- substance or radiation. Manifestation occurs, on
tion of reactive oxygen species. These are so- an average, 24-48 hours following exposure to
called “delayed reactions”, which are related to UVA. Presentation may occur in the form of
the destructive action of free radicals on the struc- eczema, itching or burning and can develop into
ture of proteins and nucleic acids. Such changes in a permanent hypersensitivity to sunlight 8. Pho-
structure of collagen and elastin lead to premature toallergic substances may be derivatives of sali-
aging of the skin. UVA irradiation plays a signifi- cylates, non-steroidal anti-inflammatory drugs
cant role in phototoxic and photoallergic reactions, (NSAIDs), fragrances, and even constituents of
leading to immunosuppression and photocarcino- sunscreens.
genesis. UVA2 is a transitional range of UV radia- Extracts can also be dermatoses, in which sun-
tion, which can be used to detect the biological ef- light is a factor in exacerbation or triggering,
fects of both UVA and UVB radiation1. (e.g. Lupus erythematosus)9.

Biological Effects of UV Radiation on Chronic Adverse Reactions of UV

Human Skin Radiation

Positive Effects of UV Radiation Photoaging

In moderate amounts, ultraviolet rays promote Prolonged exposure to ultraviolet rays causes
wellbeing by reducing stress, increasing mental the formation of visible skin changes, through

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 K. Skotarczak, A. Osmola-Man´kowska, M. Lodyga, A. Polan´ska, M. Mazur, Z. Adamski

the deterioration of the skin’s structure and func- cells, vascular endothelial cells, macrophages,
tion. All these changes are defined as premature granulocytes, mast cells and melanocytes,
skin aging or photoaging10. Clinical presentation Langerhans cells are part of lymphoid tissue as-
of photoaging of the skin includes lines and sociated with the skin (skin associated lymphoid
wrinkles, dryness and hyperkeratosis, hyperpig- tissue – SALT), where its primary function is to
mentation, telangiectasia, and loss of elasticity of provide immune surveillance. Exposure to UV
the epidermis11. Formation of these changes is radiation can significantly reduce the amount of
contributed by both UVA, as well as the shorter Langerhans cells, which can lead to impairment
in wavelength UVB rays. UVB radiation is re- of immune surveillance mechanisms, and conse-
sponsible for damage to the lipid barrier and quently contribute to the development of skin
structural changes within Langerhans cells. UVA, cancer13. As a result of UVR penetration, photon
although largely responsible for damage to con- energy is absorbed by chromophores in the skin.
nective tissue, enhances the effect of UVB on the DNA that is damaged by UVB radiation forms
epidermis. Weakening of the connective tissue pyrimidine dimers and 4,6-photoproducts11. If the
and the changes in skin microcirculation can resulting photoproducts are numerous and cannot
cause permanent dilation of blood vessels, which be repaired, the damaged DNA enters into the
emerge in the form of telangiectasia. As in the next replication cycle. Accumulation in the epi-
case of physiological aging, where a decrease in dermis undergoes photoisomerization by chang-
collagen content in the skin is observed, UV radi- ing the molecule’s structure from trans to cis
ation stimulates metalloproteinases to promote form. This photoelectrochemical process is re-
breakdown of collagen. sponsible for the immunosuppression. Ultraviolet
The most characteristic for the process of pho- radiation, especially UVA, indirectly influences
toaging is the elastase phenomenon, namely the membrane lipids, such as cholesterol and phos-
accumulation of abnormal elastin masses. At pholipids. As a result of these reactions, free rad-
first, elastic fibers undergo hyperplasia and thick- icals are produced and consequently, reaching the
ening. Subsequently, these fibers develop into a inhibition of lipid peroxidation and membrane
twisted and highly branching compact mass. Re- enzymes and transport proteins.
peatedly exposing the skin to sunlight results in
consistent darkening. A feature of photoaging is Photocarcinogenesis
the uneven stimulation of melanocytes, which The most serious consequences of UV radia-
most commonly results in the manifestation of tion are associated with the increased risk of neo-
freckles and lentigines. plasia. Carcinogenesis by UV radiation is a long-
Photoaging is not solely influenced by UV term process. The first stage is initiation or the
radiation (e.g. UVA) but also infrared (IR), carcinogenic action (UV) on the cell DNA, caus-
largely of the infrared A (IRA) spectral range. ing mutations therein. After adoption of UV pho-
IRA has the ability to penetrate deeply into the tons, DNA is excited, resulting in the formation
subcutaneous tissue causing mutations in of various types of photoproducts. The passage
mitochondrial DNA (mtDNA) called common of at least one replication cycle results in the fix-
deletions and also has the ability to stimulate the ation of mutation. Promotion is the subsequent
formation of free radicals reactive oxygen stage, during which the initiated cells acquire
species. Topical application of mixtures of phenotypic characteristics of neoplastic cells.
antioxidants such as grape seed extract, The following stage is that of progression, where
ubiquinone, vitamin C and E, have an inhibitory tumor cell counts increase. There are DNA repair
effect on oxidative stress resulting from the mechanisms, which are responsible for the re-
impacts of infrared radiation12. moval of harmful photoproducts14. One of them
is incorrect nucleotide excision, which is respon-
Photoimmunosuppresion sible for the NER system – nucleotide excision
The skin is an organ, equipped with its own repair. Malfunctioning of this system leads to du-
immune system, which protects against plication of DNA mutation and the development
pathogens and identifies and eliminates damaged of tumors. Mutations induced by UVB radiation
cells. Langerhans cells, or primary dendritic epi- consist of transitions of thymine instead of cyto-
dermal cells, are macrophages of myeloid lineage sine (CT or CC-TT) and are referred to as mark-
that present antigens to T cells and begin immune ers of UVB damage, which are found in all types
reactions in the skin. Along with keratinocytes, T of skin neoplasms.

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 Photoprotection: facts and controversies

The form of exposure to ultraviolet radiation Photoprotection

plays a significant role. Actinic keratosis (AK) Modern photoprotection is based upon on
and squamous cell carcinoma (SCC) are conse- three basic pillars of sunscreen. These include
quences of chronic exposure to cumulative doses appropriate behavior during expose to sunlight,
of ultraviolet radiation, while malignant use of clothing and sunscreen preparations. The
melanoma and basal cell carcinoma are associat- most effective method of sun protection is avoid-
ed with excessive exposure or periodic high dos- ing exposure to sunlight by seeking shade and re-
es of radiation in childhood15. ducing the time of exposure, especially during
the hours of 10 am and 2 pm.
An important element of photoprotection is
Natural Skin Protection Against UV the correct choice of clothing, which provides
Radiation adequate protection against both UVA and UVB
radiation. In contrast to creams, clothing does not
Human skin is constantly exposed to sunlight cause allergies and irritation. However, not all
and consequently, has developed a number of fabrics provide the same protection from the sun.
various protective mechanisms against the im- To accurately determine efficacy levels of differ-
munosuppressive and mutagenic effects of ultra- ent sun protective fabrics, ultraviolet protection
violet light. Endogenous mechanisms include factor (UPF) is utilized. Similar to sun protective
thickening of the epidermal layer, mechanisms of factor (SPF), which only measures the level of
DNA repair, apoptosis, antioxidant enzymes and UVB radiation blocked, UPF measures levels of
pigmentation. blocked radiation of both UVA and UVB. The
Darkening of color of the skin, or tan, indi- higher the UPF, the more superior the protection
cates increased melanin production in response against UV rays19.
to environmental factors such as ultraviolet light. Taking into account types of fabric composi-
There are three types of pigment reactions: im- tion and their levels of protection, synthetic ma-
mediate-type, permanent-type and delayed-type. terials should be chosen over natural fibers, as
Darkening immediately (IPD – immediate pig- they reflect and block radiation more effectively.
ment darkening) caused by UVA, occurs after a Densely woven fabrics block more UV rays than
few minutes of exposure to the sun. The skin be- those with looser weaves. Thick fabrics, such as
comes a grayish hue, which turns brown within denim, are more effective at blocking UV rays
minutes or even days, depending on the dose of than cotton. Dark hues absorb more radiation
UV radiation and the natural color of the skin. than lighter tints, which reflect sunrays. The
Immediate pigment darkening is the result of pre- darker the pigment, there is a greater absorption
existing melanin photooxidation and redeploy- of radiation. While, the lighter the pigment, there
ment of the nuclear part of melanosomes to den- is greater reflection of radiation. Moisture con-
dritic 16. A consequence of IPD is permanent tent also plays a significant role in photoprotec-
darkening of pigmentation (PPD – permanent tion. Dry textiles provide better protection over
pigment darkening), which is also considered the moist counterparts. After washing, some types of
effect of oxidation of melanin. Manifestation oc- fabric undergo structural changes. The weaves
curs after a few hours of exposure to UV rays morph and fuses together, allowing the shorten-
and maintains approximately 3-5 days17. More ing of gaps between fibers and, thereby, reducing
strongly induced by UVA than UVB rays, this the area of penetration and increasing protection.
observation is the basis for examination of effica- UV absorbers may be added to laundry deter-
cy of different filters that protect against UVA ra- gents. Studies have shown an increase in UPF by
diation18. Delayed darkening reactions (DT- de- 400% after impregnating fabrics with such
layed tanning) are consequences of the action of preparations. Stain-resistant fabrics have similar
UVB rays. Browning of the skin is visible ap- effects20.
proximately 2-3 days after exposure to sunlight. An important element of dress is headgear.
This is due to stimulation of melanocytes, an in- Recommended are wide-brimmed hats, not only
crease in melanin synthesis and increase in for the protection of the head, but also the skin of
melanosome count. Darkening effects are main- the forehead, eyes, cheeks and nose. In addition
tained from 10 days up to 3 weeks depending on to a hat that protects the face, sunglasses are rec-
the amount of doses of UV radiation and the nat- ommended to protect the skin around the eyes,
ural color of the skin. eyelids and eyes, as to protect from the onset of

101
 K. Skotarczak, A. Osmola-Man´kowska, M. Lodyga, A. Polan´ska, M. Mazur, Z. Adamski

ocular complications. Exposure to UV light can against UV radiation. Many people believe that
lead to changes in organs of vision; cornea, con- the percentage difference between a sun protec-
junctiva, lens and retina. Photoprotective proper- tion of SPF 30 and SPF 50 is negligible and that
ties of glasses depend on the following factors: higher filters do not provide greater protection.
• Shape and fit – glasses should lie close to the However, it is not a preparation’s filtered radia-
face without touching the eyes. tion dose that determines the degree of protec-
• Colors of lens – darker lenses unnecessarily tion, but rather the dose of radiation that pene-
filter more visible rays, causing mydriasis and trates deep into skin and is responsible for sun-
allowing increased penetration of unfiltered burn. As exemplified by comparing SPF 15 and
light from the UV spectrum and blue light SPF 30 preparations, doses that are able to pene-
(400-440 nm) to access the retina. trate the skin are reduced by one-half. The same
• UV filtering properties21. goes for preparations with SPF 30 and SPF 50.
This signifies the fact that SPF 30 provides pro-
Frequent exposure of the retina to blue light tection two times greater than SPF 15, as does
radiation is a potential risk factor for macular de- SPF 50 compared to SPF 3026.
generation22. In addition to appropriate lenses
and high-degree of UV protection, glasses should
have a suitable shape to prevent UV light from Substances Used As Physical Filters
passing through the sides. Orange and yellow
lenses provide the best protection against both Physical filters are substances of mineral ori-
UV and visible blue light. Sunglasses should also gin, which operate on the principle of knocking
be worn in the morning and evening, when the and scattering radiation from the entire wave-
sun shines more parallel to our eyes. length range. Molecules of these filters are large
enough to not penetrate the skin, but form a bar-
rier to UV radiation on its surface. Physical fil-
Sun Protection Factor (SPF) ters include color pigments and micronized pig-
ments. This group of compounds includes titani-
The measure of effectiveness of a sunscreen is um dioxide (TiO2) and zinc oxide (ZnO). Both
SPF (sun protection factor), which is the ratio of compounds are snowy white in color and are in-
the amount of UV radiation causing erythema- soluble in water. Currently, the only acceptable
tous reactions (MED – minimal erythema dose) material is titanium dioxide6. Less commonly
using a filter to the amount of radiation resulting used compounds are iron oxides, talc, kaolin and
in the same burn without filter protection23. De- mica. Titanium dioxide is the purest and most
termining the minimum erythematous dose of durable pigment. Macromolecules of sizes
sun protection factor can be expressed by the for- greater than 200nm guarantee complete protec-
mula: tion from radiation from the entire UV spectrum.
Despite these properties and given size of mole-
MED protected skin cules, chromatic pigments are matt and inconve-
SPF = ________________________ nient to use as they leave a white coating on the
MED unprotected skin skin. Moreover, to provide sufficient protection, a
thick occlusive application layer is required,
Frequently, SPF is misinterpreted24. For in- which can be comedogenic. Micronized titanium
stance, a preparation’s label advertising “SPF 4”, dioxide particles have a size of 20-80 nm. They
does not signify that the time of skin exposure to are able to diffuse radiation with a wavelength
sunlight can increase 4-fold, but that the UV dose 400 nm and greater, but do not leave a visible
required for inducing erythema after preparation white coating on the skin. However, less protec-
use must be four times stronger than that of un- tion against UV is provided, as the particles can
protected skin. A preparation with a degree of accumulate and create a single break in the first
protection of SPF 2 that is applied at a rate of 2 coating layer. Maximum concentrations in cos-
mg/cm2 absorbs 50% of UVB rays. SPF 15 pro- metic formulations may be 25%. Micronized par-
vides 93% protection against UVB rays. SPF 30 ticles can, however, enter into photochemical re-
is effective in 97% for UVB, while SPF 50 pro- actions produced by reactive oxygen species
vides 98% protection25. No preparation contain- (ROS) and contribute to efficacy reduction of sun
ing UV filters can provide 100% protection protection. To avoid such reactions, particles are

102
 Photoprotection: facts and controversies

coated with silicone. Newer methods have al- Maximum authorized concentration is 5% in cos-
lowed for the development of higher quality nat- metic products.
ural filters. One method is to combine inorganic The most commonly used derivative is an ester
carnauba wax, which acts synergistically with ti- called octyldimethyl-p-aminobenzoate, which is
tanium dioxide, providing a solid dispersion of characterized by increased rates of absorption and
microparticles. Combination provides for an ide- stability at elevated temperatures and in presence
al viscosity and increase in protective effect27. of light. Furthermore, activation on skin is quite
Physical filters do not cause allergies or react good. Tendencies to degrade into acid, levels of
with skin; thus, are recommended for children absorption depend on the environmental pH.
and adults with allergies. Maximum authorized concentration is 5% in
cosmetic products. Common synonym names
used in creams are Escalol 507, Eusolex 6007
Substances Used As Chemical Filters and Padimate O.

Chemical filters are molecules of aromatic Salicyclic Acid Dervivatives

structure, having a carboxyl group that undergoes These compounds are rarely used due to a low
isomerization under the influence of absorbed absorption coefficient, and the need of high con-
energy from radiation. Rays short, less than 380 centrations (at least 8%) to maintain a reasonable
nm, are absorbed and converted into thermal en- level of protection. Benefits include: low irritant
ergy, while the remaining portion of radiation properties and inability to penetrate into the epi-
with a wavelength longer than 380 nm, i.e. visi- dermis.
ble and IR, is reflected28. Examples of compounds belonging to this
Synthetic substances are most active. They are group are homomenthyl salicylate and octyl sali-
regulated and authorized for use by ministries cylate. Both compounds are insoluble in water,
and departments of health around the world. which makes them more stable under conditions
Such authorization lists include permitted con- of increased perspiration and bathing. Homo-
centrations at which substances can be used as menthyl salicylate (Homosalate) goes under the
ingredients in UV protectant preparations29. following names: Homosalate or Helipan. At a
Efficacy of chemical substances as filters is maximum authorized concentration of 10%, ho-
mainly due to physicochemical properties, e.g. momenthyl salicylate is rarely used in Europe,
absorption coefficient and absorption spectra, but still remains the product of choice for refer-
and properties of remaining particles on the skin ence for calculations of sun protection in the
surface, which depend on chemical structure. United States.

Derivatives of P-methoxycinnamic Acid

Substances that Protect Against UVB Compounds belonging to this group are often
Radiation used in Europe. Two most common are octyl
Compounds that provide protection against methoxycinnamate (Parsol MCX) and isopentyl
UVB radiation can be structurally divided into p-methoxycinnamate. Both compounds are used
several groups. These are: derivatives of para- in products at a maximum authorized concentra-
aminobenzoic acid, salicylic acid derivatives, p- tion of 10%. Characterized by a high absorption
methoxycinnamic acid derivatives, camphor and rate, absorbing radiation within a narrow range,
mixtures. including the most intense wavelength of 308
nm. Despite the good tolerability of these com-
Para-aminobenzoic Acid (PABA) and pounds in cosmetic products, data from various
Derivatives literature finds that chronic results in an increase
The main substance of this group, para- rate of hypersensitivity to cinnamates.
aminobenzoic acid (PABA), has been introduced
as one of the first chemical filters in the 1920s. Camphor Derivatives
Use is limited, due to its staining properties and Compounds from the group of camphor deriv-
photoallergic contact dermatitis (PCD). Addition- atives are common in Europe. They are charac-
al limitations include poor solubility in water, terized by high photostability and rare reported
which can lead to precipitation of PABA from causes of allergic. Five compounds are clinically
preparations and crystallization on skin surfaces. approved for use which include the following:

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 K. Skotarczak, A. Osmola-Man´kowska, M. Lodyga, A. Polan´ska, M. Mazur, Z. Adamski

• 4-methylbenzylindene camphor (4-MBC, en- The most effective at UVA protection are
zacamene), in Europe known under the name dibenzoylmethane derivatives, such as avoben-
of Eusolex 6300. Maximum authorized con- zone with trade names of Parsol 1789, Eusolex
centration is 4%. 9020 and Escalol 517. Avoenzone is a derivative
• Benzylidene camphor (Mexoryl SD). Maxi- of butyl methoxydibenzoylmethane and has been
mum authorized concentration is 2%, long used in Europe with a maximum authorized
• Benzylidene camphor sulfonic acid (Mexoryl concentration of 5%. Despite benefits such as
SL). Maximum authorized concentration is 6%. nonirritating to skin, disadvantages are its low
• Polyacrylamidomethyl benzylidene camphor stability of isomerization resulting in shorting be-
(Mexoryl SW). Maximum authorized concen- tween the keto and enol forms, thereby changing
tration is 6%. the absorption maximum30. This property can,
• Camphor benzalkonium methosulfate. Maxi- however, be changed by photostabilizing sub-
mum authorized concentration is 6%. stances. Combinations of physical filters, TiO2
and ZnO, are not recommended.
Other Chemical UVB Filters In contrast to the previous compounds, Mexo-
Other approved chemical compounds that are ryl SX, a benzylidene camphor derivative, has a
listed for use in cosmetic products are the following: very high stability against UVA rays. The maxi-
mum authorized concentration in cosmetic prod-
• Phenylbenzimidazole sulfonic acid ucts is 10%. Phenylobenzimidazole sulfonic acid
• Octocrylene exhibits maximum absorption at a wavelength of
• Ethylhexyl triazone (Not approved by the 335 nm, and authorized concentrations do not ex-
United States FDA). ceed 10%.

Phenylbenzimidazole sulfonic acid, known un- Filters of Broad Spectrum (UVA + UVB)
der the name of Eusolex® 232, is often used in Chemical filters of broad spectrum include
salt form. The chemical compound absorbs radia- benzophenones and phenylobenzotriazole sulfon-
tion having wavelengths of 310 nm. Due to its ic acid. Two absorption peaks are observed due
water-soluble properties, actions of fat-soluble to the properties of dual absorption of UVA and
filters are enhanced. Maximum authorized con- UVB radiation.
centration is 8%.
Octocrylene was just recently approved for use Benzophenones
in Europe. Absorbing UVB radiation with the There are 12 types of benzophenones, but only
greatest absorption of larger wavelength lengths, three are authorized for marketed use and include
303 nm. The maximum authorized concentration the following:
is 10%. • Benzophenone-3 (Oxybenzone)
Ethylhexyl triazone (Uvinul T150) is a water- • Benzophenone-4 (Sulisobenzone-sulfonic
insoluble compound and frequently used in cos- acid)
metic products labeled as “waterproof”. Maxi- • Benzophenone-5 (Sulisobenzone sodium-sodi-
mum authorized concentration is 5%. um salt)

Substances that Protect Against UVA Benzophenone-3, a fat-soluble substance, pro-

Radiation vides the photoprotective basis in cosmetic prod-
Awareness of the negative effects of UV radia- ucts as oxybenzone. Concentrations may not ex-
tion is increasing. Also known, are adverse ef- ceed 10%. Due to the frequent cases of hypersen-
fects of UV radiation, such as skin photoaging, sitivity, product descriptions should list the pres-
which is mainly responsible by UVA. Only a ence of this compound as an active ingredient.
small number chemical compounds, absorbing Benzophenone-4 and benzophenone-5 are
UV rays of the UVA range, are registered on the both water-soluble substances with less cases of
FDA and European list for authorized active sub- hypersensitivity. Concentrations may not exceed
stances in sunscreens. This small group includes: 5% in cosmetic products.

• Dibenzoylmethane derivatives Phenylbenzotriazole Sulfonic Acid

• Benzylidene camphor derivatives Compounds of phenylbenzotriazole sulfonic
• Phenylobenzimidazole sulfonic acid acid origin are just recently introduced for cos-

104
 Photoprotection: facts and controversies

metic purposes. Their action covers a wide spec- main allergens causing photoallergetic contact
trum ranging from UVB to visible light, while si- dermatitis31. Chemical filters with unstable mole-
multaneously being a very good absorbent of cules can be inactivated by UV light, thereby,
UVA radiation. Registered substances of this losing protective ability. Accordingly, mixtures of
group include the following: different UV-filters cannot be produced without
proper scrutiny, because there is the possibility of
• Drometrizole trisiloxane (Mexoryl® XL) negative interactions.
• Bisoctrizole (Tinosorb® M) Unfortunately, older substances (e.g. PABA
• Bemotrizinol (Tinosorb® S) and its derivatives, salicylic acid esters and ben-
zophenones) relied on molecules of low molec-
Drometrizole trisiloxane is a compound that is ular weight, which could penetrate the skin, and
well persisting on the skin suface, due to the further be absorbed into the dermis. PABA and
siloxane portion of the molecule. Concentrations its derivatives are responsible for many causes
may not exceed 15% in cosmpetic products. of allergic reactions. Any chemical compound
Bisoctrizole, or Tinosorb® M, is a pigment that providing UV protection can cause such allergic
is water-soluble. Its fine particles remain on the reactions, but in addition to PABA, the most
skin surface, but physicochemical properties do common allergenic compounds are avobenzone,
not allow for penetration of the compound octocrylene, and benzophenone-3. Despite
through the skin. In cosmetics, presence may not strong allergenic properties, benzophenone-3 is
exceed a concentration more than 10%. widely used in cosmetics. Studies in human vol-
Tinosorb® S is a compound very similar to unteers have shown the presence of benzophe-
Tinosorb® M, but is fat-soluble. The maximum none-3 in urine and plasma even four days after
authorized concentration in cosmetic products is the initial topical application of substances on
also 10%. the skin. Finding the substance in the urine sug-
gests its capacity to pass into the circulatory
system and its potential effects on other organs
The Safety of Sunscreens or accumulate sites. The tested concentration
was 10%, which is the permitted maximum con-
All substances permitted for use in marketed centration of benzophenone-3 in the European
products are registered under regulated lists. Be- Union. However, concentrations of benzophe-
fore approval, these substances must first pass none-3 cannot exceed 6% in the United States
many tests, including toxicology, in order to en- as approved by the FDA. After four days of ini-
sure the greatest possible safety. These com- tial topical application, octyl methoxycinnamate
pounds cannot penetrate the skin barrier and en- was also observed in human plasma. The Euro-
ter systemic circulation nor penetrate into cells pean Union approved concentration, 10%, was
where they could cause mutations in the cellular used during the study; however, concentrations
DNA. Ideal UV protectants are non-toxic and do cannot exceed 7.5% in the United States32. Con-
not cause allergic reactions. Modern cosmetic cerningly, studies show PABA being able to in-
formulations are based on completely insoluble duce the formation of free radicals in phosphate
compounds, which minimize the risk of a com- buffered saline (PBS) without sunlight. Similar
pound’s penetration. Additionally, these prepara- effects are alleged in octocrylene and octyl
tions contain more than one UV protectant com- methoxycinnamate23.
pound to ensure a wider-range of protection. Another danger cosmetics with chemical fil-
Most combine several compounds of different ters pose, is the inhibition of erythema, which is
chemical groups with different absorption maxi- an alarming sign of skin irritation. Without the
mums in order to reduce the concentration of physiologic sign of erythema, individuals are al-
each individual substance, hence, obtaining the lowing for longer periods of exposure to radia-
widest possible range of protection and improv- tion. Hence, preparations should not contain
ing durability and stability by combining filters both sunscreens and anti-inflammatory agents,
fat-soluble and water-soluble filters. Increased as erythema formation reduction encourages
use of these compounds is the cause for allergic longer stays in sunlight. This exposes a much
reactions, mainly photoallergic contact dermati- longer exposure to radiation. Anti-inflammatory
tis. A study conducted in 2010 confirmed that the agents are used in mitigation formulations la-
compounds used as chemical filters were the beled “after sun”.

105
 K. Skotarczak, A. Osmola-Man´kowska, M. Lodyga, A. Polan´ska, M. Mazur, Z. Adamski

A recent major topic of discussion is sun- Policy on the Use of Sunscreen Creams
screens and potential inhibition of vitamin D3 In order to provide comprehensive protection,
synthesis, which could lead to vitamin D short- crutial is adequate knowledge about the applica-
ages. Theoretically, the correct application of tion of sunblock sunscreen. The main reasons
sunblock could cause a significant reduction in for the use of UV-creams are: protection against
the level of vitamin D3, but this is not clinically sunburn, photoaging, cancer prevention, and in-
proven. In most cases, filters are not properly ap- creasing planned exposure time in the sun31,34.
plied or in the correct amount. Moreover, extend- Despite the frequent use photoprotectants, sun-
ing the duration of exposure to sun’s synthesis of burn is a very common phenomenon. This is
vitamin D3 occurs despite application of skin due to improper use of cosmetics, which re-
preparations. A proper diet also minimizes the duces its effectiveness. The amount and fre-
risk of deficiency. A recent study by Lindqvist et quency of preparation application are determi-
al33, conducted in Sweden, suggested that avoid- nants of effective protection. International stan-
ing exposure to the sun increases the risk of mor- dards recommend that application of 2 mg/cm2
tality. In people deliberately sunbathing, there to achieve the degree of protection provided by
was no proven increased risk of melanoma or the manufacturer. However, studies in human
mortality associated with the activity. There are volunteers have shown that only 0.5 mg/cm2 is
also reports that lower levels of vitamin D may needed to considerably reduce the effects of ul-
be associated with an increased risk of cardiovas- traviolet radiation37. To achieve the desired pro-
cular disease and the presence of a thicker and tection, the teaspoon rule should be applied. In
more invasive melanoma. It is additionally hy- order to attain a density of 2 mg/cm2, one tea-
pothesized that UVA increases the activity of ni- spoon of preparation should be applied on the
tric oxide (NO) lowering blood pressure and face, neck and nape. For each upper limb, one
risks of cardiovascular complications10. teaspoon is required and two teaspoons for the
Many controversies surround the use of nan- stomach, back and each lower limb. Mouth and
otechnology, mainly concerning physical filters. ears should not be omitted. A total of 12 tea-
Particles of a small size avoid an unpleasant spoons (approximately 60 ml) of the solution
white film remaining on the skin after application should be applied on one occasion38.
of a formulation containing the titanium dioxide Physical filters containing mineral pigments
macromolecule. Particle size is significant. The may leave a white film on the skin, hence are ap-
smaller the molecular size, the greater the risk of plied in lower doses39. Often overlooked is the
penetration of substances into the skin and fur- need for additional applications. Sunscreen
ther, into the bloodstream. Many studies alert the should be re-applied after each swim, persping,
ability of very small titanium dioxide particles to toweling and every 2-3 hours during a stay at the
penetrate into the skin, and then, under the influ- beach. Even the use of creams labeled, “water-
ence of UVA, to induce DNA mutations that can proof”, requires re-applying. Wind causes cool-
be the starting point for the development of can- ing of the skin and can give a false sense that the
cer34. These mutations are induced by excessively next application of the product is unnecessary40.
generated reactive oxygen species, resulting in Using creams with a lower filter, so called “city
damage to proteins and lipids. There is also sus- blockers”, is recommended throughout the year,
picion of accumulation of nanoparticles in hair even during the winter months, especially when
follicles and sweat glands35. In order to avoid the the sun’s rays work harder, eg. in the mountains
above mentioned adverse effects, TiO2 particles in the presence of ice and snow. Reasons for why
are coated with organic or inorganic compounds. people resign completely from the use of photo-
This procedure ensures greater stability and low- protective filters are: not easily burnt skin photo-
er toxicity of the substance. A study23 conducted types, having a tan, high length of application
in 2009 showed the absence of titanium dioxide process, high costs, desire for a deeper tan and
particles in the deeper layers of the skin, even af- spending too little time outdoors to consider the
ter application under an occlusion. A year later, need of filter application41.
the reciprocal influence of physical and chemical An important aspect of proper protection is the
filters was also examined. Studies have shown right choice for the sunscreen preparation for
that nanoparticles of TiO2 coated with PABA did skin phototype. Individuals with phototype I
not activate Langerhans cells, which indicates skin, taking photosensitive or phototoxic medica-
absence of immune response and inflammation36. tions or phototoxic procedures, e.g. aesthetic

106
 Photoprotection: facts and controversies

surgery, laser and chemical peels, should choose Carotenoids

creams with the highest degree of SPF protection Carotenoids are organic substances responsi-
(SPF 50+)42. Individuals with phototype II skin ble for the yellow, orange and red pigments in
should use preparations with at least SPF 30, plants and animals. A requirement for such ob-
while those with darker skin phototypes can use served colors is the presence of at least 7 double
SPF 15 preparations. Ideally, all phototypes and bonds in the chain. Compounds with fewer bonds
ages should use prepartions with SPF 50+ daily are colorless. The main feature of carotenoids is
regardless of the time of the year43. a high activity against reactive oxygen species50.
Extreme caution should be used in exposing Antiradical activity of carotenoids is achieved by
young children to the sun. In babies under 6 two mechanisms: the first one relies on the trans-
months of age, the use of hats, protective cloth- fer of electrons and the other from the formation
ing, and staying in the shade is recommended of radical adducts. The most well known
over the use of sunscreen preparations. In older carotenoids are β-carotene and lycopene, which
children, in addition to protective clothing, you are compounds present in carrots, tomatoes and
can sunscreen can be added, preferably with a peppers. β-carotene prevents skin burns, which is
natural filter, designed for children44. associated with its ability to scavenge free radi-
cals caused by UVA51. This compound is also
Oral and Systemic Photoprotection provitamin A. Conversely, lycopene is more ef-
fective in neutralizing nitric oxide radicals 11.
Protection against harmful UV rays with oral When dissolved in vegetable oils, carotenoids are
formulations has several advantages. The main the complementary ingredient in synthetic sun-
ones include the convenience and ease of use45. blocks52.
Their performance is not affected by external
conditions, such as swimming, types of garment Vitamins
or sweating. In contrast to agents used externally, Vitamins C and E are the strongest duo of
oral and systemic agents are not dependent on antioxidants used both orally and topically. The
the degree of absorption through the skin46. Sub- term “vitamin E” includes fat-soluble compounds
stances used orally have antioxidant capacity, from the group of tocopherols and tocotrienols.
neutralizing free radicals formed under the influ- There are eight forms of vitamin E, which is the
ence of ionizing radiation, ultraviolet radiation, most active α-tocopherol. Due to its chemical
inflammation or metabolism of xenobiotics 47. structure, they are excellent inhibitors of free
The increase of fixed concentrations of free radi- radicals. The main source of vitamin E are
cal species is referred to as oxidative stress. Free vegetable oils. The most important function of
radicals first attack the fatty acids of cell mem- tocopherols is to protect lipid substances in the
branes of the skin and structural proteins, in par- intercellular cement. Demonstrating a high
ticular collagen and enzymatic proteins. affinity for cell membrane lipids, vitamin E is a
Antioxidants are substances that inhibit the great inhibitory agent for oxidation of these
oxidation of other molecules. Due to their prop- substances. It works by breaking the chain of
erties and mode of action, antioxidants are divid- radical reactions in the skin. Has the ability to
ed into hydrophilic and hydrophobic. Hy- easily enter into reactions of radicals, but does
drophilic antioxidants protect the aquatic envi- not itself converted into another reactive radical.
ronment of cells, while hydrophobic protect cell Products, vitamin E radicals and tocopherol
membranes. They can be delivered to the body radicals, resulting from this reaction are harmless
locally or systemically with a proper diet48. Sub- for cellular structures. This form may be
stances, which are used as antioxidants, must dispersed as chemically inactive compounds or
meet a number of requirements. The first condi- converted back into active antioxidant molecule
tion is to have a strong capacity to neutralize re- of vitamin E. This process, however, requires the
active oxygen species. The end products of a re- presence of vitamin C, therefore, combinations
action cannot be free radicals and demonstrate a of these two vitamins are frequently used in
high degree of stability. preparatations. The demand for tocopherols is
Unfortunately, to date, there are no reported very high especially under conditions of
substances that can provide sufficient protection oxidative stress. Lipophilic structures allow for
when used alone. However, antioxidants are good penetration by vitamin E through the skin.
proven to complement photoprotection49. External application has a great number of

107
 K. Skotarczak, A. Osmola-Man´kowska, M. Lodyga, A. Polan´ska, M. Mazur, Z. Adamski

positive actions, such as reduction in erythema The best-known group of polyphenolic com-
and delay of photoaging. pounds is flavonoids, belonging to secondary
Vitamin C, or ascorbic acid, belongs to the plant metabolites. Rich sources are flowers and
group of water-soluble vitamins. As a powerful leaves, where they can be found in the superficial
antioxidant, it is capable of disposing of free rad- layers of tissues give them intense color, while
icals. As a result of these reactions, it is convert- protecting against UV radiation. Other common
ed to dehydroascorbic acid, which under the in- sources are fruits, especially grapes and citrus,
fluence of enzymes is converted back to vitamin vegetables, seeds, legumes, and green tea55. Al-
C. The natural source of this vitamin is rosehips, most all flavonoids have biological activity. An-
black and red currant, red and green pepper, and tioxidant capacities are possible through different
citrus fruits53. In preparations for the skin, ascor- mechanisms of action. Direct mechanisms are
bic acid, due to high instability, is replaced by based on the capture of free radicals and limiting
other formulas, where antioxidant activity is con- their arrangement in cells by inhibiting the activi-
siderably lower. ty of enzymes that participate in the formation of
reactive oxygen species. Indirect antioxidant ac-
Plant Extracts tion involves interupting the cascade of reactions
Medicinal plants and their extracts are rich in of free radicals and the chelation of metal ions,
compounds of different chemical structure and which prevents reactive hydroxyl radicals in
varying degrees of photoprotective and cells. Compounds from the group of flavonoids
antioxidant activity. Plant extracts have a having significance in photoprotection are genis-
relatively low absorption coefficient, therefore, tein, silymarin, equol and quercetin.
cannot form the basis of UV-preparations. Due to A new material of plant origin used in photo-
the absorption properties of only part of a protection is ferulic acid, which belongs to the
radiation spectrum, they are the perfect group of hydroxycinnamic acids. Rich sources
complement of synthetic filters. are cell walls of plants, such as citrus fruits,
A group of compounds naturally-occurring in wheat, spinach and beets. Ferulic acid is a com-
plants and presenting the strongest antioxidant pound of low toxicity, absorbed easily and safely
activity are polyphenols, which are organic com- when applied to the skin surface. Reduction in
pounds from the phenol group containing at least oxidative stress is achieved by increasing the ac-
two hydroxyl groups attached to an aromatic tivity of enzymes responsible for neutralizing re-
ring. Green tea is a rich source of polyphenols. active oxygen species and prevents them from
The strongest active substance comprised in it is occurring. It also possesses the ability to absorb
epigallocatechin gallate (EGCG). It prevents radiation from the entire UVB spectrum and a se-
damage caused by UVA radiation, reduces free lected portion from the UVA, thereby providing
radicals damaging cellular lipids, and inhibits the adequate protection against the formation of ery-
expression of enzymes responsible for the degra- thema, photoaging and development of tumors.
dation of collagen fibers. Pycnogenol ® is an interesting substance,
A compound classified as a part of the plant which is extracted from pine bark. Its photopro-
polyphenol group is resveratrol, which was iso- tective effects complement synthetic substance,
lated for the first time in 1940 from the roots of a as its activity is exhibited after exposure of UV
white hellebore. It is found in the skin and seeds radiation to skin. Active compounds are mainly
of grapes, nuts, fruit and red wine. Resveratrol flavonoids, which act as antioxidants. Pyc-
has potent antioxidant activity, neutralizing free nogenol® also has anti-inflammatory and anti-
radicals and being neuroprotective. It also has an- carcinogenic56.
ti-inflammatory properties, as was demonstrated Gaining popularity is the Polypodium leucoto-
by tests in mice, when this compound inhibited mos or Polypodium aureum, an epiphytic fern na-
the formation of edema, and infiltration of lym- tive to tropical and subtropical regions of the
phocytes after exposure to UV radiation54. Addi- Americas. Extracts contain photoprotective prop-
tionally, contributing to the reconstruction of erties and are a blend of hydroxycinnamic acids,
damaged cells in the deeper layers of the skin by such as ferulic and caffeic acid. Offering strong
stimulating regeneration processes of collagen antioxidant properties by both external applica-
and elastin. Subsequently, preventing the sagging tion and oral ingestion, it has the ability to reduce
of skin by strengthening skin structure and accel- free radical counts and limit the extent of lipid
erating regeneration. peroxidation of cell membranes, resulting in de-

108
 Photoprotection: facts and controversies

lays of pathology changes associated with pho- that allows it to reach the deeper layers of the
toaging and tumor development 57. This com- skin. During the time of penetration through the
pound also helps in the prevention of sunburn af- cell membrane, pH of the environment decreases,
ter phototherapy in conjunction with psolarens. which causes opening of the envelope and
Use of oral formulations of the P. leucotomos ex- enzymes released. In this manner, carriers are
tract decreases phototoxicity experienced during able to reach the living layers of skin and have
PUVA therapy17. This extract is the first oral for- the enzyme go into the cells. In addition to the
mulation that effectivitly lowers acute phototoxi- ability to repair damaged DNA, photolyase aids
city and hyperpigmentation associated with pho- in cell regeneration and reduces formation of
totherapy. Its application leads to a significant skin inflammation caused by exposure to sun
protection of Langerhans cells, a decrease of light. The mechanism involves inhibition of pro-
“sunburn cells” formation and the prevention of inflammatory cytokine, interleukin 6 (IL-6). This
inflammatory cell infiltration. involves the ability to reduce the secretion of
mediator prior zapalnego-interleukin-6 (IL-6).
Presence of this enzyme in cells inhibits UV-
The Future of Photoprotection induced apoptosis60. Even after 30 minutes of
exposure to light, photolyase starts to work with
Use of UV filters in cosmetic products maximum efficiency. An in vivo study of 12
function on the prinicple of UV wave absorption volunteers showed a reduction in number of
or reflection or neutralization of reactive oxygen cellular damages by approximately 45%, when
species. These constituents have protective applied skin nanosmomes of photolyasis
properties against cell damage. The future of sun followed by exposure to sunlight61.
protection agents will include a new generation Another enzyme responsible for the repair of
of compounds with the ability of absorbing cells is endonuclease. Obtained from the
harmful radiation in combination with substances bacteria Micrococcus luteus, which are one of
having the ability to repair damage caused within the best known organisms protected from
DNA. Modern cosmetic products, found on the ultraviolet radiation. In cosmetic preparations,
market, have enzymes capable of regenerating this enzyme is also encased in a multi-layer
genetic material. Current research identifies phospholipid coated envelope, which allows for
certain enzymes, which are responsible for the the enzyme to easily enter cells. Endonuclease
identification and removal of damaged cell DNA improves the efficiency and speed of DNA
fragments. Two major enzymes are photolyase repair approximately four-fold57. It stimulates
and endonuclease. There is much promise with skin regeneration, reconstruction, as well as
the introduction of these natural occuring preventing the destruction of extracellular
enzymes into cosmetic products58. matrix components32. In addition, alleviates skin
The photolyase enzyme is not present in irritation by reducing pro-inflammatory
genomes of all mammals, however, may be mediators8.
found in other animal species, plants and Recent studies emphasize the importance of
bacteria. Knowledge of this enzyme has been the new photoprotective protein afamelanotide,
around for a long time, but the mechanisms which is a 13 amino acid analog of alpha-
behind function is still unclear. Photolyase was melanocyte stimulating hormone (α-MSH). This
first isolated from the cyanobacteria, Anacystis protein stimulates skin cells to produce melanin
nidulans, which are a component of plankton59. through activation of the melanogenesis process.
Activated by blue or violet light from the visible The α-MSH analogue repairs damage induced by
spectrum, photolyase is able to repair alterations UV radiation by removing pyrimidine dimers. A
and damage of DNA caused by exposure to UV recent investigation32 observed a reduction of
radition. The most common alteration in DNA is photohypersensitivity in subjects with erythro-
the formation of pyrimidine dimers, which distort poietic porphyria and solar urticaria after the
the double helix structure at the site of damage. subcuntaneous administration of afamelanotide.
These changes may cause errors in reading of the Negative effects of ultraviolet radiation is
strands during phases of transcription and weakening of the immune system, however,
replication. The action of photolyasis is to naturally occuring repair enzymes are able to
destroy pyrimidine dimer. The enzyme is restore skin immune capacity. With advancements
enclosed in a multi-layer phospholipid envelope of science, researchers are able to examine

109
 K. Skotarczak, A. Osmola-Man´kowska, M. Lodyga, A. Polan´ska, M. Mazur, Z. Adamski

different severities of immunosuppression caused 10) HOLICK MF. Sunlight and vitamin D for bone health
by radiation. The Immune protection factor (IPF), and prevention of autoimmune diseases, cancers,
similar to SPF, quantifies the radiation dose and cardiovascular disease. Am J Clin Nutr 2004;
80: 1678-1688.
necessary for immunosuppression. Studies have
shown that the IPF for photolyase was 2.3 and 3.3 11) LIU D, FERNANDEZ BO, HAMILTON A, LANG NN, GAL-
LAGHER JM, NEWBY DE, FEELISCH M, WELLER RB. UVA
endonuclease. In comparison to control subjects, irradiation of human skin vasodilates arterial vas-
patients applying preparations with cell repair culature and lowers blood pressure independently
enzymes required three times as much of a dose of nitric oxide synthase. J Invest Dermatol 2014;
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P HELPS R, S HYONG E, L EBWOHL MG. Isoflavone
–––––––––––––––––-–––– genistein: photoprotection and clinical implica-
Conflict of Interest
tions in dermatology. J Clin Nutr 2003; 133: 3811-
The Authors declare that they have no conflict of interests. 3819.
15) BURGAZ A, KESSON A, ÖSTER A, MICHAËLSSON K, WOLK
A. Associations of diet, supplement us and ultrav-
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