CONTINUING MEDICAL EDUCATION
Photoprotection
Part I. Photoprotection by naturally occurring, physical,
and systemic agents
Rebecca Jansen, MD,a Steven Q. Wang, MD,b Mark Burnett, MD,b Uli Osterwalder, MS,c and Henry W. Lim, MDa
Detroit, Michigan; New York, New York; and Monheim, Germany
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Dr Lim has served as consultant for Ferndale, La Roche-Posay, Pierre Fabre, Uriage,
and Palatin. He has received research grants from Clinuvel and Estee Lauder. Mr
Osterwalder is a full time employee of BASF. Dr Wang has served on the advisory
board of L’Oreal. Drs Burnett and Jansen have no conflicts of interest to declare.
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After completing this learning activity, participants should be able to provide an
overview of natural, physical, and systemic photoprotective agents.
Date of release: December 2013
Expiration date: December 2016
Ó 2013 by the American Academy of Dermatology, Inc.
http://dx.doi.org/10.1016/j.jaad.2013.08.021
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853.e1
853.e2 Jansen et al J AM ACAD DERMATOL
DECEMBER 2013

The acute and chronic consequences of ultraviolet radiation on human skin are reviewed. An awareness of
variations in naturally occurring photoprotective agents and the use of glass, sunglasses, and fabric can lead
to effective protection from the deleterious effects of ultraviolet radiation. New systemic agents, including
Polypodium leucotomos, afamelanotide, and antioxidants have potential as photoprotective agents. ( J Am
Acad Dermatol 2013;69:853.e1-12.)

Key words: afamelanotide; antioxidants; glass; photoprotection; photoprotective agents; physical systemic
photoprotective agents; ultraviolet radiation.

Effective protection from Light in August 1932, UVR is

the harmful effects of ultravi-
olet radiation (UVR) requires
the regular practice of photo-
protective strategies, which
include seeking shade, the
use of clothing, wide-
brimmed hats, sunglasses,
and the application of sun-
screens. Geographic and
CAPSULE SUMMARY divided into ultraviolet C
(UVC; 270-290 nm), ultravio-
Ultraviolet radiation exposure leads to
d
let B (UVB; 290-315 nm), and
harmful acute and chronic effects on ultraviolet A (UVA; 315-400
human skin. nm) wavelengths.1 More re-
Variations in naturally occurring
d cently, because of the recog-
photoprotective agents affect the nition that the biologic
degree of ultraviolet radiation exposure. effects of shorter spectrum
UVA are close to that of
Physical photoprotective agents,
d

environmental variations af- UVB, UVA is further subdi-

especially glass, are often underused in
fecting UVR transmission,
photoprotection strategies.
protective cutaneous chro-
Limitations of topical photoprotection
d
mophores, glass, sunglasses,
have driven the search for systemic
and fabric will be discussed
alternatives.
in this article, along with the
multiple systemic agents that
show potential as photoprotective agents. Part II of
our review will focus on sunscreen development,
efficacy, and controversies.
ULTRAVIOLET RADIATION
Key points
d Acute effects of UVR include erythema, pig-
ment darkening, delayed tanning, epidermal
hyperplasia, free radical formation, and vi-
tamin D synthesis.
d Chronic effects of UVR include photoaging,
immunosuppression, photocarcinogenesis,
and exacerbation of photodermatoses.
Acute effects of ultraviolet radiation exposure
on human skin
The sun emits UVR with wavelengths shorter than
visible light (VL; 400-760 nm) but longer than x-rays.
As agreed in the Second International Congress on
vided into UVA2 (315-340
nm) and UVA1 (340-400
nm). Because ozone in the
stratosphere filters UVC radi-
ation, the cutaneous effects
of UVR exposure are attrib-
uted to UVA and UVB.
The initial response of human skin exposure to
UVR includes erythema, immediate pigment dark-
ening (IPD), persistent pigment darkening (PPD),
delayed tanning, epidermal hyperplasia, free radical
formation, and vitamin D synthesis.2,3
Erythema. Sunburn, primarily caused by UVB
exposure (and to a lesser extent UVA2 exposure), is
the best recognized acute effect of ultraviolet (UV)
light exposure on human skin. UVB-induced ery-
thema reaches its peak between 6 and 24 hours after
exposure. An immediate erythema reaction, which
lasts for 48 to 72 hours after exposure, characterizes
skin reaction to high-dose UVA.
Immediate and persistent pigment
darkening. Exposure to UVR also results in pig-
mentary alteration. IPD, predominantly caused by
UVA light, is often gray in color. It develops within
minutes of irradiation and fades within hours. At UVA

From the Department of Dermatology,a Henry Ford Hospital,
Detroit; Division of Dermatology,b Memorial Sloan Kettering
Cancer Center, New York; and BASF Personal Care and Nutrition
GmbH,c Monheim.
Funding sources: None.
Dr Lim has served as consultant for Ferndale, La Roche-Posay,
Pierre Fabre, Uriage, and Palatin. He has received research
grants from Clinuvel and Estee Lauder. Mr Osterwalder is a full
time employee of BASF. Dr Wang has served on the advisory
board of L’Oreal. Drs Burnett and Jansen have no conflicts of
interest to declare.
Reprint requests: Henry W. Lim, MD, Department of Dermatology,
Henry Ford Medical Center e New Center One, 3031 W Grand
Blvd, Ste 800, Detroit, MI 48202. E-mail: hlim1@hfhs.org.
0190-9622/$36.00
J AM ACAD DERMATOL
VOLUME 69, NUMBER 6
Abbreviations used:
a-MSH: aemelanocyte-stimulating hormone
AO: antioxidant
BCC: basal cell carcinoma
IPD: immediate pigment darkening
IR: infrared radiation
MMP: matrix metalloproteinase
NMSC: nonmelanoma skin cancer
NSAID: nonsteroidal antiinflammatory drug
PPD: persistent pigment darkening
ROS: reactive oxygen species
SCC: squamous cell carcinoma
SPF: sun protection factor
UVA: ultraviolet A light
UVB: ultraviolet B light
UVC: ultraviolet C light
UPF: ultraviolet protection factor
UVR: ultraviolet radiation
UCA: urocanic acid
VL: visible light
doses of [10 J/cm2, PPD follows IPD.4 PPD is
characterized by brownish discoloration that begins
2 hours after exposure and lasts for up to 24 hours.
Both IPD and PPD are caused by photooxidation and
the redistribution of existing melanin in epidermal
melanocytes; new melanin is not synthesized. In
dark-skinned individuals, VL has been shown to
induce both IPD and PPD responses.5
Delayed tanning. Delayed tanning is induced
by both UVA and UVB light. It is usually observed
beginning 3 days after exposure. It is the result of
increased tyrosinase activity, which leads to the
synthesis of new melanin, and it remains for weeks.
Similar to IPD and PPD, delayed tanning can also be
induced by exposure to VL in dark-skinned persons.5
Epidermal hyperplasia. Epidermal hyperplasia
is an adaptive process that limits damage from subse-
quent UVR exposure,2 especially in light-skinned
individuals. It occurs within days of UVR exposure,
follows the initial growth arrest associated with sun-
burn, and lasts for up to 1 month. UVB light is more
efficient in inducing hyperplasia than UVA light.
Free radical formation. UV-induced reactive
oxygen species (ROS) include singlet oxygen and
likely hydrogen peroxide and superoxide radicals.6
Damage to DNA, proteins, and cellular membranes
caused by ROS is thought to be the cornerstone of
UVA mutagenesis. However, ROS-induced damage
can also be caused by UVB light and VL.7 UVA-
induced ROS result in increased melanin synthesis
and cell membrane lipid peroxidation, leading to
inflammation.8 ROS trigger matrix metalloproteinase
(MMP) activation and the release of proinflammatory
cytokines and growth factors that alter both collagen
and elastin in the extracellular matrix, culminating in
the degradation of skin structural integrity.9
Jansen et al 853.e3
Vitamin D synthesis. Exposure to sunlight,
diet, and vitamin D supplementation serve as the
only 3 sources of vitamin D. UVB (300 6 5 nm) is
the action spectrum for the conversion of
epidermal 7-dehydrocholesterol into vitamin D3
(cholecalciferol). This process is influenced by sev-
eral factors, including the intensity of sunlight, skin
type, age, and photoprotection.10
Chronic consequences of ultraviolet light
exposure on human skin
Chronic exposure to UVR leads to photoaging,
immunosuppression, photocarcinogenesis, and
exacerbation of photodermatoses.
Photoaging. UVA light, because of its longer
wavelengths, penetrates deeper into the dermis
compared to UVB light. Therefore, it plays a larger
role in the development of photoaging at exposed
sites. Clinical signs of photoaging include wrinkling,
solar lentigines, poikiloderma, loss of elasticity, tel-
angiectasias, and large open comedones.
Immunosuppression. UVR has both pro- and
antiinflammatory effects on the cutaneous immune
system. Cutaneous irradiation suppresses cell-
mediated immunity by altering Langerhans cell mi-
gration, producing suppressor T lymphocytes, and
altering the cutaneous cytokine profile.11 Sunburn and
the flaring of lesions and symptoms of systemic lupus
erythematosus after UVR exposure are examples of
proinflammatory effects.12 Immunosuppression is
shown both by the effective use of UVR to treat
inflammatory skin disorders and by the mutations in
the p53 tumor suppression gene reported in the
majority of nonmelanoma skin cancers (NMSCs).13
Photocarcinogenesis. UVR induces DNA muta-
tions and malignant transformations, and the immu-
nosuppressive properties of UVR concurrently impair
host immune system recognition of damaged malig-
nant cells. The relationship between UVR exposure
and the development of skin cancer, including malig-
nant melanoma, basal cell carcinoma (BCC), and
squamous cell carcinoma (SCC) is well documented.14
Superficial spreading and nodular melanoma are asso-
ciated with intermittent and intense UVR exposure,
lentigo maligna melanoma and SCC are related to
cumulative sun exposure, and the pattern of UVR
contribution to the development of BCC is being
elucidated.14-18 Artificial UVR exposure via tanning
beds, which emit predominantly UVA, is associated
with an increased risk of melanoma, BCC, and SCC.19-22
Photodermatoses. UVR and VL exposure can
lead to reduced quality of life for individuals with
immunologically mediated photodermatoses, such
as polymorphic light eruption, chronic actinic der-
matitis, solar urticaria, photoallergic drug reactions,
853.e4 Jansen et al
hydroa vacciniforme, and inherited disorders char-
acterized by defective DNA repair, including xero-
derma pigmentosum and the porphyrias.23,24
NATURALLY OCCURRING
PHOTOPROTECTIVE AGENTS
Key points
d Geographic and environmental variations
affect UVR transmission.
d Chromophores in the skin protect the body
from the deleterious effects of UVR.
Agents in the atmosphere and environment
Atmosphere. In the atmosphere, scattering by
nitrogen and oxygen molecules and absorption by the
ozone layer attenuate essentially all UVC light emitted
by the sun, 90% of UVB light, and minimal to no solar
UVA light and VL. This is the reason that UVA accounts
for [95% of UVR reaching the earth’s surface on a
summer day and UVB light accounts for just 4%.25
Unfortunately, depletion of the protective ozone layer
by substances such as chlorofluorocarbons has led to
substantially increased UVB irradiance at high lati-
tudes. A reduction in greenhouse gasses and ozone-
depleting substances in recent years has stabilized
ozone columns, and slow recovery of ozone is antic-
ipated over the coming decades.26
Latitude and altitude. UVR exposure is greatest
at the equator and high altitudes. Because UVR
travels a longer distance before reaching the earth’s
surface as latitude increases, the transmission of UVB
light decreases by 3% for every degree increase in
latitude. For every 1000-foot increase in elevation,
there is an increase of 4% to 10% of UVB light that
reaches the earth’s surface, with transmission in-
creasing exponentially at higher elevations because
of less UVR-absorbing atmosphere.27
Time of day and season. UVB light is strongest
from 10 AM to 2 PM, with transmission peaking at the
solar zenith when the path of UVR through the ozone
layer is shortest.28 Because of the better penetration
of long-spectrum UVA light, the intensity of UVA light
is relatively constant throughout the daylight hours.
UVA light is also minimally affected by cloud cover.
Seasonal variations in solar radiation are caused by
the elliptical orbit of the sun; terrestrial UVR is
strongest in the summer.
Clouds. Cloud cover reduces the intensity of
UVR, VL, and infrared radiation (IR). IR produces
the cutaneous sensation of warmth. On cloudy days,
because the reduction of solar IR is much greater
than UVR, the decrease in the warning sensation of
warmth can increase the risk of overexposure to
UVR, especially UVA light.29 The US National
Weather Service calculation of the UV index assumes
J AM ACAD DERMATOL
DECEMBER 2013
that clear skies allow virtually 100% of UV transmis-
sion of solar UVR, scattered clouds 89%, broken
clouds 73%, and overcast skies 31%.30
Pollutants. Pollutants (ie, ozone, nitrogen diox-
ide, and sulfur dioxide) and scattering particulates
(clouds and soot) in the troposphere reduce the
effects of shorter wavelength UVR more than longer
wavelength.29 Large reductions in UV irradiance have
been observed in polluted, urban areas when com-
pared to pristine locations.31 Significant reductions in
UVB radiation can occur with naturally occurring
pollutants, such as dust, volcanic ash, and wild fire
aerosols.32 While snow, ice, sand, glass, and metal
can reflect up to 85% of UVB light, reflection of UVR
from most terrestrial surfaces is usually \10%.8
Shade. An estimated 50% of exposure to UVA
light occurs in the shade.33 Small shade structures
like umbrellas provide only low UV light protection.
Sun Protection Factors (SPFs) of single trees range
from 4 to [50, depending on foliage density and
proximity to the shadow perimeter.34
Agents in the skin
Because UVR does not penetrate deeper than the
skin, human skin protects the rest of the body from
harmful solar UVR. Factors that influence the effects
of UVR on this protective barrier include depth of
cutaneous penetration of specific wavelengths, skin
type, and the absorption spectra of different skin
chromophores.3 Human skin absorbs UVB radiation,
scatters most VL, and reflects 5% to 10% of all solar
radiation from 250 to 3000 nm.35 Most UVB light is
absorbed in the epidermis, while UVA light readily
reaches the dermis. Darker skin types have de-
creased UVR penetration, primarily because of in-
creased melanin.36 On average, 5 times less UVA and
UVB light penetrate the epidermis of black skin
compared to white skin.37 Within individuals, UVR
penetration varies at different body sites because of
differences in thickness of the epidermis.38,39
DNA and protein. Chromophores are light en-
ergyeabsorbing molecules. Purine and pyrimidine
bases are the major cellular chromophore for most of
the biologic effects of UVB.40 Other cutaneous UV
chromophores include melanin, tryptophan, tyro-
sine, urocanic acid (UCA), nicotinamide adenine
dinucleotide, and flavins.
Melanin. Epidermal melanin is a large opaque
molecule that quenches ROS and reduces UVR and
VL penetration into the skin by scattering and phys-
ically blocking UVR and converting the absorbed
energy into heat. The extent of photoprotection
provided by melanin correlates with skin thickness
and degree of constitutive skin pigmentation. Thin
facial skin develops erythema more easily than
J AM ACAD DERMATOL Jansen et al 853.e5
VOLUME 69, NUMBER 6

Table I. Types of glass

Annealed Slowly cooled to achieve low levels of residual stress; breaks into large pieces when fractured
Tempered Four times stronger than annealed glass; breaks into small pieces when fractured
Tinted/heat-absorbing Contains special color components that reduce unwanted heat gain by reflecting, transmitting,
or absorbing solar radiation
Reflective A thin layer of metal or metallic oxide added to the surface results in reflection of VL and IR and
a mirror-like appearance
Laminated Made by adding a plastic layer (PVB) between $ 2 layers of glass; blocks 99% of UVR; frequently
used in skylights and motor vehicle windshields; when broken, PVB layer holds most of the
small pieces of glass in place, minimizing injury
Low E (emissivity) Popular in residential and office buildings; made by stacking microscopic metallic and oxide
layers on glass surface; reflects IR while selectively transmitting VL
Insulating Comprised of $ 2 layers of any type of glass with air- or gas-filled space in between; decreases
heat transfer

IR, Infrared radiation; PVB, polyvinylbutyral; UVR, ultraviolet radiation; VL, visible light.

thicker skin, and darkly pigmented skin is less
susceptible to the effects of UVR than lightly pig-
mented skin.
Other agents. Other photoprotective agents in
the skin include heme, porphyrins, and water.
Oxyhemoglobin and reduced hemoglobin in blood
absorb bands in the UV, blue, green, and yellow VL
regions. Water absorbs strongly in the infrared
region.41 Porphyrin, an endogenous photosensitiz-
ing molecule that can generate ROS upon exposure
to the Soret band (400-410 nm), accumulates to
abnormally high levels in cutaneous porphyrias and
causes photosensitivity.
PHYSICAL PROTECTIVE AGENTS
Key points
d Standard residential and commercial win-
dows block transmission of UVB light.
d New laminated glass, tinted glass, and films
could offer protection from UVA light up to
380 nm.
Glass
Although Americans spend much time in vehicles
or indoors, the potential for UVR exposure through
car and building windows is often overlooked.
Current photoprotection strategies and educational
campaigns target limiting UVR exposure during
outdoor activities. The modulation of UVR transmis-
sion through motor vehicle glass, building window
glass, and sunglasses offers an important opportu-
nity for improved photoprotection.
Standard residential and commercial window glass
blocks the transmission of UVB. The newer types of
window glass can also partially block the transmission
of UVA light and VL.42 The clinical relevance of UVR
exposure via glass-filtered sunlight is supported by
studies documenting an increased prevalence of
facial photodamage, actinic keratoses, NMSCs, and
malignant melanoma in situ on the driver’s exposed
side.43-46 In the United States, 2 recent retrospective
studies identified a significant increase in left-sided
distribution of BCCs, SCCs, Merkel cell carcinomas,
and malignant melanoma.46,47
Types of glass. Transmission of UVR through
windows depends on glass type, thickness, and
color. For details on commonly used glass types,
see Table I. The combination of low Eecoated glass
and lamination yields the best performance for
comfort, security, safety, and health.48-50
Automotive glass. To promote safety, all auto-
mobile window shields are made of laminated glass,
which filters UVB and most UVA light radiation.51
Side, rear, and overhead windows are usually made
from tempered glass that does not as effectively
block UVA. Tinted window glass decreases transmis-
sion of UVA when compared to untinted window
glass.52,53 New government standards for vehicle
safety54 will likely lead to an increased use of
laminated glass, which is stronger than tempered
glass, for side windows in an attempt to decrease
ejections from motor vehicles. This will indirectly
decrease transmission of UVR.50
Window films and tints provide an after-market
opportunity to reduce the transmission of VL and IR.
Most films are comprised of multiple layers of poly-
ethylene terephthalate, a polyester resin, and they can
block up to 99% of UVR up to 380 nm.55 The use of
window films must comply with federal and state
regulations regarding the minimal allowable transmis-
sion of VL. In the United States, federal mandates limit
the minimum VL transmission of windshields to 70%.56
Heat generated by IR contributes to skin aging via
the stimulation of MMPs and angiogenesis, de-
creased synthesis of procollagen 1, and increased
cytokines that regulate extracellular matrix
853.e6 Jansen et al
proteins.57-61 New regulations requiring automobile
manufacturers to produce cars with high fuel econ-
omy will result in the more common incorporation of
reflective coatings to laminated glass, decreasing the
transmission of heat into motor vehicle interiors,
reducing the need for air conditioning. These reflec-
tive coatings could result in the reduction of prema-
ture skin aging.50
Architectural glass for buildings. UVA light
transmission (up to 380 nm) through building glass is
highest through smooth ordinary glass and lowest in
laminated glass.62 The use of energy efficient glaz-
ings (developed by incorporating microscopic me-
tallic and oxide layers onto glass surface) in
contemporary residential and commercial building
windows can significantly reduce heat gain/loss
through windows, and can also provide some addi-
tional degree of UVR protection.42
Sunglasses
Key points
d Sunglasses provide important ocular protec-
tion from UVR.
d While national sunglass standards exist,
compliance by US manufacturers is
voluntary.
Consequences of UV light on ocular
tissue. Short-term ocular complications of UVR
include self-limited photokeratoconjunctivitis, while
long-term problems include climatic droplet kera-
topathy, pterygium, pinguecula, cortical cataract
formation, and certain types of ocular mela-
noma.63-67 Although UVR cannot reach the retina
except in young children and individuals with apha-
kia, blue VL can increase the risk of developing
macular degeneration.68 Sunglasses are especially
important for children because their clear ocular
lenses transmit more VL when compared to adult
lenses, increasing the risk of developing macular
degeneration.69,70 The time of the day for maximum
UVR risk differs for eyes and skin. Maximum UVR
exposure to the eye occurs when solar radiation is
parallel to the eye, usually during early morning or
later afternoon, but does vary with latitude and
season.71
Sunglasses guidelines. Three national stan-
dards for sunglasses exist: the European standard
EN 1836:2005, the Australian standard AS/NZS
1067:2003, and the American standard ANSI Z80.3,
which was last updated in 2010. While the Australian
and European standards differ in the maximum
amount of UVB light transmission allowed and the
definition of UVA light, they are overall very simi-
lar.72,73 Compliance with the ANSI standard is
J AM ACAD DERMATOL
DECEMBER 2013
voluntary in the United States,74 whereas compliance
with the respective standards in Australia and Europe
is mandatory. Only the Australian standard is man-
dated by law to be assessed by an independent party.
According to the US Food and Drug
Administration, sunglasses should meet a standard
of \0.001% permissiveness for UVB light and
\0.01% for UVA light radiation.75 UVR protection
by sunglasses depends on sunglass size and distance
from face.76 The best protection from UVR is
achieved by sunglasses with a wraparound style or
side shields.77 Mirror coating reduces the amount of
VL that reaches the eyes, but neither this nor gradient
tint, color, or darkness is indicative of UV protection.
Tinted lenses with good UV protection intended for
outdoor use can eliminate nearly all UV transmit-
tance.78 Dark lenses result in pupil dilatation, which
can potentially result in more exposure to UV if the
lenses are not UV protective. Expensive brands do
not guarantee good UVA protection.79 The use of
UVR-blocking contact lenses can increase the time
the wearer can be exposed to solar UVR before a
toxic ocular dose is achieved.80
Polycarbonate. Polycarbonate is a thermoplas-
tic that was first developed and used in the aerospace
industry. A study of airplane window screens found
that polycarbonate airplane windshields transmitted
almost no UVR below 380 nm.81 The material offers a
lightweight, impact resistant, photoprotective option
for eyeglass. A newer plastic, developed in 2001 and
marketed as Trivex (PPG Optical Products,
Pittsburgh, PA), provides a lightweight, strong, high
index eyeglass lens. According to the manufacturer,
urethane-based monomer Trivex lenses block
‘‘100%’’ of UVR.81
Fabric
The UV protectiveness of fabrics is measured as
‘‘UV protection factor’’ (UPF), a term coined in
Australia in 1996, and analogous to the SPF of
sunscreens. UPF is assessed in in vitro studies by
measuring transmission of UVA and UVB light
through fabrics with a spectrophotometer. Tightly
woven fibers, thick fabrics, dark colors, wool and
polyester materials, shrinkage that occurs after laun-
dering, and washing fabrics with additives like
Tinosorb FD (BASF, Basel, Switzerland), an UV
absorber, all promote decreased UVR transmission
(Table II).82-86 Stretching of fabric and chemical
processing methods, such as desizing, removing
agents such as starch that are added to the warp
yarns before weaving, or bleaching can increase UV
light transmission by decreasing reflection of inci-
dent UV.87,88 Hydration leads to increased or de-
creased UPF, depending on the fabric type.89
J AM ACAD DERMATOL
VOLUME 69, NUMBER 6
Table II. Factors affecting ultraviolet protection
factor of fabric
Fabric construction
Thickness
Fiber type
Laundering
Hydration
Color
Chemical processing
Stretch
Incorporation of compounds with photoprotective
property
Hats. Depending on the brim width, hat material,
and weaving, hats and visors provide variable sun
protection. Wide-brimmed hats (7.5 cm) provide SPF
7 for the nose, 3 for cheek, 5 for neck, and 2 for chin,
whereas narrow-brimmed hats provide only SPF 1.5
for the nose, and minimal, if any, protection for other
areas.90
Makeup. Although applied primarily for adorn-
ment, the pigment found in colored cosmetic
makeup can deliver or enhance photoprotection.
Facial foundations without sunscreen provide a SPF
of 2 to 6.91 Facial foundations that contain organic
plus inorganic filters can provide an SPF of 15 or
higher and broad-spectrum protection. Daily facial
moisturizers that contain sunscreen ingredients pro-
tect the skin from casual sun exposure.
SYSTEMIC PHOTOPROTECTIVE AGENTS
Key points
d Multiple systemic agents have potential as
photoprotective agents.
d In small studies, some have shown effective-
ness as a monotherapy.
Limitations of topical photoprotection products
include inconsistent and inadequate dosing and the
need for frequent reapplication. Therefore, easier to
use systemic alternatives have been pursued.
However, none of the currently available and prom-
ising agents have been studied extensively enough
to be used as the only photoprotective strategy.
Polypodium leucotomos
Polypodium leucotomos is a natural fern leaf
extract with antiinflammatory and antioxidant (AO)
properties. The administration of oral P leucotomos
to a group of high-risk patients with malignant
melanoma or atypical mole syndrome led to a
significant reduction in sensitivity to UVR in all
patients.92 Other studies have found that oral
Jansen et al 853.e7
administration of 480 to 1200 mg daily of this well
tolerated extract can prevent polymorphous light
eruption lesions in patients with polymorphous light
eruption.93,94 P leucotomos has been shown to
reduce the known effects of UVR, including minimal
erythema dose, minimal phototoxic dose, UV-
induced epidermal proliferation, development of
DNA damage and isomerization, decomposition of
trans-UCA, and the generation of ROS.95,96
Afamelanotide
Afamelanotide ([Nle4-D-Phe7]-aemelanocyte-
stimulating hormone [a-MSH]) is a linear, 13eamino
acid analogue of a-MSH that induces epidermal
melanin formation by binding to melanocortin-1 re-
ceptors on melanocytes, leading to increased mela-
nocyte proliferation and tyrosinase activity.97,98
a-MSH analogues reduce UV-induced DNA damage
via enhanced repair of DNA photoproducts, such as
removal of cyclobutane pyrimidine dimers.99,100
Afamelanotide was granted investigational new
drug status by the US Food and Drug
Administration in 2009. The subcutaneous adminis-
tration of the peptide has been shown to decrease
the photosensitivity response in patients with eryth-
ropoietic protoporphyria and solar urticaria. 101-103
The use of unregulated, subcutaneously self-
administered, synthetic analogues of a-MSH by per-
sons seeking to obtain a tan and weight loss has been
publicized in the lay press. In contrast to afamelano-
tide, this is a cyclic analogue of a-MSH that interacts
with a wide range of melanocortin receptors.
Regulatory agencies in the United States and
Europe have issued warnings against the use of this
cyclic peptide.98,104
Carotenoids
Carotenoids, a form of vitamin A that includes
b-carotene, lycopene, lutein, and zeaxanthin, are
micronutrient pigments present in plants that exhibit
AO activity and contribute to photoprotection.105
Human skin concentrations of b-carotene and lyco-
pene decreased after UVR exposure.106 Long-term
supplementation with b-carotene or consumption of
a carotenoid-rich diet can provide protection from
UV-induced erythema.107,108 Mice given dietary
lutein had decreased ROS in the skin and down-
regulation of the suppression of contact hypersensi-
tivity response after UVB light exposure.109 The oral
administration of carotenoids, such as lutein and
zeaxanthin, can provide better photoprotection
when compared to the topical application of
AOs.110 Two multiyear randomized controlled trials
of oral intake of b-carotene failed to show a protec-
tive effect on the development of NMSCs.111,112
853.e8 Jansen et al J AM ACAD DERMATOL
DECEMBER 2013

Table III. Additional photoprotective agents: antioxidants and others

Photoprotective agent Function and use
Retinoids (vitamin A) Topical retinoids inhibit MMP-1 expression, leading to increased collagen production and
epidermal thickness that reverses photoaging128; retinyl palmitate (storage form of
retinol) incorporation into sunscreens for its antioxidative property has not been
shown to cause photocarcinogenesis129; oral retinoids have been used for
chemoprevention in individuals at high risk for skin cancers130
Vitamin C (L-ascorbic acid) Water soluble AO that is an essential enzyme cofactor in collagen synthesis; topical
concentrations of at least 10% are photoprotective, reducing erythema131 and
immunosuppression132; orally, even at high doses (2-3 g/day), it has not shown a
photoprotective effect in humans133
Vitamin E (tocopherols Various topical forms reduce photoaging,134 cell membrane lipid peroxidation,135 and
and tocotrienols) photocarcinogenesis136; human response to UVB may be altered by high oral doses
(1200 IU/day), but other studies have shown no benefit133
Tea polyphenols Have high AO activity, but low stability and short duration of biologic activity; topical
application results in dose-dependent inhibition of UVR-induced erythema137; topical
application can result in contact, allergic, and phytophotodermatitis138
Silymarin Polyphenol derived from milk thistle seeds with strong AO effects; has demonstrated
photostability and UVB filtering properties when applied topically in in vivo studies139
Algae extract Have been incorporated into skin care products and sunscreens; has been shown to
stimulate proteasome peptidase activity in irradiated human keratinocytes, reducing
the extent of protein oxidative damage140
Soy isoflavones Have been shown to preserve cutaneous proliferation and repair mechanisms in full-
thickness human reconstituted skin141; diets rich in soybeans are protective against
various cancers142
Senna alata Plant native to Central America that is traditionally used to treat ringworm143;
incorporated into sunscreen products because of AO properties; keratinocyte cultures
treated with Senna alata extract had decreased UVB-induced thymine dimer
formation144
Phytomelanin Date-palm fruit derivative found in select sunscreens that is intended to mimic human
melanin
Selenium Essential element required for effective functioning of enzymatic endogenous AOs;
cofactor for vitamin E regeneration; topical application decreases MED in
humans136,145
Nicotinamide Amide form of vitamin B3, required for the production of adenosine triphosphate;
increased levels of intracellular nicotinamide are associated with enhanced protection
against photooxidative stress146,147; topical application provides broad-spectrum
protection against UVR-induced immunosuppression148

AO, Antioxidant; MED, minimal erythema dose; MMP, matrix metalloproteinase; UVB, ultraviolet B light; UVR, ultraviolet radiation.

Polyphenols Nonsteroidal antiinflammatory drugs

Polyphenols, a large family of naturally occurring
plant products, are found in dry legumes, honey, red
wine, chocolate, green tea, milk thistle, and many
fruits and vegetables. The most common polyphe-
nols are phenolic acids, flavonoids, catechins, stil-
benes, and proanthocyanidins.113 Polyphenols have
AO, antiinflammatory, immunomodulatory, and an-
ticarcinogenic properties.113,114 Many in vivo animal
studies have confirmed the antiphotocarcinogenic
potential of dietary polyphenols.115-118 A recent
double blind, placebo controlled study revealed
decreased UV-induced erythema in women consum-
ing green tea polyphenols.119 Human consumption
of chocolate rich in flavanols has also shown pro-
tection from UVR.120
While epidemiologic studies have yielded
conflicting evidence regarding an association
between nonsteroidal antiinflammatory drug
(NSAID) use and decreased cutaneous SCC
risk,121-123 several recent studies have suggested
a role for NSAIDs in cutaneous chemoprevention.
A population-based study found that NSAIDs
may reduce the risk of melanoma and cutaneous
SCC by inhibiting cyclooxygenase-2 enzymes that
are involved in carcinogenesis. 124 A double
blind, placebo controlled, randomized controlled
trial concluded that celecoxib may prevent SCC
and BCC in individuals with extensive photo-
damage who are at high risk for developing
NMSCs.125
J AM ACAD DERMATOL
VOLUME 69, NUMBER 6
Other AOs
ROS derived from both endogenous and exoge-
nous stresses can be quenched by the topical appli-
cation of AOs.9 Many pharmaceutical and
cosmeceutical companies have undertaken the
challenge of incorporating high concentration,
high oxidative capacity AOs into stable, stratum
corneumepenetrating sunscreens and skin care pro-
ducts in an attempt to improve sunscreen efficacy.9
Vitamins C and E, topically and orally, work syner-
gistically to reduce oxidative stress. Simultaneous
topical application of both AOs better protects
against UV-induced erythema, sunburn cell forma-
tion, and thymine dimer formation than when
vitamin C alone is applied.126,127 Table III summa-
rizes photoprotective agents with AO and other
properties.
The authors thank Ms Stephanie Stebens, MLIS, librar-
ian, Henry Ford Hospital, for her assistance with manu-
script preparation.
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