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UV photoprotection by combination topical antioxidants vitamin C and E

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Virtually all plants and animals protect themselves from the sun using vitamins C and E. The purpose of this study was to see if a combination of topical vitamins C and E is better for UV protection to skin than an equivalent concentration of topical vitamin C or E alone. We developed a stable aqueous solution of 15% L-ascorbic acid (vitamin C) and 1% alpha-tocopherol (vitamin E). We applied antioxidant or vehicle solutions to pig skin daily for 4 days. We irradiated (1-5x minimal erythema dose) control- and antioxidant-treated skin using a solar simulator with a 295-nm band-pass filter. On day 5, we measured antioxidant protection factor, erythema, sunburn cells, and thymine dimers. The combination of 15% L-ascorbic acid and 1% alpha-tocopherol provided significant protection against erythema and sunburn cell formation; either L-ascorbic acid or 1% alpha-tocopherol alone also was protective but the combination was superior. Application during 4 days provided progressive protection that yielded an antioxidant protection factor of 4-fold. In addition, the combination of vitamins C and E provided protection against thymine dimer formation. Appreciable photoprotection can be obtained from the combination of topical vitamins C and E. We suggest that these natural products may protect against skin cancer and photoaging.
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UV photoprotection by combination topical
antioxidants vitamin C and vitamin E
Jing-Yi Lin, MD,
a,
* M. Angelica Selim, MD,
a
Christopher R. Shea, MD,
b,
**
James M. Grichnik, MD, PhD,
a
Mostafa M. Omar, PhD,
c
Nancy A. Monteiro-Riviere, PhD,
d
and Sheldon R. Pinnell, MD
a
Durham, North Carolina; Chicago, Illinois; Elmwood Park, New Jersey;
and Raleigh, North Carolina
Background: Virtually all plants and animals protect themselves from the sun using vitamins C and E.
Objective: The purpose of this study was to see if a combination of topical vitamins C and E is better for
UV protection to skin than an equivalent concentration of topical vitamin C or E alone.
Methods: We developed a stable aqueous solution of 15% L-ascorbic acid (vitamin C) and 1%
-tocopherol
(vitamin E). We applied antioxidant or vehicle solutions to pig skin daily for 4 days. We irradiated (1-5minimal
erythema dose) control- and antioxidant-treated skin using a solar simulator with a 295-nm band-pass filter. On
day 5, we measured antioxidant protection factor, erythema, sunburn cells, and thymine dimers.
Results: The combination of 15% L-ascorbic acid and 1%
-tocopherol provided significant protection
against erythema and sunburn cell formation; either L-ascorbic acid or 1%
-tocopherol alone also was
protective but the combination was superior. Application during 4 days provided progressive protection
that yielded an antioxidant protection factor of 4-fold. In addition, the combination of vitamins C and E
provided protection against thymine dimer formation.
Conclusion: Appreciable photoprotection can be obtained from the combination of topical vitamins C and
E. We suggest that these natural products may protect against skin cancer and photoaging. (J Am Acad
Dermatol 2003;48:866-74.)
T
he skin naturally uses antioxidants to protect
itself from the damaging effects of sunlight.
1
Skin predominantly uses L-ascorbic acid (vi-
tamin C) to protect the aqueous environment and
-tocopherol (vitamin E) to protect lipid structures
including membranes.
2
In many biologic systems,
vitamins C and E work synergistically; when vitamin
E becomes oxidized by free radicals, it is regener-
ated in the membrane by vitamin C.
3-5
Previously, we have reported that L-ascorbic acid
applied topically to the skin reduces the photoinjury
produced by both UVB and UVA irradiation.
6
The
critical role of
-tocopherol for the antioxidant pro-
tection of the stratum corneum lipid bilayer and
protection against stratum corneum protein oxida-
tion has been recently reviewed.
7
In this study, we
report on a combination of antioxidants, L-ascorbic
acid and
-tocopherol, optimized with regard to con-
centration and pH for maximum photoprotective ef-
fects. We demonstrate that this combination of vita-
mins C and E is superior to either antioxidant alone.
The combination provides for a 4-fold protection
when compared with vehicle against erythema pro-
duced by solar-simulated irradiation and inhibits the
generation or accumulation of thymine dimers in skin.
MATERIALS AND METHODS
Chemicals
Fifteen percent (15%) L-ascorbic acid (Merck,
Darmstadt, Germany) and/or 1% dl-
-tocopherol
From Duke University Medical Center,
a
University of Chicago,
b
Phy-
toCeuticals,
c
and North Carolina State University, College of Vet-
erinary Medicine.
d
Supported in part by R43CA83538 and a Kenan Grant from North
Carolina Biotechnology Center. Dr Lin was supported by Chang
Gung Memorial Hospital, Taiwan.
Disclosure: Dr Pinnell is a consultant for SkinCeuticals, Garland, Tex.
Dr Omar is president of PhytoCeuticals, Elmwood Park, NJ.
Presented in part as a poster at the 63rd Annual Meeting of the
Society for Investigative Dermatology, Los Angeles, Calif, May 15-
18, 2002.
Accepted for publication July 20, 2002.
Reprint requests: Sheldon R. Pinnell, MD, Duke University Medical
Center, Department of Medicine, Division of Dermatology, PO
Box 3135, Durham, NC 27710. E-mail: pinne002@mc.duke.edu.
* Dr Lin is currently at Chang Gung Memorial Hospital, Taipei, Taiwan.
** Dr Shea is currently at the University of Chicago.
Copyright © 2003 by the American Academy of Dermatology, Inc.
0190-9622/2003/$30.00 0
doi:10.1067/mjd.2003.425
866
(Roche, Nutley, NJ) was formulated in an aqueous
vehicle containing 5% Brij 30 (Uniqema, New Castle,
Del) and 15% ethanol. All solutions were adjusted to
pH 3.2. For the purposes of these experiments, con-
centrations of ingredients and pH of the solution
chosen for testing was formulated to provide maxi-
mum percutaneous absorption of L-ascorbic acid
and
-tocopherol.
Experimental design
Experiments were performed in weanling white
Yorkshire pigs. In conducting research using ani-
mals, the investigators adhered to the guide for the
care and use of laboratory animals prepared by the
Committee on Care and Use of Laboratory Animals
of the Institute of Laboratory Resources, National
Research Council (National Institutes of Health, pub-
lication No. 86-23, revised 1996).
UV irradiation
A 1000-W UV radiation (UVR) source (Lightning
Cure 200, Hamamatsu, Japan) was used for deliver-
ing solar-simulated radiation to pig skin. The lamp
was combined with a dichroic mirror assembly re-
ecting most of the visible and infrared emission, to
reduce the heat load on the skin, and with a 1-mm
WG295 Schott selective UVB band-pass lter (295
nm) to eliminate wavelengths less than 295 nm. A
1-cm diameter liquid light guide was connected to
the exit port of the lamp housing to deliver energy to
the surface of the skin. The light guide was posi-
tioned just above the surface of the skin. The inten-
sity used in the experiment was 5 mW/cm
2
of UVB
as measured by a research radiometer (IL1700, In-
ternational Light, Newburyport, Mass). At this irradi-
ance, there was about 40 mW/cm
2
of UVA; because
of the much greater erythemal effectiveness of UVB,
the latter is expected to be the dominant wave band
in the observed biologic effects.
Treatment and irradiation procedure
Yorkshire pigs were clipped 24 hours before ex-
posure. The antioxidant or vehicle formulations (500
L) were applied to each patch of back skin (7.5
10 cm) daily for 4 days. To determine the minimal
erythema dose (MED), on day 3 we gave 30 to 100
mJ/cm
2
at 10-mJ/cm
2
intervals of solar-simulated
UVR to untreated skin. On day 4, MED was deter-
mined as the lowest dose that induced perceptible
erythema with distinct borders (ordinarily 40-60 mJ/
cm
2
). From 1 to 5MED at 1-MED intervals of
solar-simulated UVR was given in triplicate to each
7.5- 10-cm area of back skin. On day 5, the
antioxidant protection factor was calculated for each
formulation as the ratio of the MED in antioxidant-
treated skin in comparison with untreated skin. Each
treatment area was photographed using polarizing
lters to minimize surface reection. Each irradiated
spot was biopsied with an 8-mm skin punch.
Measurement of erythema
By using 8- 12-inch color photographic en-
largements, erythema was measured with a chro-
mameter (ColorMouse Too, Color Savvy Systems
Ltd, Springboro, Ohio). Previously, we found that
skin erythema varied appreciably depending on
blood ow to the area. By photographing the area,
the depth of erythema was documented at a mo-
ment in time and could be reliably measured in
high-quality photographic enlargements. Three sep-
arate sites from each irradiated spot on photographs
were chosen to measure the average erythemal re-
sponse. Nonirradiated adjacent skin was measured
for comparison. Erythema was measured in the a*
mode as instructed by the supplier. The difference of
the a* value between irradiated skin and nonirradi-
ated skin determined the erythema.
Measurement of sunburn cells
Skin biopsy specimens were xed in 10% neutral-
buffered formalin and processed for routine histol-
ogy. Hematoxylin-eosinstained center-cut sections
of each biopsy specimen were analyzed for sunburn
cells (keratinocytes with pyknotic nuclei having an
eosinophilic cytoplasm). The entire 8-mm center
section of the histologic ribbon was analyzed and
the results expressed as sunburn cells/mm. When
photodamage is extensive, it may be difcult to
precisely dene a sunburn cell in the presence of
epidermal necrosis. For analysis, whenever sunburn
cells could not be accurately identied, an upper
limit of 35 sunburn cells/mm was used.
Thymine dimer immunohistochemistry
Formalin-xed, parafn-embedded tissue sec-
tions were deparafnized with xylene and rehy-
drated through a graded alcohol-water series. After
equilibrium in phosphate-buffered saline, slides
were incubated in 1.5% horse serum to block non-
specic binding. Antithymidine dimer antibody,
Clone KTM-53 (Kamiya Biomedical, Seattle, Wash),
was diluted 1/50 in 15% horse serum and applied for
30 minutes at 37°C. Antibody binding was detected
using a kit (avidin-biotin ABC-elite kit, Vector, Bur-
lingame, Calif) as instructed by the vendor. Bound
peroxidase was also visualized using a kit (AEC
substrate kit, Vector). Slides were then counter-
stained with hematoxylin and mounted using aque-
ous mounting medium (Biomedia, Foster City,
Calif).
Lin et al 867
JAMACAD DERMATOL
VOLUME 48, NUMBER 6
Statistics
Results are expressed as mean SD (n 3). The
Pvalues were calculated by Student ttest.
RESULTS
In these experiments, concentrations of ingredi-
ents and pH of the solution chosen for testing was
formulated to provide maximum percutaneous ab-
sorption of L-ascorbic acid and
-tocopherol. We
have previously reported that skin levels of L-ascor-
bic acid were maximal after 3 days of application of
15% L-ascorbic acid in aqueous solution at pH 3.2.
8
Under these conditions, L-ascorbic acid levels in-
creased in tape-stripped skin from 56 to 1145
pmol/mg skin. Levels of
-tocopherol in tape-
stripped skin after topical application of 1% solution
for 24 hours increased from 14 to 31 pmol/mg skin
as determined by high-pressure liquid chromatogra-
phy. Higher levels of
-tocopherol up to 5% were no
more effective at delivering
-tocopherol into skin.
Antioxidant protection factor
Four days of combination 15% L-ascorbic acid
and 1%
-tocopherol provided 4-fold protection
against erythema (Fig 1), whereas 15% L-ascorbic
acid or 1%
-tocopherol alone protected 2-fold
when compared with vehicle-treated skin.
Erythema
Chromameter readings conrmed the visual ery-
thema evaluations (Fig 2). The combination of 15%
L-ascorbic acid and 1%
-tocopherol signicantly
reduced erythema at 1, 2, 3, 4, and 5 MEDs. L-
ascorbic acid alone was signicantly effective at 1, 2,
4, and 5 MEDs.
-Tocopherol alone lessened ery-
thema but this effect was not statistically signicant.
Sunburn cells
Enumeration of sunburn cells revealed statisti-
cally signicant reductions at 1 and 2 MEDs by
combination 15% L-ascorbic acid and 1%
-tocoph-
erol, and L-ascorbic acid and
-tocopherol alone
(Fig 3). At 3 and 4 MEDs, only the combination of
L-ascorbic acid and
-tocopherol was signicantly
protective.
Thymine dimers
Solar-simulated irradiation generated numerous
thymine dimers as determined by immunohisto-
chemistry. Combination 15% L-ascorbic acid and 1%
Fig 1. Vehicle (VEH) and combination vitamins C and E (C
&E) were applied to pig skin daily for 4 days. Skin was
irradiated with solar-simulated UV irradiation, 1 to 5 min-
imal erythema dose (MED) at 1-MED intervals. Erythema
was determined 1 day later.
Fig 2. Vehicle, vitamin C (C), vitamin E (E), and combi-
nation (C&E) were applied to pig skin daily for 4 days.
Skin was irradiated with solar-simulated UV irradiation, 1
to 5 minimal erythema dose (MED) at 1-MED intervals.
Clearly delineated erythema was determined 1 day later.
Antioxidant protection factor was determined as ratio of
MED in antioxidant-treated skin in comparison with con-
trol skin. Mean SD (n 3). *P.05.
Fig 3. Vehicle, vitamin (Vit) C, Vit E, and combination (Vit
C&E) were applied to pig skin daily for 4 days. Skin was
irradiated with solar-simulated UV irradiation, 1 to 5 min-
imal erythema dose (MED) at 1-MED intervals. Erythema
was measured by colorimeter. Mean SD (n 3). *P
.05.
868 Lin et al JAMACAD DERMATOL
JUNE 2003
-tocopherol almost completely protected against
this DNA alteration (Fig 4).
Kinetics
To determine the kinetics of photoprotection of
combination 15% L-ascorbic acid and 1%
-tocoph-
erol, applications were made at 1, 2, 3, and 4 days.
Progressive protection as measured by erythema
and sunburn cells was observed (Fig 5). To deter-
mine if the dosage was critical, the amount applied
during 4 days (2 mL) was applied 30 minutes before
irradiation (Fig 6). Single application of the entire
amount (2 mL) produced appreciable but incom-
Fig 6. Combination vitamins C and E (C&E) was applied
to pig skin daily for 4 days. Treated and control skin was
irradiated with 4 minimal erythema doses of solar-simu-
lated UV irradiation. One day later thymine dimers were
determined by immunohistochemistry.
Fig 4. Vehicle and combination vitamins C and E (C&E) were applied to pig skin daily for 4
days. Skin was irradiated with 1 minimal erythema dose of solar-simulated UV irradiation. One
day later skin was biopsied and sunburn cells were delineated in tissue sections stained with
hematoxylin-eosin.
Fig 5. Vehicle, vitamin (Vit) C, Vit E, and combination (Vit
C&E) were applied to pig skin daily for 4 days. Skin was
irradiated with solar-simulated UV irradiation, 1 to 5 min-
imal erythema dose (MED) at 1-MED intervals. Sunburn
cells were counted and are expressed as cells per milli-
meter of epidermis. Mean SD (n 3). *P.05.
Lin et al 869JAMACAD DERMATOL
VOLUME 48, NUMBER 6
plete protection when compared with application in
split doses for 4 consecutive days. Additional pro-
tection may have required time for percutaneous
absorption. Single application of 0.5 mL and 2 mL
resulted in appreciable but approximately the same
protection (Figs 5 and 6).
DISCUSSION
Antioxidants protect the skin against damage pro-
duced by UV irradiation.
1,9
L-ascorbic acid is the
major uid-phase antioxidant, glutathione protects
the intracellular compartment, and vitamin E and
ubiquinol protect membranes. On a molar basis,
Fig 7. Combination vitamins C and E (C&E) were applied to pig skin daily for 1 to 4 days. Skin
was irradiated with solar-simulated UV irradiation 1 to 4 minimal erythema dose (MED)at
1-MED intervals. Results of colorimeter readings of erythema (A) and sunburn cells (B) 1 day
after irradiation. Error bars have been eliminated for clarity. Mean SD (n 3). In comparison
with control P.05 for all observations.
Fig 8. Combination vitamins C and E (C&E) were applied to pig skin (500
L) daily for 4 days
or entire amount (2000
L) as single application. Skin was irradiated with solar-simulated UV
irradiation, 1 to 4 minimal erythema dose (MED) at 1-MED intervals. Results of colorimeter
readings of erythema (A) and sunburn cells (B) 1 day after irradiation. Mean SD (n 3). In
comparison with control, P.05 for all observations.
870 Lin et al JAMACAD DERMATOL
JUNE 2003
L-ascorbic acid is the predominant antioxidant in
skin; its concentration is 15-fold greater than gluta-
thione, 200-fold greater than vitamin E, and 1000-
fold greater than ubiquinol/ubiquinone.
2
Concentra-
tions of antioxidants are higher in epidermis than
dermis: 6-fold for L-ascorbic acid and glutathione,
and 2-fold for vitamin E and ubiquinol/ubiquinone.
In aged and photoaged skin, levels of
-tocopherol
and L-ascorbic acid were reduced signicantly, by as
much as 60% to 70%.
10
UV irradiation depleted an-
tioxidants; ubiquinol and vitamin E were the most
photosensitive, whereas L-ascorbic acid was rela-
tively resistant.
11
Antioxidants work in concert in the
skin
9,12
; after oxidation, the lipophilic antioxidants
ubiquinol and vitamin E are regenerated by L-ascor-
bic acid, which in turn is regenerated by glutathio-
ne.
9,13,14
Virtually all plants and animals synthesize
L-ascorbic acid. Human beings have lost this capac-
ity as a result of a mutation in L-gulono-
-lactone
oxidase that renders the gene nonfunctional.
15
In-
stead, human beings must consume L-ascorbic acid
in their diet.
16
Although many persons consume
large oral supplements of this vitamin, biologic con-
trol mechanisms limit the amount that can be ab-
sorbed and subsequently transported to skin. There-
fore, the only way to get large concentrations into
skin is to apply L-ascorbic acid topically, in this way
targeting the area to be protected. To achieve per-
cutaneous delivery, the pH of the formulation must
be below 3.5 to accomplish protonation of the ascor-
bic acid. Previously we have determined that maxi-
mal concentrations into skin can be achieved with
daily applications of 15% L-ascorbic acid for 3 days.
8
We have previously reported that topical L-ascorbic
acid is capable of protecting skin against erythema
produced by UVB and UVA irradiation by a mech-
anism unrelated to absorption of the UVR.
6
More-
over, we have demonstrated that topical L-ascorbic
acid can provide protection against UVB-induced
immunosuppression and systemic tolerance to con-
tact allergens.
17
In biologic systems, L-ascorbic acid is an ex-
tremely effective antioxidant capable of neutralizing
superoxide anion,
18
hydroxyl radical,
19
singlet oxy-
gen,
20
and peroxynitrite.
21
In addition to its antiox-
idant properties, L-ascorbic acid is necessary for
collagen synthesis. It is an essential cofactor for
prolyl hydroxylase and lysyl hydroxylase, enzymes
critical for collagen structure and cross-linking.
22
L-
ascorbic acid induces collagen gene transcription
23
and is essential for proper wound healing.
24,25
L-
ascorbic acid may inhibit elastin synthesis
26
and,
therefore, could be useful for photoaged skin where
elastin synthesis is increased.
24,25,27
L-ascorbic acid is
a useful skin lightener; it inhibits tyrosinase.
28
L-
ascorbic acid is important for epidermal barrier func-
tion;
29,30
it stimulates sphingolipid production.
31
Vitamin E is the bodys major lipid soluble anti-
oxidant and functions to protect membranes from
free radical attack. It is our major peroxyl radical
scavenger and ends the chain reaction damage
caused when free radicals attack membranes. Vita-
min E is particularly abundant in the stratum cor-
neum of skin, and is delivered there in sebum.
7
It
protects the outer layers of skin against pollutants
and UV light; UV light causes depletion.
32
The li-
pophilic nature of vitamin E makes it attractive for
application to and percutaneous absorption into
skin.
33
Topical vitamin E applied to skin protected
against UV-induced erythema,
34
lipid peroxida-
tion,
35
and photoaging changes
36-38
in mice. Topical
application protected against UV-immunosuppres-
sion.
39-41
Topical vitamin E prevented photocarcino-
genesis in mice
40,42
and UV-induced thymine dimer
formation.
43
In addition to its photoprotective ef-
fects, vitamin E inhibits melanogenesis; its major
effect may be through inhibition of tyrosinase.
44
This study demonstrates that synergistic photo-
protection can be achieved when vitamin C is com-
bined with vitamin E. Although both L-ascorbic acid
and
-tocopherol are prone to oxidize in solution,
combining the hydrophilic and lipophilic antioxi-
dants together helps to stabilize the formulation. It is
not entirely clear why an antioxidant formulation
would have a major effect on thymine dimer forma-
tion. Thymine dimer formation results from direct
absorption of UVB by DNA.
1,45
DNA may also be the
chromophore for erythema.
46
Protection by combi-
nation L-ascorbic acid and
-tocopherol apparently
is not a sunscreen effect.
47
Although
-tocopherol
has modest UVB absorption ([molar extinction of
3500 {mol/l}
1
/cm] and lmax at 290 nm),
48
we were
unable to detect absorption above 295 nm in our
solution. L-ascorbic acid does not absorb UV light
above 295 nm.
6
Moreover, in our study, application
of a 4-fold amount of vitamins C and E before irra-
diation was no more protective than a single appli-
cation (Figs 5 and 6); if the protective effect were a
sunscreen absorption phenomenon, one would ex-
pect more protection from more product. Topical
-tocopherol has been demonstrated to prevent
photocarcinogenesis.
40,42
McVean and Liebler
43,49
studied the photocarcinogenic effect of
-tocoph-
erol and demonstrated that it protected DNA photo-
damage by preventing thymine dimers. They re-
ported better protection with
-tocopherol than
derivatives of
-tocopherol with similar UVR ab-
sorption and better protection than several sun-
screen chemicals.
49
Their studies suggested that cel-
Lin et al 871
JAMACAD DERMATOL
VOLUME 48, NUMBER 6
lular uptake was necessary for the protective effect.
UVR generates reactive oxygen species in skin
(UVA UVB), resulting in oxidation of proteins.
50
DNA repair enzymes appear to be especially prone
to UVA damage,
51
which may lead to inefcient
excision of pyrimidine dimers. Topical antioxidants
may help to prevent this damage. Chen et al
52
dem-
onstrated, in UV-irradiated mice, a 55% reduction of
pyrimidine dimer formation in epidermal p53 by
topical
-tocopherol. However, they saw little
change in effect from 1 to 10 hours after irradiation
and reasoned that it was unlikely that the effect
related to repair.
52
Although we cannot completely
eliminate a sunscreen effect to explain our data with
vitamins C and E, we believe that the effect is min-
imal. In support, protection against photocarcino-
genesis and pyrimidine dimer formation has been
reported using other antioxidants including green
tea polyphenols
53,54
and silymarin
55
in the apparent
absence of UVR absorption.
Photochemistry requires absorption of photons
by a chromophore. Transurocanic acid is a major
chromophore for generation of singlet oxygen in
skin.
56,57
Its maximum concentration is in the upper
epidermis and stratum corneum. The peak UV spec-
trum for singlet oxygen generation from urocanic
acid is about 345 nm. The stratum corneum antiox-
idant system is strategically placed to deal with this
insult to the skin barrier.
Photoprotection against erythema has been pre-
viously reported by combination vitamins C and E
administered systemically
58,59
or applied topically to
skin.
47,60
This combination was particularly effective
at preventing the tanning response and immunosup-
pression of contact hypersensitivity.
61
Because
-to-
copherol is the major antioxidant of the outer layers
of skin, its lipophilic nature lends itself to topical
application; absorption occurs in minutes.
39
Simul-
taneous application of L-ascorbic acid may be an
advantage because it adds a coantioxidant to the
outer layers of skin. It may then be available to
regenerate
-tocopherol whenever it is oxidized,
regenerating it for further protection.
Because L-ascorbic acid and
-tocopherol are rel-
atively unstable in cosmetic formulations, these
compounds have been esteried to improve stabil-
ity. These esters are readily converted when taken
orally, but not necessarily changed to active com-
pounds when topically applied to skin. Indeed, nei-
ther magnesium ascorbyl phosphate nor ascorbyl-6-
palmitate topically applied appreciably changed
skin levels of L-ascorbic acid.
8
Likewise, esters of
-tocopherol, including tocopherol acetate are only
poorly converted and are functionally ineffective
when used topically for skin.
62,63
CONCLUSION
We demonstrate that protection against UV irra-
diation can be achieved with a solution containing a
combination of vitamins C and E. Combination an-
tioxidants may be particularly efcacious in that they
may eliminate toxic free radicals by transfer of single
hydrogen atoms rather than electrons.
14
In this way,
they may reduce damaging free radicals while min-
imizing the reduction of molecular oxygen to super-
oxide and adding additional free radical stress. An-
tioxidants do not work individually in the skin but
work synergistically in an integrated and regulated
way to protect against oxidative stress.
9,12
Combin-
ing these 2 antioxidants, vitamins C and E, can pro-
vide useful supplementation to sunscreen protection
against photocarcinogenesis and photoaging dam-
age produced by the sun.
Thanks and appreciation to Dr Doren Madey for her
excellent ideas and support as well as for her dedicated
help in preparing the manuscript.
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... Besides endogenous enzymes, skin is equipped with a non-enzymatic set of antioxidant molecules that can be absorbed through the diet and they play a key role in protecting the skin from oxidative reactions, and lipid peroxidation, and promote keratinocyte differentiation, as well as skin barrier function [14,[149][150][151]. The most abundant antioxidant components within the cutaneous tissue are tocopherol (vitamin E) and ascorbic acid (vitamin C) [152,153]. Carotenoids, uric acid, and co-enzyme Q 10 (CO-Q 10 ) are other important micronutrients with antioxidant properties for human skin [55]. Pollutant-induced photooxidative stress can lead to the depletion of skin surface antioxidants, especially vitamin E, vitamin C and glutathione, resulting in structural skin damage and an impairment of the barrier function, as well as skin aging. ...
... Cutaneous stressors, skin damage and protection technologies.TopicalAOX-[151][152][153][165][166][167][168] ...
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Our current understanding of the pathogenesis of skin aging includes the role of ultraviolet light, visible light, infrared, pollution, cigarette smoke and other environmental exposures. The mechanism of action common to these exposures is the disruption of the cellular redox balance by the directly or indirectly increased formation of reactive oxygen species that overwhelm the intrinsic antioxidant defense system, resulting in an oxidative stress condition. Altered redox homeostasis triggers downstream pathways that contribute to tissue oxinflammation (cross-talk between inflammation and altered redox status) and accelerate skin aging. In addition, both ultraviolet light and pollution increase intracellular free iron that catalyzes reactive oxygen species generation via the Fenton reaction. This disruption of iron homeostasis within the cell further promotes oxidative stress and contributes to extrinsic skin aging. More recent studies have demonstrated that iron chelators can be used topically and can enhance the benefits of topically applied antioxidants. Thus, an updated, more comprehensive approach to environmental or atmospheric aging protection should include sun protective measures, broad spectrum sunscreens, antioxidants, chelating agents, and DNA repair enzymes.
... Vitamin C merupakan antioksidan terkenal sebagai nutrisi penting yang terlibat dalam berbagai bidang dematologis, farmasi, dan fungsi biologis, hingga membantu pengolahan makanan. Vitamin ini memiliki kelebihan dapat mengurangi kerusakan akibat radikal bebas pada kulit, menunda penuaan dan mengurangi pembentukan melanin [1][2][3]. Vitamin C juga memiliki kekurangan di antaranya mudah teroksidasi dalam kondisi ruang, suhu dan paparan cahaya [4], sehingga untuk mengatasi kelemahannya maka enkapsulasi merupakan salah satu metode untuk melindungi vitamin C dari kerusakan [5]. ...
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Enkapsulasi vitamin C telah dilakukan dengan membuat matriks silika gel dengan prekursor Tetraethylorthosilicate- Methyltriethoxysilane (TEOS-MTES), menggunakan katalis basa NaOH dan penambahan bahan polimer Polivinil Alkohol (PVA). Larutan dibuat dengan metode sol-gel, kemudian ditambahkan vitamin C untuk model pengenkapsulasian dan dilakukan variasi matriks TEOS:MTES:PVA berturut-turut (2:1:1, 2:1:3, dan 2:1:6) untuk meningkatkan kestabilan enkapsulasi. Penelitian ini bertujuan untuk menentukan matriks yang terbaik untuk bahan enkapsulasi. Karakterisasi sampel yang digunakan adalah FTIR untuk mengetahui gugus fungsi dari vitamin C dalam silika, analisis efisiensi enkapsulasi, loading capacity dan pelepasan terkendali menggunakan UV-Vis. Kemudian untuk mengetahui morfologi permukaan dengan SEM. Hasil penelitian menunjukkan bahwa adanya bilangan gelombang 1751 cm-1 yang merupakan gugus fungsi dati vitamin C yang terenkapsulasi, matriks terbaik untuk enkapsulasi dengan parameter tingginya persentase efisiensi enkapsulasi pada perbandingan 2:1:1 yaitu 65,5%, loading capacity setinggi 0,56% dan pelepasan terkendali paling lambat. Pada karakterisasi SEM tidak terlihat jelas vitamin C terenkapsulasi.
... According to the results, the group that was treated with collagen-and Vit C-loaded NEs mixture showed the most healthy skin features, as collagen was found to elevate the degree of hydration at the inner layers of the skin through the topical treatment with cosmetic formulations containing collagen peptides, 69 and boost the smoothness and the luminosity of the skin surface at the microtextural level. 3 Besides, Vit E (as a component of NE) and Vit C are famous for their skin protectant and topical antioxidants characteristics, 70,71 where applying the three ingredients led to the superlative results. ...
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Introduction: Damage to human skin occurs either chronologically or through repetitive exposure to ultraviolet (UV) radiation, where collagen photodegradation leads to the formation of wrinkles and skin imperfections. Consequently, cosmeceutical products containing natural bioactives to restore or regenerate collagen have gained a remarkable attention as an ameliorative remedy. Methods: This study aimed to develop and optimize collagen-loaded water-in-oil nanoemulsion (W/O NE) through a D-optimal mixture design to achieve an ideal multifunctional nanosystem containing active constituents. Vit E was included as a constituent of the formulation for its antioxidant properties to minimize the destructive impact of UV radiation. The formulated systems were characterized in terms of their globule size, optical clarity, and viscosity. An optimized system was selected and evaluated for its physical stability, in vitro wound healing properties, and in vivo permeation and protection against UV radiation. In addition, the effect of collagen-loaded NE was compared to Vit C-loaded NE and collagen-/Vit C-loaded NEs mixture as Vit C is known to enhance collagen production within the skin. Results: The optimized NE was formulated with 25% oils (Vit E: safflower oil, 1:3), 54.635% surfactant/cosurfactant (Span 80: Kolliphor EL: Arlasolve, 1:1:1), and 20.365% water. The optimized NE loaded with either collagen or Vit C exhibited a skin-friendly appearance with boosted permeability, and improved cell viability and wound healing properties on fibroblast cell lines. Moreover, the in vivo study and histopathological investigations confirmed the efficacy of the developed system to protect the skin against UV damage. The results revealed that the effect of collagen-/Vit C-loaded NEs mixture was more pronounced, as both drugs reduced the skin damage to an extent that it was free from any detectable alterations. Conclusion: NE formulated using Vit E and containing collagen and/or Vit C could be a promising ameliorative remedy for skin protection against UVB irradiation.
... [68] . Combining L-ascorbic acid (15%) with α-tocopherol (1%) gives four-fold protection against clinical minimal erythema dose (MED) and against thiamine dimer formation alone [74] ; addition of another plant antioxidant ferulic acid (0.5%) yields 8-fold protection [72] . This formulation was shown to prevent the up-regulation of oxidative and inflammatory markers in human skin explants exposed to UV plus O 3 and diesel engine exhaust [75] . ...
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The appearance of aging is determined primarily by extrinsic factors through exposure to environmental sunlight and airborne pollution. That solar ultraviolet B (λ = 290-320 nm) directly causes photoaging (with wrinkles, dryness, and mottled pigmentation) and skin cancer has been recognized for decades; the contribution by ultraviolet A (λ = 320-400 nm) was only more recently understood. New research further implicates visible light (λ = 400-700 nm) as well as the heat rays of infrared radiation (λ > 800 nm). Particularly in urban environments, airborne pollutants such as ozone (O3), polycyclic aromatic hydrocarbons, particulate matter (PM) in smog, and tobacco smoke contribute to photoaging and skin cancer. Furthermore, exposure simultaneously to both solar ultraviolet (UV) and these pollutants results in even greater synergistic damage. The volatile pollutants generate reactive oxygen species which oxidize surface lipids leading to deeper damaging inflammatory reactions. PM carries high concentrations of environmental organic compounds and trace metals. These pollutant-laden particles deliver toxins to the skin transcutaneously through hair follicles and through the blood after respiratory inhalation. The predominant natural mechanism of clearing these xenobiotic chemicals is through the ligand-activated transcription factor the arylhydrocarbon receptor (AHR) found on all skin cells. AHR activity regulates keratinocyte differentiation and proliferation, maintenance of epidermal barrier function, melanogenesis, and immunity. With chronic activation by UV exposure and pollutants, AHR signaling contributes to both extrinsic aging and carcinogenesis.
... Topical solutions of vitamin C, or L-ascorbic acid, have demonstrated antioxidant activity in skin and photoprotective action against UV radiation. [28,29] Vitamin C's efficacy in reducing UV induced pigmentation in Fitzpatrick type III skin has been reported. [30] The results indicate that the combination of these 3 AOs with Diethylhexyl Syringylidene Malonate and Vitamin E provided a strong AO defense in mitigating VL+UVA1 induced pigmentation. ...
Article
Objective: The synergistic effects of VL and long wavelength UVA1 (VL+UVA1, 370-700 nm) on inducing pigmentation and erythema in skin have been demonstrated and linked to exacerbation of dermatologic conditions including melasma and post-inflammatory hyperpigmentation. This study aims to compare the photoprotection of organic sunscreens enriched with antioxidant (AO) combinations against VL+UVA1 induced biologic effects. The efficacy was compared to that offered by a commercially available tinted sunscreen. Methods: Ten healthy adult subjects with Fitzpatrick skin phototypes IV-VI were enrolled (nine completed). VL+UVA1 dose of 380 J/cm2 was utilized. Assessment methods were polarized photography, investigator global scoring, and diffuse reflectance spectroscopy (DRS). Measurements were obtained at baseline and immediately, 24 hours, and 7 days after irradiation. Results: Sites treated with tinted sunscreen product had significantly less pigmentation compared with untreated but irradiated skin at all time points. However, DRS results demonstrated that the 5-AO sunscreen performed comparably or better than all sunscreens tested with relatively lower dyschromia, delayed erythema and pigmentation. Conclusion: These results highlight the potential of AO enriched sunscreens to be photoprotective against VL+UVA1. The combination of efficacy and the cosmetic appearance of this product may provide wider acceptability which is crucial considering the limited available means of protection against this waveband.
... A report by Lykkesfeldt et al. demonstrated the capability of VTC in the regeneration of vitamin E (tocopherols) from its oxidised form (tocopheroxyl radical), thereby affording VTC to indirectly inhibit lipid peroxidation [125]. Moreover, the combination of VTC and vitamin E has been demonstrated to afford maximum photoprotection of the skin, thereby limiting photoageing [149][150][151][152][153]. ...
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The rapid rise in the health burden associated with chronic wounds is of great concern to policymakers, academia, and industry. This could be attributed to the devastating implications of this condition, and specifically, chronic wounds which have been linked to invasive microbial infections affecting patients’ quality of life. Unfortunately, antibiotics are not always helpful due to their poor penetration of bacterial biofilms and the emergence of antimicrobial resistance. Hence, there is an urgent need to explore antibiotics-free compounds/formulations with proven or potential antimicrobial, anti-inflammatory, antioxidant, and wound healing efficacy. The mechanism of antibiotics-free compounds is thought to include the disruption of the bacteria cell structure, preventing cell division, membrane porins, motility, and the formation of a biofilm. Furthermore, some of these compounds foster tissue regeneration by modulating growth factor expression. In this review article, the focus is placed on a number of non-antibiotic compounds possessing some of the aforementioned pharmacological and physiological activities. Specific interest is given to Aloe vera, curcumin, cinnamaldehyde, polyhexanide, retinoids, ascorbate, tocochromanols, and chitosan. These compounds (when alone or in formulation with other biologically active molecules) could be a dependable alternative in the management or prevention of chronic wounds.
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Background: Skin aging is a process regulated by chronological aging and amplified by exposome factors including chronic UV exposure and pollution, which both induce reactive oxygen species. Topical antioxidants have the potential to counteract this process and to improve skin aging signs, including wrinkles and hyperpigmentation. Objective: To evaluate the efficacy of a topical antioxidant serum containing 15% L-ascorbic acid, neohesperidin, Pinus pinaster bark, tocopherol and hyaluronic acid (HA) ex vivo on air pollution-induced pigmentation and gene expression, as well as in vivo on skin aging signs in Brazilian volunteers, after 90 days of use. Methods: Ex vivo human skin samples were repetitively exposed to Diesel Exhaust Particles (DEP) and subsequently analyzed for changes in pigmentation and gene expression. Clinical efficacy was evaluated in 40 healthy adult females with phototype II to IV and visible photoaging signs, including facial hyperpigmentation, through dermatological evaluation and instrumental analysis including Reflectance Confocal Microscopy. Results: Ex vivo, the topical anti-oxidant serum significantly reduced DEP-induced skin pigmentation and expression of proinflammatory genes. A significant improvement of skin aging signs was observed after 90 days. Local tolerance was good. Conclusion: The tested serum is effective in protecting human skin ex vivo against air pollution-induced skin pigmentation/aging and reduced in vivo skin aging signs, with a good safety profile after 90 days of daily use.
Chapter
Chronic absorption of UV radiation leads to photoaging, sunburn, immunosuppression, and carcinogenesis. Photoaging is the most common form of skin damage caused by UV exposure, affecting connective tissue, melanocytes, and the microvasculature. In photoaged skin, the thickness of the epidermis can either increase or decrease, corresponding to areas of keratinocyte atypia. Changes in the dermis of photoaged skin can vary based on the amount of acquired UV damage. Substantial progress has been made to ascertain the molecular mechanisms accountable for photoaging in human skin. DNA damage and defective DNA repair mechanisms have been implicated in carcinogenesis as well as the intrinsic aging process. One of the histologic hallmarks of photoaging is elastolysis and an accumulation of abnormal elastin in the superficial dermis known as solar elastosis. The pathophysiology of photoaging stems from the ability of UV irradiation to exploit established molecular mechanisms that have evolved to maintain the internal milieu of human skin connective tissue.
Chapter
This chapter presents a basic skin regimen to protect from photodamage and to reverse the appearance of aging. The four necessary steps are cleansing, exfoliation, protection, and treatment. Proper cleansing is an essential component of skincare. The inclusion of medications as components of cleansers can be effective in actually treating the skin. Exfoliation is the rejuvenation treatment providing the most immediate improvement in appearance. The single most effective therapy for aging skin is sun protection. The ability of a sunscreen to prevent UVB‐mediated erythema is measured by the internationally accepted standard sun protection factor, the ratio of equivalent exposure by UVB in sunscreen‐protected compared with unprotected skin. Retinoids are the "gold standard" for reversing photoaging of the skin. The skin naturally uses nutritional antioxidants to protect itself from photodamage and topical application has been investigated. Ferulic acid is a potent antioxidant present in the cell walls of grains, fruits, and vegetables.
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Topical application of vitamin E has been shown to decrease the incidence of ultraviolet (UV)-induced skin cancer in mice. Vitamin E provides protection against UV-induced skin photodamage through a combination of antioxidant and UV absorptive properties. Topical application of alpha-tocopherol on mouse skin inhibits the formation of cyclobutane pyrimidine photoproducts. However, topically applied alpha-tocopherol is rapidly depleted by UVB radiation in a dose-dependent manner. The photooxidative fate of the alpha-tocopherol depends on the local environment of the vitamin E. alpha-Tocopherol quinone and alpha-tocopherol quinone epoxides are principal photoproducts of vitamin E that has penetrated into the epidermal layer of the skin, whereas tocopherol dimers and trimers are formed from alpha-tocopherol in a bulk phase at the skin surface. Dimer and trimer products may participate in prevention of UV-induced photodamage.
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We measured enzymic and non-enzymic antioxidants in human epidermis and dermis from six healthy volunteers undergoing surgical procedures. Epidermis was separated from dermis by currettage and antioxidants were measured by high-performance liquid chromatography (HPLC) or standard spectrophotometric methods. The concentration of every antioxidant (referenced to skin wet weight) was higher in the epidermis than in the dermis. Among the enzymic antioxidants, the activities of superoxide dismutase, glutathione peroxidase, and glutathione reductase were higher in the epidermis compared to the dermis by 126, 61 and 215%, respectively. Catalase activity in particular was much higher (720%) in the epidermis. Glucose-6-phosphate dehydrogenase and isocitrate dehydrogenase, which provide reduced nicotinamide adenine dinucleotide phosphate (NADPH), also showed higher activity in the epidermis than the dermis by 111% and 313%, respectively. Among the lipophilic antioxidants, the concentration of α-tocopherol was higher in the epidermis than the dermis by 90%. The concentration of ubiquinol 10 was especially higher in the epidermis, by 900%. Among the hydrophilic antioxidants, concentrations of ascorbic acid and uric acid were also higher in the epidermis than in the dermis by 425 and 488%, respectively. Reduced glutathione and total glutathione were higher in the epidermis than in the dermis by 513 and 471%. Thus the antioxidant capacity of the human epidermis is far greater than that of dermis. As the epidermis composes the outermost 10% of the skin and acts as the initial barrier to oxidant assault, it is perhaps not surprising that it has higher levels of antioxidants.
Article
The improvement of the wound healing process in humans by vitamin supplements is still controversial because of the lack of a clearly demonstrated correlation with the mechanical properties of scars. Objective: The aim of this work was to study the effects of high doses of ascorbic acid (AA) and pantothenic acid (PA) on the wound healing process of human skin. Method: Two groups of patients undergoing surgery for tattoo removal by the successive resection procedure received AA (1 or 3 g/day) and PA (0.2 or 0.9 g/day). More than 80 mechanical, biological and histological parameters were investigated in both preoperated skin and the scars. Results: The breaking energy of scars was higher in group 2, and energy and treatment were directly correlated (p = 0.006). Mg and Mn significantly rose in group 2 whereas Fe decreased in a dose-dependent manner. Intragroup comparison showed patient and treatment effects for Mg, a time •treatment effect for Cu and a treatment effect for Fe. Conclusion: The degree and rapidity of variations rather than the variations of the absolute values themselves of fibroblasts, hydroxyproline, Fe, Cu and Mg are significantly related to the enhancement of the mechanical properties of scars. From this study, it may be assumed that in order to obtain ‘better’, more solid and resistant scars, the decrease of Fe must be quick and acute in order to avoid the harmful effects of toxic radicals; the increase of Cu, Mg and Mn must be early and high in order to have more stable and solid collagen.
Article
Despite convincing in vitro evidence, a vitamin C–E interaction has not been confirmed in vivo. This study was designed to examine the effects of supplementation with either vitamin C or E on their respective plasma concentrations, other antioxidants, lipids and some haemostatic variables. Fasting blood was collected before and after intervention from thirty healthy adults in a double-blinded crossover study. Baselines for measured variables were established after 2 weeks of placebo supplementation, followed by daily supplementation with 73·5 mg RRR-α-tocopherol acetate or 500 mg ascorbic acid, and placebo, for 6 weeks. A 2 month washout preceded supplement crossover. Mean values showed that plasma lipid standardised α-tocopherol increased with ascorbic acid supplementation: from 4·09 (SEM 0·51) TO 4·53 (sem 0·66) μmol/mmol total cholesterol plus triacylglycerol (P < 0·05), and plasma ascorbic acid increased from 62·8 (sem 14·9) to 101·3 (sem 22·2) μmol/l (P < 0·005). Supplementation with (RRR)-α-tocopherol acetate increased plasma α-tocopherol from 26·8 (sem 3·9) to 32·2 (sem 3·8) μmol/l (P < 0·05), and lipid-standardised α-tocopherol from 4·12 (sem 0·48) to 5·38 (sem 0·52) μmol/mmol (P < 0·001). Mean plasma ascorbic acid also increased with vitamin E supplementation, from 64·4 (sem 13·3) to 76·4 (sem 18·4) μmol/l (P < 0·05). Plasma ferric reducing (antioxidant) power and glutathione peroxidase (U/g haemoglobin) increased in both groups, while urate, total cholesterol and triacylglycerol levels decreased (P < 0·05 throughout). Results are supportive of an in vivo interaction between vitamins C and E.