Vitamin E: Critical Review of Its Current Use in Cosmetic and

Clinical Dermatology
JENS J. THIELE, MD, SHERRY N. HSIEH, PHD, AND SWARNA EKANAYAKE-MUDIYANSELAGE, MD
Department of Dermatology, Northwestern University Medical School, Chicago, Illinois
BACKGROUND AND OBJECTIVE. The lipophilic antioxidant vitamin
E has been used for more than 50 years in clinical and experi-
mental dermatology. However, although a large number of case
reports were published, there is still a lack of controlled clinical
studies providing a rationale for clinical indications and dosage.
In contrast, advances in basic research on the physiology, mech-
anism of action, penetration, bioconversion, and photoprotec-
tion of vitamin E in human skin have led to the development of
numerous new formulations for use in cosmetics and skin care
products.
RESULTS. This article reviews the basic mechanisms and possible
cosmetical and clinical implications of the recent advances in
cutaneous vitamin E research. Experimental evidence suggests
that topical and oral vitamin E has anticarcinogenic, photopro-
tective, and skin barrierstabilizing properties.
CONCLUSION. Although its current use is largely limited to cos-
metics, controlled clinical studies for indications such as atopic
dermatitis or prevention of photocarcinogenesis are needed to
evaluate the clinical benefit of vitamin E.
2005 by the American Society for Dermatologic Surgery, Inc. Published by BC Decker Inc
ISSN: 10760512 Dermatol Surg 2005;31:805813.
JENS J. THIELE, MD, SHERRY N. HSIEH, PHD, AND SWARNA EKANAYAKE-MUDIYANSELAGE, MD, HAVE
INDICATED NO SIGNIFICANT INTEREST WITH COMMERCIAL SUPPORTERS.
VITAMIN E is an essential nutrient that is receiving grow-
ing attention in dermatology because of its antioxidant
properties. Whereas some antioxidants, such as glu-
tathione or ubiquinol 10, can be synthesized by humans,
vitamin E is supplied by oral intake. The main natural
sources of vitamin E are fresh vegetables, vegetable oils,
cereals, and nuts. A recently published study analyzing
dietary data from almost 10,000 individuals suggests that
the majority of men and women in the United States fail to
meet the current recommendations for vitamin E intake.
1
The aim of this article is to review experimental and clin-
ical data available on the biologic activity of vitamin E in
human skin, with special emphasis on its antioxidative and
photoprotective properties.
Terminology and Definitions
Vitamin E is the major lipophilic antioxidant in plasma,
membranes, and tissues.
2
The term vitamin E collec-
tively refers to the eight naturally occurring molecules
(four tocopherols and four tocotrienols) that exhibit vita-
min E activity. Tocotrienols differ from tocopherols in
that they have an isoprenoid instead of a phytyl side
chain; the four forms of tocopherols and tocotrienols dif-
fer in the number of methyl groups on the chromanol
nucleus ( has three, and have two, and has one;
Figure 1). In humans, tocopherol is the most abundant
vitamin E homologue, followed by tocopherol. To com-
pare the potency of different vitamin E derivatives, their
biologic activities are measured and compared with RRR-
-tocopherol. The potency is expressed as international
units (IU) and -tocopherol equivalents (-TE).
Indications and Biologic Activity
Despite more than half a century of research, there is still
insufficient evidence from controlled studies concerning
vitamin Es effectiveness in treating specific dermatologic
disorders. In mostly small trials and case reports, oral vita-
min E supplementation is recommended in the therapy of
yellow nail syndrome, vibration disease, epidermolysis
bullosa, cancer prevention, claudication, cutaneous ulcers,
and collagen synthesis and wound healing.
3,4
Clearly, with
vitamin E not being a pharmaceutical, there is a lack of
placebo-controlled studies for treatment of these condi-
tions. However, in the field of skin care, which includes
cosmeceuticals, there is a large body of experimental evi-
dence pointing to photoprotective effects (Table 1). More-
over, recent studies indicate that the use of vitamin E may
provide dermatologic benefits that surpass the purpose of
Address correspondence and reprint requests to: Jens Thiele, MD,
Department of Dermatology, Northwestern University, Ward Build-
ing 9321, 303 East Chicago Avenue, Chicago, IL 60611, or e-mail:
j-thiele@northwestern.edu.
cosmetics and may extend into an area that has been
termed cosmeceuticals.
Although anecdotal reports support the topical use of
vitamin E for scar prevention, the benefit of vitamin E on
scar formation remains inconclusive. Two controlled stud-
ies failed to show scar prevention by topical vitamin E.
5,6
However, it remains unclear as to how far the stability and
formulation of topical vitamin E may have affected the
outcome of these studies. New evidence from studies on
diabetic mouse models point to an involvement of oxida-
tive stress in diabetic wound healing and significantly
improved wound healing by topical vitamin E.
7,8
Recently, Tsoureli-Nikita and colleagues performed a
clinical single-blind, placebo-controlled study in which 96
atopic dermatitis patients were treated with either placebo
or oral vitamin E (400 IE/d) for 8 months. They found an
improvement and near-remission of atopic dermatitis and
a 62% decrease in serum IgE levels in the vitamin
Etreated group. The correlation between -tocopherol
intake, immunoglobulin E levels, and the clinical manifes-
tations of atopy suggests that oral vitamin E could be an
excellent therapeutic adjunct for atopic dermatitis.
9
Another multiclinical double-blinded study revealed a sig-
nificant improvement of melasma and pigmented contact
dermatitis lesions using topical vitamins E and C, with the
combination clearly proving superior to the single-vitamin
treatment groups.
10
Topical formulations used for depig-
mentation that contain vitamins C and E, besides the com-
monly used hydroquinone and sunscreens, appear to be
safe and efficient.
11
Recent evidence suggests that oxida-
tive stress is involved in the pathophysiology of melanoma
and nonmelanoma cancer
12
and that vitamin E slows
melanoma growth by promoting tumor cell apoptosis and
inhibiting vascular endothelial growth factormediated
angiogenesis.
13,14
Despite these and other encouraging results on the ben-
eficial clinical effects of vitamin E, further research in the
form of well-designed controlled trials is needed to clar-
ify the role of vitamin E and its derivatives in the above-
mentioned and other skin disorders.
Mechanisms of Action
Vitamin E is among the earliest recognized biologic
antioxidants, and its redox and free radical chemistry are
well documented.
2
The major antioxidant role of vitamin
E is generally considered to be the arrest of chain propa-
gation by scavenging lipid peroxyl radicals. The initial oxi-
dation product of tocopherol is the metastable toco-
pheroxyl radical, which can be reduced to tocopherol by
coantioxidants or reacts with another lipid peroxyl radi-
cal, yielding tocopherol quinone.
15
Thus, one molecule of
tocopherol has the ability to scavenge two peroxyl radical
molecules. Because the physiologic molar ratio of toco-
pherols to polyunsaturated phospholipids is less than
about 1:1,000 in most biologic membranes, regeneration
of tocopherol is essential for its high antioxidant efficacy
in vivo. Several hydrophilic coantioxidants, such as ascor-
bate and glutathione, regenerate vitamin E from the toco-
pheroxyl radical and thus enhance the antioxidant capac-
ity of vitamin E.
16
Furthermore, there is some in vitro
evidence that ubiquinol 10 (coenzyme Q) protects
-tocopherol from photo-oxidation by recycling mecha-
nisms.
17
Consequently, the lack of such coantioxidants
from the antioxidant network may diminish the antioxi-
dant properties of vitamin E and result in limited antioxi-
dant protection of lipid bilayers or other lipophilic
domains. A series of studies investigating nonenzymatic
stratum corneum antioxidants have demonstrated that, in
human skin, vitamin E is the predominant physiologic bar-
rier antioxidant.
18
When compared with nucleated epider-
mal layers, there is a lack of important coantioxidants,
such as vitamin C, in the stratum corneum and in the der-
mis. Taken together, these findings suggest that the skin
barrier and the upper dermis reveal a lack of antioxidant
protection. In fact, on solar ultraviolet (UV) exposure,
these are the cutaneous sites exhibiting the most pro-
nounced oxidative protein damage.
19
Accordingly, antiox-
idant supplementation with vitamin E and synergistically
active coantioxidants, such as vitamin C, may enhance the
photoprotective strategies of sunscreens.
Photoprotection Provided by Vitamin E
The largest body of scientific evidence for a beneficial role
of topical vitamin E exists for photoprotection (Table 2).
Numerous topical studies have demonstrated that vitamin
E application prior to UV exposure significantly reduces
acute skin responses, such as erythema and edema, sun-
806 THIELE ET AL: USE OF VITAMIN E IN DERMATOLOGY Dermatol Surg 31:7 Part 2:July 2005
Figure 1. Chemical structure of tocopherols and tocotrienols. Tocopherols: : R
1
= R
2
= CH
3
, 430.7 g mol
1
; : R
1
= CH
3
, R
2
= H, 416.7 g mol
1
;
: R
1
= H, R
2
= CH
3
, 416.7 g mol
1
; : R
1
= R
2
= H, 402.7 g mol
1
. Tocotrienols: : R
1
= R
2
= CH
3
, 424.7 g mol
1
; : R
1
= CH
3
, R
2
= H, 410.6 g mol
1
;
: R
1
= H, R
2
= CH
3
, 410.6 g mol
1
; : R
1
= R
2
= H, 396.6 g mol
1
.
Dermatol Surg 31:7 Part 2:July 2005 THIELE ET AL: USE OF VITAMIN E IN DERMATOLOGY 807
Table 1. Studies on the Photoprotective Potential of Topical Vitamin E and Its Derivatives In Vivo
Compound(s) Species End Point(s) Efficacy Remarks Reference
Vitamin E, vitamin E Rabbit Erythema (MED) Vitamin E protective; BHT also protective; Roshchupkin et al,
acetate vitamin E acetate vitamin E also protective 1979
68
not protective when applied after UVR
exposure
Vitamin E Human Mechanoelectrical Protection against Potapenko et al,
properties of skin UVR- and 1983
69
PUVA-induced
damage
Vitamin E, Vitamin E Human, PUVA-induced Vitamin E and No protection of vitamin Potapenko et al,
derivatives with rabbit erythema and derivatives with E and derivatives when 1984
70
shorter hydrocarbon changes in shorter hydrocarbon applied after UVR
chains, vitamin E mechanoelectrical chain protective; exposure
acetate properties of skin vitamin E acetate
not protective
Vitamin E Mouse Lipid peroxidation Protective Vitamin A, BHT, and Khettab et al,
-carotene also 1988
23
protective
Vitamin E Mouse Skin wrinkling, skin Protective Bissett et al,
tumor incidence, 1989
31
and histology
Vitamin E Human Erythema (MED) Protective SPF determination Mller et al,
1989
71
Vitamin E, Trolox, Mouse Skin wrinkling and Vitamin E esters Glutathione, Bissett et al,
vitamin E acetate, sagging, skin tumor not as protective -carotene, BHT, 1990
32
vitamin E succinate incidence, and as vitamin E or and mannitol not
vitamin E linoleate, histology vitamin E analog protective
vitamin E nicotinate, Trolox; no protection
against UVA-induced
skin sagging
Vitamin E Mouse Skin tumor incidence Protective Prolonged pretreatment Gensler and
and immuno- Magdaleno,
suppression 1991
26
Vitamin E, Rat UVA-induced binding Vitamin E protective Limited conversion of Schoonderwoerd
vitamin E acetate of 8-MOP and CPZ after single vitamin E acetate into et al, 1991
28
to epidermal application; vitamin vitamin E after single
biomacromolecules E acetate protective application
only after prolonged
application
Vitamin E acetate Mouse Lipid peroxidation Protective Record et al,
and DNA synthesis 1991
36
rate
Vitamin E Mouse Skin wrinkling, skin Protective Additive protection in Bissett et al,
tumor incidence, and combination with 1992
30
histology anti-inflammatory
agents
Vitamin E acetate Mouse Erythema, edema, Protective Treatment immediately Trevithick et al,
and skin sensitivity after UVR exposure 1992
37
Vitamin E acetate Mouse Edema and histology Protective Delayed treatment after Trevithick et al,
UVR exposure; increased 1993
38
skin vitamin E
concentration
Vitamin E, Mouse Skin wrinkling Vitamin E and sorbate Sorbate ester more Jurkiewicz et al,
vitamin E acetate, ester protective; protective than free 1995
33
vitamin E sorbate vitamin E acetate vitamin E
ester only modestly
protective
continued on next page
808 THIELE ET AL: USE OF VITAMIN E IN DERMATOLOGY Dermatol Surg 31:7 Part 2:July 2005
Table 1. Studies on the Photoprotective Potential of Topical Vitamin E and Its Derivatives In Vivo (continued)
Compound(s) Species End Point(s) Efficacy Remarks Reference
Vitamin E, vitamin E Human Erythema (skin color) Moderate protection No protection when Montenegro et
acetate of vitamin E and applied occlusively before al, 1995
72
vitamin E acetate UVR exposure
when applied
occlusively after
UVR exposure
Vitamin E, Rat UVA-induced binding Vitamin E protective; Conversion of vitamin E Beijersbergen
vitamin E acetate of 8-MOP to vitamin E acetate acetate into vitamin E van Henegouwen
epidermal protective only after slow et al, 1995
27
biomacromolecules prolonged application
Vitamin E acetate, Mouse Skin tumor incidence No protection Gensler et al,
vitamin E succinate and 1996
73
immunosuppression
Vitamin E Yorkshire Sunburn cell Protection against Minimal protection in Darr et al, 1996
20
pig formation UVR-induced reducing PUVA-induced
damage damage
Vitamin E Mouse Immunosuppression Protective No protection when Yuen and Halliday,
and lipid applied after UVR 1997
24
peroxidation exposure
Vitamin E Mouse Histology (sunburn Protective Ritter et al,
cell formation and 1997
21
skin thickness)
Vitamin E, vitamin E Mouse Formation of Vitamin E derivatives Sunscreening properties McVean and ,
acetate, vitamin E DNA photoadducts less protective than of vitamin E Liebler 1997
74
methylether, vitamin E vitamin E
Mouse Chemiluminescence Protective -Carotene also Evelson et al,
after UVA exposure protective 1997
29
Vitamin E Mouse Formation of DNA Protective Chen et al,
photoadducts in 1997
epidermal p53
gene
75
Vitamin E Mouse Lipid peroxidation Protective Skins enzymatic and non- Lopez-Torres et al,
enzymatic antioxidant 1998
25
capacity investigated
Vitamin E Human Erythema (skin color Moderate protection No protection when Dreher et al,
and skin blood flow) applied after UVR 1999
76
exposure; SPF Dreher et al,
(determined in vitro) = 1 1998
77
Vitamin E, Mouse Formation of Vitamin E , Application as dispersion McVean and
-tocopherol, DNA-photoadducts -tocopherol in cream Liebler, 1999
78
-tocopherol, and -tocopherol
vitamin E acetate, protective; vitamin E
vitamin E methylether acetate and vitamin E
methylether not
protective
Vitamin E, vitamin E Mouse Erythema, Protective after No sign of toxicity Burke et al, 2000
34
succinate pigmentation, skin prolonged observed for vitamin E
tumor incidence application and vitamin E succinate
Vitamin E Human Formation of Protective with 5% Pretreatment of skin with Chung et al,
macrophage vitamin E occlusive 20% NAC also protective 2002
35
metalloelastase application for
mRNA after UVR 24 h prior UVR
exposure exposure
Vitamin E Yorkshire Antioxidant protection 1% vitamin E Appliction on 4 Lin et al, 2003
22
pig factor, erythema, protective but consecutive days
sunburn cells, stronger protection in
thymine dimers combination with 15%
vitamin C
BHT = butylated hydroxytoluene; CPZ = chlorpromazine; DNA = deoxyribonucleic acid; MED = minimal erythema dose; mRNA = messenger ribonucleic acid; 8-MOP
= 8-methoxypsoralen; NAC = N-acetylcysteine; PUVA = 8-methoxypsoralen and ultraviolet A treatment; SPF = sun protection factor; UVA = ultraviolet A; UVR = ultra-
violet radiation.
Dermatol Surg 31:7 Part 2:July 2005 THIELE ET AL: USE OF VITAMIN E IN DERMATOLOGY 809
burn cell formation,
2022
lipid peroxidation,
2325
deoxyri-
bonucleic acid (DNA) adduct formation, immunosuppres-
sion,
24,26
and ultraviolet A (UVA)-induced binding of pho-
tosensitizers
27,28
and chemiluminescence.
29
Chronic skin
reactions owing to prolonged ultraviolet B (UVB) or UVA
exposure, such as skin wrinkling,
3033
and skin tumor inci-
Table 2. Cosmetical Concentration of Use, Function, and Product Formulation Data of Vitamin E and Its Derivatives
Antioxidant Function as
Compound Concentration of Use (%) Function Skin-Conditioning Agent
Tocopherol Baby products: 1 Antioxidant; Occlusive; humectant;
Bath products/shampoo/rinse-off products: 0.010.8 humectant; emollient; miscellaneous
Deodorants: 0.05 skin protectant
Hair products: 0.010.6
Aftershave lotion: 0.2
Moisturizing preparations, creams, lotions, body/hand
ointments: 0.052
Suntan gels and creams: 0.0010.3
Makeup preparations (eg, liquids, eye shadows, lipsticks,
face powders, blushers, foundations): 0.0010.9
Tocopheryl Baby products: 0.0011 Antioxidant; Humectant; emollient;
acetate Bath products/shampoo/rinse-off products: 0.000125 humectant; miscellaneous
Deodorants: 0.2 skin protectant
Hair products: 0.0010.3
Aftershave lotion: 0.2
Moisturizing preparations, creams, lotions, body/hand
ointments: 0.00125
Suntan gels and creams: 0.051
Cosmetics (eg, makeup liquids, eye shadows, lipsticks, face
powders, blushers, foundations): 0.020.8
Tocopheryl Shaving cream: 2 Antioxidant Miscellaneous
linoleate
Tocopheryl Moisturizing preparations, creams, lotions, body/hand Antioxidant Emollient; miscellaneous
linoleate/oleate ointments: 0.12
Suntan gels and creams: 2
Cosmetics (eg, make up liquids, eye shadows, lipsticks, face
powders, blushers, foundations): 0.12
Tocopheryl Shampoo/rinse-off products: 0.00011 Antioxidant Miscellaneous
nicotinate Hair conditioner: 0.11
Aftershave lotion: 0.2
Moisturizing preparations, creams, lotions, body/hand
ointments: 0.1
Makeup preparations (eg, liquids, eye shadows, lipsticks,
face powders, blushers, foundations): 0.1
Potassium Moisturizing preparations, creams, lotions, body/hand Antioxidant Antidandruff agent
ascorbyl ointments: 0.02
tocopheryl Suntan gels and creams: 0.02
phosphate Makeup preparations (eg, liquids, eye shadows, lipsticks, face
powders, blushers, foundations): 0.02
Tocophersolan Moisturizing preparations, creams, lotions, body/hand Antioxidant
ointments: 0.2
Skin freshener: 0.05
Tocopheryl Use in food supplementation; 1 mg D--tocopheryl Antioxidant; Humectant; emollient
succinate succinate = 1.21 IU -tocopherol humectant; skin
protectant
According to data compiled by the Cosmetic, Toiletry, and Fragrance Association; modified after Zondlo Fiume M.
52
810 THIELE ET AL: USE OF VITAMIN E IN DERMATOLOGY Dermatol Surg 31:7 Part 2:July 2005
dence
26,3032,34
were also diminished by topical vitamin E
formulations. Although few studies have demonstrated a
significant penetration of topical vitamin E into dermal
layers, there is still debate concerning the efficacy of topi-
cal vitamin E for protecting dermal components in human
skin. Recently, Chung and colleagues demonstrated that a
topical, occlusive pretreatment with 5% vitamin E for 24
hours protected against UV-induced up-regulation of
human macrophage metalloelastase in human skin in
vivo.
35
Together with other studies,
25
this work suggests
that topically applied vitamin E has the potential to pene-
trate into dermal layers, where oxidative stress occurs,
19
and thus protects against photoaging.
Vitamin E esters, particularly vitamin E acetate, were
also shown to be promising agents in reducing ultraviolet
radiation (UVR)-induced skin damage.
27,28,3234,3638
How-
ever, their photoprotective effects appear to be less pro-
nounced compared with vitamin E; as a result, some stud-
ies failed to detect photoprotection provided by vitamin E
esters. Because the antioxidant properties of vitamin E are
attributed to its free aromatic hydroxyl group, vitamin E
esters need to be hydrolyzed during skin absorption to
show activity. Vitamin E acetate was shown to be
absorbed and to penetrate skin.
3941
For better stability,
vitamin E is commonly used as a biologically nonactive
esterified form, such as vitamin E acetate. Vitamin E esters
act as a prodrug because they are hydrolyzed to the active,
free vitamin E (-tocopherol) on penetration into skin.
However, there is conflicting evidence as to what extent
this conversion actually takes place in the stratum
corneum.
4245
Most studies suggest that in human stratum
corneum, the bioconversion of vitamin E esters into vita-
min E is far less than in nucleated epidermal layers. There-
fore, -tocopherol should provide a more efficient antiox-
idant protection of skin surface lipids and skin barrier
constituents than vitamin E esters. In the nucleated epi-
dermis, however, the bioconversion of vitamin E acetate
into vitamin E occurs at a much higher rate but seems to
be dependent on formulation.
45,46
Some evidence suggests
that the bioconversion of vitamin E acetate into vitamin E
might be enhanced owing to UVR exposure.
47
UVB expo-
sure was demonstrated to cause an increase in esterase
activity in murine epidermis.
47
In view of the vast experimental evidence for the photo-
protective properties of antioxidants, it was suggested that
the addition of synergistic coantioxidants, such as vitamins
C and E, may increase the photoprotective potential of
modern sunscreen formulations.
48
Indeed, recent reports
suggest that currently available broad-spectrum sunscreen
formulations, although efficient in preventing erythema
formation, poorly protect against UVA-induced free radical
formation in human skin.
49
Importantly, vitamin E acetate
and sodium ascorbyl phosophatate have been shown to be
bioconverted to vitamins E and C and thus to significantly
improve photoprotection of sunscreens against free radical
formation in viable epidermal layers.
50
Dosage and Practical Use
Although numerous topical skin care products claim to
contain vitamin E, these products may actually contain
very different concentrations and formulations, including
active vitamin E, its several esters, and many other deriv-
atives. Product formulation data submitted by the US
Food and Drug Administration in 1998 reported that -
tocopherol was present in 1,072 cosmetic formulations,
tocopheryl acetate in 1,322, tocopherol linoleate in 279,
tocopherol nicotinate in 3, tocopherol succinate in 4,
potassium ascorbyl tocopheryl phosphate in 15, and
tocophersolan in 2 formulations.
51
Although topical
-tocopherol is mostly used at concentrations of 5% or
less, products with concentrations of 0.0001% and more
than 20% vitamin E and/or vitamin E esters have been
developed and marketed in Europe and the United States.
According to data submitted to the Cosmetic, Toiletry,
and Fragrance Association, vitamin E acetate was used at
concentrations 36%, tocopherol linoleate and nicoti-
nate at 2% (the latter recommended at 0.1 to 1%),
dioleyl tocopheryl methylsilanol at 3 to 6%, potassium
ascorbyl tocopheryl phosphate at 0.02%, and tocopher-
solan at 0.2%.
52
Notably, there is a striking lack of published data on
dose-response studies defining the optimal dosage of vita-
min E. This could certainly be due to limited-efficacy con-
trol requirements for nonpharmaceuticals, such as vitamin
E. Furthermore, it may also be attributed to ill-defined
study end points and to the difficulty of measuring oxida-
tive stress in vivo. Recent advances in biophysical (eg,
ultraweak photon emission; near-infrared/Raman spec-
troscopy; electron paramagnetic resonance
53
) and bio-
chemical research (eg, the recent identification of highly
sensitive and specific skin surface lipid photo-oxidation
products/squalene monohydroperoxide
54
) have led to the
development of noninvasive assays (eg, the sebum photo-
oxidation test
55
) that will help better define relevant dose-
response curves of antioxidants such as vitamin E.
Using this approach, we recently demonstrated that
even the use of rinse-off products containing -tocopherol
in concentrations of less than 0.2% leads to significantly
increased levels of vitamin E in the stratum corneum of
human skin and protects against lipid peroxidation in
vivo.
56
Therefore, if the product claim is improved antiox-
idant protection of the skin barrier, topical formulations
with -tocopherol at concentrations ranging from 0.1 to
1% are likely to be effective. According to the antioxidant
network theory outlined earlier, combinations with coan-
tioxidants such as vitamin C may help enhance the
antioxidant effects and stability of vitamin E.
Cautions, Contraindications, and Adverse
Effects
Although vitamin E and its derivatives are widely used in
many topical cosmetic products, reports of side effects, such
as allergic or irritant skin reactions, are rare. In clinical stud-
ies, tocopherol and tocopherol acetate were found to be safe
for use in topical skin formulations because irritant or sen-
sitizing reactions were found only in very small percentages.
With respect to oral supplementation, reproductive and
developmental toxicity tests in animals using tocopherol
and many of its derivatives were overwhelmingly negative
or even showed some effect of reducing toxicity (reviewed
in Zondlo Fiume
52
). In case reports, however, clinical side
effects have been described after topical application of vita-
min Econtaining products, for example, local and general-
ized contact dermatitis, contact urticaria, and erythema
multiformelike eruptions.
57
In 1992, an epidemic out-
break of approximately 1,000 cases of allergic papular and
follicular contact dermatitis caused by -tocopherol
linoleate in a cosmetic line was reported in Switzerland.
58
The authors found that this compound was easily oxidized
under the storage condition used. Therefore, secondary or
tertiary oxidation products of -tocopherol linoleate, rather
than the reduced vitamin E ester, are likely to have caused
irritation or even the oxidation of proteins and subsequent
hapten formation. Positive patch test reactions were also
reported in several cases after application of -tocopherol
acetate.
59,60
In general, however, positive patch test results
owing to -tocopherol are rare and need to be critically
reviewed. Some authors of case reports have used the oil of
vitamin E capsules for patch testing assuming to test pure
vitamin E without evaluating the containing tocopherol
derivatives, source, or further components of these cap-
sules.
61,62
After correspondence with the manufacturer, some
authors could not exclude the fact that the symptoms of
their patients could have been caused by soybean oil, glyc-
erin, or gelatin, which were all also present in the accused
topically applied vitamin E capsules.
62
Some animal studies
even suggest that topical vitamin E at a concentration of
20% suppressed allergic and irritant contact dermatitis,
exerting an effect comparable to that of a 0.5% pred-
nisolone ointment. Furthermore, this vitamin E formulation
protected efficiently from contact dermatitisinduced loss of
skin barrier function.
63
Oral vitamin E doses between 50 and 1,000 IU/d have
been tolerated in humans with no or minimal side effects.
Vitamin E supplements for pregnancy usually contain
small doses of vitamin E, although adverse effects have
not been observed even at higher doses.
64
Theoretically,
however, owing to the involvement of the cytochrome P-
450 system in the metabolism of orally supplemented
RRR--tocopherol, drug interactions must be taken into
account when supranutritional dosages of vitamin E are
provided. Because tocopherols and their oxidation prod-
ucts are able to inhibit platelet aggregation, simultaneous
supplementation of anticoagulants and vitamin E is not
recommended.
64
Current Research
As indicated above, topical strategies alone may not be suf-
ficient to bolster the skins antioxidative defense in the der-
mis and thus prevent or lessen photoaging in this skin com-
partment. Therefore, current research on vitamin E focuses
on systemic delivery of vitamin E to the various compart-
ments of human skin. It was recently discovered that human
sebum contains high amounts of -tocopherol and that
sebaceous gland secretion is a relevant physiologic delivery
pathway of -tocopherol to sebaceous glandrich skin
regions, such as facial skin.
65
Similarly, orally administered
drugs have been reported to be transported to the skin sur-
face and stratum corneum by the sebaceous gland secretion
route.
66
Ongoing studies investigate the relevance and time
course of this delivery pathway for increasing the levels of
vitamin E in human skin.
67
If relevant, this mechanism
would have implications for conditions of sebostatic, dry
skin (eg, atopic dermatitis) and for the skin of prepubertal
children, who have a low activity of sebaceous glands.
References
1. Maras JE, Bermudez OI, Qiao N, et al. Intake of alpha-tocopherol is
limited among US adults. J Am Diet Assoc 2004;104:56775.
2. Traber MG, Sies H. Vitamin E in humans: demand and delivery.
Annu Rev Nutr 1996;16:32147.
3. Fuchs J. Oxidative injury in dermatopathology. Berlin: Springer;
1992.
4. Pehr K, Forsey RR. Why dont we use vitamin E in dermatology? Can
Med Assoc J 1993;149:124753.
5. Baumann LS, Spencer J. The effects of topical vitamin E on the cos-
metic appearance of scars. Dermatol Surg 1999;25:3115.
6. Jenkins M, Alexander JW, MacMillan BG, et al. Failure of topical
steroids and vitamin E to reduce postoperative scar formation fol-
lowing reconstructive surgery. J Burn Care Rehabil 1986;7:30912.
7. Galeano M, Torre V, Deodato B, et al. Raxofelast, a hydrophilic vita-
min E-like antioxidant, stimulates wound healing in genetically dia-
betic mice. Surgery 2001;129:46777.
8. Altavilla D, Saitta A, Cucinotta D, et al. Inhibition of lipid peroxi-
dation restores impaired vascular endothelial growth factor expres-
sion and stimulates wound healing and angiogenesis in the geneti-
cally diabetic mouse. Diabetes 2001;50:66774.
9. Tsoureli-Nikita E, Hercogova J, Lotti T, Menchini G. Evaluation of
dietary intake of vitamin E in the treatment of atopic dermatitis: a
study of the clinical course and evaluation of the immunoglobulin E
serum levels. Int J Dermatol 2002;41:14650.
10. Hayakawa R, Ueda H, Nozaki T, et al. Effects of combination treat-
ment with vitamins E and C on chloasma and pigmented contact der-
matitis. A double blind controlled clinical trial. Acta Vitaminol Enzy-
mol 1981;3:318.
11. Guevara IL, Pandya AG. Safety and efficacy of 4% hydroquinone
combined with 10% glycolic acid, antioxidants, and sunscreen in the
treatment of melasma. Int J Dermatol 2003;42:96672.
12. Sander CS, Hamm F, Elsner P, Thiele JJ. Oxidative stress in malignant
melanoma and non-melanoma skin cancer. Br J Dermatol
2003;148:91322.
Dermatol Surg 31:7 Part 2:July 2005 THIELE ET AL: USE OF VITAMIN E IN DERMATOLOGY 811
13. Malafa MP, Fokum FD, Smith L, Louis A. Inhibition of angiogenesis
and promotion of melanoma dormancy by vitamin E succinate. Ann
Surg Oncol 2002;9:102332.
14. Malafa MP, Fokum FD, Mowlavi A, et al. Vitamin E inhibits
melanoma growth in mice. Surgery 2002;131:8591.
15. Kamal-Eldin A, Appelqvist LA. The chemistry and antioxidant prop-
erties of tocopherols and tocotrienols. Lipids 1996;31:671701.
16. Packer JE, Slater TF, Willson RL. Direct observation of a free radical
interaction between vitamin E and vitamin C. Nature 1979;278:7378.
17. Stoyanovsky DA, Osipov AN, Quinn PJ, Kagan VE. Ubiquinone-
dependent recycling of vitamin E radicals by superoxide. Arch
Biochem Biophys 1995;323:34351.
18. Thiele JJ, Schroeter C, Hsieh SN, et al. The antioxidant network of
the stratum corneum. Curr Probl Dermatol 2001;29:2642.
19. Sander CS, Chang H, Salzmann S, et al. Photoaging is associated with
protein oxidation in human skin in vivo. J Invest Dermatol
2002;118:61825.
20. Darr D, Dunston S, Faust H, Pinnell S. Effectiveness of antioxidants
(vitamin C and E) with and without sunscreens as topical photopro-
tectants. Acta Dermatol Venereol 1996;76:2648.
21. Ritter EF, Axelrod M, Minn KW, et al. Modulation of ultraviolet
light-induced epidermal damage: beneficial effects of tocopherol.
Plast Reconstr Surg 1997;100:97380.
22. Lin JY, Selim MA, Shea CR, et al. UV photoprotection by combina-
tion topical antioxidants vitamin C and vitamin E. J Am Acad Der-
matol 2003;48:86674.
23. Khettab N, Amory MC, Briand G, et al. Photoprotective effect of
vitamins A and E on polyamine and oxygenated free radical metab-
olism in hairless mouse epidermis. Biochimie 1988;70:170913.
24. Yuen KS, Halliday GM. Alpha-tocopherol, an inhibitor of epidermal
lipid peroxidation, prevents ultraviolet radiation from suppressing
the skin immune system. Photochem Photobiol 1997;65:58792.
25. Lopez-Torres M, Thiele JJ, Shindo Y, et al. Topical application of
alpha-tocopherol modulates the antioxidant network and diminishes
ultraviolet-induced oxidative damage in murine skin. Br J Dermatol
1998;138:20715.
26. Gensler HL, Magdaleno M. Topical vitamin E inhibition of immuno-
suppression and tumorigenesis induced by ultraviolet radiation. Nutr
Cancer 1991;15:97106.
27. Beijersbergen van Henegouwen GMJ, Junginger HE, de Vries H.
Hydrolysis of RRR--tocopheryl acetate (vitamin E acetate) in the
skin and its UV protecting activity (an in vivo study with the rat). J
Photochem Photobiol B Biol 1995;29:4551.
28. Schoonderwoerd SA, Beijersbergen van Henegouwen GMJ, Persons
KCM. Effect of alpha-tocopherol and di-butyl-hydroxytoluene
(BHT) on UV-A-induced photobinding of 8-methoxypsoralen to Wis-
tar rat epidermal biomacromolecules in vivo. Arch Toxicol
1991;65:4904.
29. Evelson P, Ordez CP, Llesuy S, Boveris A. Oxidative stress and in
vivo chemiluminescence in mouse skin exposed to UVA radiation.
Photochem Photobiol B Biol 1997;38:2159.
30. Bissett DL, Chatterjee R, Hannon DP. Protective effect of a topically
applied anti-oxidant plus an anti-inflammatory agent against ultra-
violet radiation-induced chronic skin damage in the hairless mouse.
J Soc Cosmet Chem 1992;43:8592.
31. Bissett DL, Hillebrand GG, Hannon DP. The hairless mouse as a
model of skin photoaging: its use to evaluate photoprotective mate-
rials. Photodermatology 1989;6:22833.
32. Bissett DL, Chatterjee R, Hannon DP. Photoprotective effect of
superoxide-scavenging antioxidants against ultraviolet radiation-
induced chronic skin damage in the hairless mouse. Photodermatol
Photoimmunol Photomed 1990;7:5662.
33. Jurkiewicz BA, Bissett DL, Buettner GR. Effect of topically applied
tocopherol on ultraviolet radiation-mediated free radical damage in
skin. J Invest Dermatol 1995;104:4848.
34. Burke KE, Clive J, Combs GF Jr, et al. Effects of topical and oral vita-
min E on pigmentation and skin cancer induced by ultraviolet irra-
diation in Skh: 2 hairless mice. Nutr Cancer 2000;38:8797.
35. Chung JH, Seo JY, Lee MK, et al. Ultraviolet modulation of human
macrophage metalloelastase in human skin in vivo. J Invest Derma-
tol 2002;119:50712.
36. Record IR, Dreosti IE, Konstantinopoulos M, Buckley RA. The influ-
ence of topical and systemic vitamin E on ultraviolet light-induced
skin damage in hairless mice. Nutr Cancer 1991;16:21926.
37. Trevithick JR, Xiong H, Lee S, et al. Topical tocopherol acetate
reduces post-UVB, sunburn-associated erythema, edema, and skin
sensitivity in hairless mice. Arch Biochem Biophys 1992;296:57582.
38. Trevithick JR, Shum DT, Redae S, et al. Reduction of sunburn dam-
age to skin by topical application of vitamin E acetate following
exposure to ultraviolet B radiation: effect of delaying application or
of reducing concentration of vitamin E acetate applied. Scan Microsc
1993;7:126981.
39. Kamimura M, Matsuzawa T. Percutaneous absorption of -tocopheryl
acetate. Vitaminology 1968;14:1519.
40. Norkus EP, Bryce GF, Bhagavan HN. Uptake and bioconversion of
-tocopheryl acetate to -tocopherol in skin of hairless mice. Pho-
tochem Photobiol 1993;57:6135.
41. Trevithick JR, Mitton KP. Topical application and uptake of vitamin
E acetate by the skin conversion to free vitamin E. Biochem Mol Biol
Int 1993;31:86978.
42. Alberts DS, Goldman R, Xu MJ, et al. Disposition and metabolism
of topically administered -tocopherol acetate: a common ingredient
of commercially available sunscreens and cosmetics. Nutr Cancer
1996;26:193201.
43. Nabi Z, Tavakkol A, Dobke M, Polefka TG. Bioconversion of vita-
min E acetate in human skin. Curr Probl Dermatol 2001;29:17586.
44. Rangarajan M, Zatz JL. Kinetics of permeation and metabolism of
alpha-tocopherol and alpha-tocopheryl acetate in micro-Yucatan pig
skin. J Cosmet Sci 2001;52:3550.
45. Baschong W, Artmann C, Hueglin D, Roeding J. Direct evidence for
bioconversion of vitamin E acetate into vitamin E: an ex vivo study
in viable human skin. J Cosmet Sci 2001;52:15561.
46. Rangarajan M, Zatz JL. Effect of formulation on the delivery and
metabolism of alpha-tocopheryl acetate. J Cosmet Sci
2001;52:22536.
47. Kramer-Stickland K, Liebler DC. Effect of UVB on hydrolysis of
alpha-tocopherol acetate to alpha-tocopherol in mouse skin. J Invest
Dermatol 1998;111:3027.
48. Thiele JJ, Dreher F, Packer L. Antioxidant defense systems in skin. In:
Elsner P, Maibach H, editors. Drugs vs. cosmetics: cosmeceuticals?
New York: Marcel Dekker; 2000. p. 14588.
49. Haywood R, Wardman P, Sanders R, Linge C. Sunscreens inade-
quately protect against ultraviolet-A-induced free radicals in skin:
implications for skin aging and melanoma? J Invest Dermatol
2003;121:8628.
50. Hanson KM, Clegg RM. Bioconvertible vitamin antioxidants
improve sunscreen photoprotection against UV-induced reactive oxy-
gen species. J Cosmet Sci 2003;54:58998.
51. US Food and Drug Administration. Frequency of use of cosmetic
ingredients. In: FDA database. Washington (DC): Food and Drug
Administration; 1998.
52. Zondlo Fiume M. Final report on the safety assessment of toco-
pherol, tocopheryl acetate, tocopheryl linoleate, tocopheryl
linoleate/oleate, tocopheryl nicotinate, tocopheryl succinate, dioleyl
tocopheryl methylsilanol, potassium ascorbyl tocopheryl phosphate,
and tocophersolan. Int J Toxicol 2002;21 Suppl 3:51116.
53. Fuchs J, Groth N, Herrling T. In vivo measurement of oxidative stress
status in human skin. Methods Enzymol 2002;352:3339.
54. Ekanayake Mudiyanselage S, Hamburger M, Elsner P, Thiele JJ.
Ultraviolet A induces generation of squalene monohydroperoxide
812 THIELE ET AL: USE OF VITAMIN E IN DERMATOLOGY Dermatol Surg 31:7 Part 2:July 2005
Dermatol Surg 31:7 Part 2:July 2005 THIELE ET AL: USE OF VITAMIN E IN DERMATOLOGY 813
isomers in human sebum and skin surface lipids in vitro and in vivo.
J Invest Dermatol 2003;120:91522.
55. Ekanayake Mudiyanselage S, Elsner P, Thiele JJ. UVA and UVB
induce depletion of vitamin E and generation of a highly sensitive
lipid photooxidation product in human sebum: basis for a new pho-
totoxicity test: SPT. J Invest Dermatol 2002;119:331A.
56. Ekanayake-Mudiyanselage S, Tavakkol A, Polefka TG, et al. Vitamin
E delivery to human skin by a rinse-off product: penetration of alpha-
tocopherol versus wash-out effects of skin surface lipids. Skin Pharm
Physiol 2005;18:206.
57. Brodkin RH, Bleiberg J. Sensitivity to topically applied vitamin E.
Arch Dermatol 1965;92:767.
58. Perrenoud D, Homberger HP, Auderset PC, et al, Swiss Contact Der-
matitis Research Group. An epidemic outbreak of papular and fol-
licular contact dermatitis to tocopheryl linoleate in cosmetics. Der-
matology (Basel) 1994;189:22533.
59. De Groot AC, Berretty PJ, van Ginkel CJ, et al. Allergic contact der-
matitis from tocopheryl acetate in cosmetic creams. Contact Der-
matitis 1991;25:3024.
60. Manzano D, Aguirre A, Gardeazabal J, et al. Allergic contact der-
matitis from tocopheryl acetate (vitamin E) and retinol palmitate
(vitamin A) in a moisturizing cream. Contact Dermatitis 1994;31:324.
61. Fisher AA. Three faces of vitamin E topical allergy. Cutis
1991;48:2724.
62. Harris BD, Taylor JS. Contact allergy to vitamin E capsules: false
negative patch tests to vitamin E. Contact Dermatitis 1997;36:273.
63. Kuriyama K, Shimizu T, Horiguchi T, et al. Vitamin E ointment at
high dose levels suppresses contact dermatitis in rats by stabilizing
keratinocytes. Inflamm Res 2002;51:4839.
64. Brigelius-Flohe R, Kelly FJ, Salonen JT, et al. The European perspec-
tive on vitamin E: current knowledge and future research. Am J Clin
Nutr 2002;76:70316.
65. Thiele JJ, Weber SU, Packer L. Sebaceous gland secretion is a major
physiologic route of vitamin E delivery to skin. J Invest Dermatol
1999;113:100610.
66. Faergemann J, Godleski J, Laufen H, Liss RH. Intracutaneous trans-
port of orally administered fluconazole to the stratum corneum. Acta
Derm Venereol 1995;75:3613.
67. Ekanayake Mudiyanselage S, Kraemer K, Thiele JJ. Dietary supple-
mentation with 400mg vitamin E: delayed bioavailability in human
skin and preferential accumulation of alpha-tocopherol in human
sebum [abstract]. J Invest Dermatol 2004;122:324.
68. Roshchupkin DI, Pistsov MY, Potapenko AY. Inhibition of ultravio-
let light-induced erythema by antioxidants. Arch Dermatol Res
1979;266:914.
69. Potapenko AJ, Piszov MJ, Abijev GA, Pliquett F. -Tokopherol, ein
Inhibitor von durch UV-Strahlung induzierten Veranderungen
mechanoelektrischer Hauteigenschaften. Dermatol Monatsschr
1983;169:3004.
70. Potapenko AY, Abijev GA, Pistsov MY, et al. PUVA-induced ery-
thema and changes in mechanoelectrical properties of skin. Inhibi-
tion by tocopherols. Arch Dermatol Res 1984;276:126.
71. Mller H, Ansmann A, Wallat S. Wirkungen von Vitamin E auf die
Haut bei topischer Anwendung. Fat Sci Technol 1989;91:295305.
72. Montenegro L, Bonina F, Rigano L, et al. Protective effect evaluation
of free radical scavengers on UVB induced human cutaneous ery-
thema by skin reflectance spectrophotometry. Int J Cosmet Sci
1995;17:91103.
73. Gensler HL, Aickin M, Peng YM, Xu M. Importance of the form of
topical vitamin E for prevention of photocarcinogenesis. Nutr Can-
cer 1996;26:18391.
74. McVean M, Liebler DC. Inhibition of UVB induced DNA photo-
damage in mouse epidermis by topically applied alpha-tocopherol.
Carcinogenesis 1997;18:161722.
75. Chen W, Barthelman M, Martinez J, et al. Inhibition of cyclobutane
pyramidine dimer formation in epidermal p 53 gene of UV-irradiated
mice by alpha-tocopherol. Nutr Cancer 1997;29:20511.
76. Dreher F, Denig N, Gabard B, et al. Effect of topical antioxidants on
UV-induced erythema formation when administered after exposure.
Dermatology 1999;198:525.
77. Dreher F, Gabard B, Schwindt DA, Maibach HI. Topical melatonin
in combination with vitamins E and C protects skin from UV-induced
erythema: a human study in vivo. Br J Dermatol 1998;139:3329.
78. McVean M, Liebler DC. Prevention of DNA photodamage by vita-
min E compounds and sunscreens: roles of ultraviolet absorbance
and cellular uptake. Mol Carcinog 1999;24:16976.
Commentary
Vitamin E is one of the most popular antioxidants in the world.
Antioxidants prevent damage to cells by absorbing free radicals.
Some studies suggest that vitamin E can help prevent the early
stages of cancer by preventing deoxyribonucleic acid (DNA)
damage, but people take it in the hope that it will ward off
almost every disease. The authors have given a complete analy-
sis of the controversial use of vitamin E in both topical and oral
forms. The public reaction to this vitamin over the years has
been guided by gut reaction, as well as the hope springs eternal
attitude. Recently, there has been a suggestion that oral adminis-
tration in large doses of 400 IU or more may be responsible for
sudden death.
1
It is important for the dermatologic surgeon to be
able to caution patients by noting the inhibition of platelet aggre-
gation during surgery and knowing the theoretical reactions on
the molecular level.
HAROLD J. BRODY, MD
Atlanta, GA
Reference
1. Guallar E. Vitamin E warning sounded. Annals of Internal Medicine
Web site. Available at: www.acponline.org/journals/annals/vit_e.htm
(accessed Nov. 10, 2004).