Asia Pacific J Clin
Nutr (1997) 6(1): 63-67
and topically applied tocotrienols accumulate in skin and protect
the tissue against ultraviolet light-induced oxidative stress
Maret G Traber, Maurizio Podda, Christine
Weber, Jens Thiele, Michalis Rallis, Lester Packer
Dept. Molecular and Cell Biology,
University of California, Berkeley
To evaluate the tissue-specific distribution of
lipophilic antioxidants including various vitamin E forms (tocotrienols
and tocopherols) and oxidised and reduced coenzyme Q (ubiquinone
and ubiquinol), a sensitive procedure was developed using gradient
HPLC with both electrochemical- and UV-detection. A unique distribution
of these antioxidants in hairless mouse tissues was found, suggesting
that their distribution may be dependent upon selective mechanisms
for maintaining antioxidant defences. Ubiquinol-9 was highest in
kidney (81 ± 29 nmol/g) and in liver (42 ± 16 nmol/g), while the
highest ubiquinone-9 concentrations were found in kidney (301 ±
123 nmol/g) and heart (244 ± 22 nmol/g). Liver contained nearly
identical amounts of each ubiquinol-9 (41 ± 16 nmol/g) and ubiquinone-9
(46 ± 18 nmol/g). These mice were fed a commercial chow diet containing
a-tocopherol (30 ± 6 mg/kg diet), g-tocopherol (10 ± 1), a-tocotrienol (3.1 ± 0.7) and g-tocotrienol (7.4 ± 1.7). Of the vitamin E forms, brain contained
only a-tocopherol (5.4 ± 0.1 nmol/g; 99.8%) and no detectable tocotrienols.
In other tissues, the a-tocopherol content was higher
(20 nmol/g), while each of the other forms represented about 1 %
of the total (g-tocopherol 0.2 to 0.4 nmol/g, a-tocotrienol 0.1, g-tocotrienol 0.2). Remarkably, skin contained
nearly 15% tocotrienols and 1% g-tocopherol. The unique distribution
of tocotrienols in skin suggested that they might have superior
protection against environment stressors. Therefore, the penetration
of topically applied vitamin E (tocotrienol enriched fraction of
palm oil, TRF) and vitamin E homologue concentrations before and
after exposure of skin to UV-light was assessed. 20 mL of 5% TRF in polyethylene
glycol-400 (PEG) was applied to 2 skin sites and 20 mL
PEG to 2 other sites. After 2 h, the skin was washed and half of
the sites exposed to UV-irradiation using a solar simulator (2.8
mW/cm2 for 29 min). The vitamin E content of hairless
mouse skin was: a-tocopherol 9.0 ± 1.0 nmol/g skin, g-tocopherol 0.44 ± 0.03, a-tocotrienol 0.48 ± 0.07, g-tocotrienol 0.92 ± 0.03. Topical TRF enriched skin vitamin E: a-tocopherol 201 ± 70 nmol/g skin, g-tocopherol 37 ± 15, a-tocotrienol 53 ± 25, and g-tocotrienol 50 ± 24. After UV-irradiation,
concentrations of all vitamin E homologues from both treatment areas
decreased significantly (p<0.01), but the TRF-treated skin contained
vitamin E at concentrations 7- to 30-fold higher than control values.
These findings provide provocative clues on the uptake and regulation
of tissue lipophilic antioxidants. The unique distribution of these
antioxidant substances suggests their distribution may be dependent
upon tissue-specific selective mechanisms.
The major lipophilic antioxidant in plasma, membranes
and tissues is vitamin E1. Vitamin E is the collective
name for the 8 naturally occurring molecules (4 tocopherols and 4
tocotrienols), which exhibit vitamin E activity. Tocotrienols differ
from tocopherols in that they have an isoprenoid instead of a phytyl
side chain; the 4 forms of tocopherols and tocotrienols differ in
the number of methyl groups on the chromanol nucleus (a- has 3, b and g have 2, while d has 1). Coenzyme Q (Q; reduced
form: ubiquinol, oxidised form: ubiquinone) also may play an anti-oxidant
role in membranes2,3. Indeed, ubiquinol protects against
lipid peroxidation more efficiently than a-tocopherol
in low density lipoproteins4-6.
A very sensitive method of detection is required for
the quantitation of each of these lipophilic antioxidants to determine
their roles in protecting tissues against oxidative damage. We developed
such a method for the simultaneous determination of individual tocopherols,
tocotrienols, ubiquinols and ubiquinones7 and measured
these lipophilic antioxidants in several mouse tissues, including
liver, kidney, heart, brain and skin7.
Skin, the outermost barrier of the body, is exposed
to oxidative stress from a variety of environmental insults. This
oxidative damage is likely an important factor in the pathogenesis
of skin cancer and photoaging8-12. Among the protective
agents in skin are the potent lipid soluble antioxidants, vitamin
E and ubiquinol9,13-15. During oxidative stress caused
by prolonged UV-exposure, skin antioxidants are severely diminished
resulting in insufficient protection and cell damage15-17.
Topical application of vitamin E may provide an efficient
way of enriching the skin with different forms of vitamin E that have
a potentially higher antioxidative activity than a-tocopherol.
There-fore, we measured the skin penetration of a mixture of tocopherols
and tocotrienols from a tocotrienol-rich palm oil fraction (TRF),
and evaluated the protection conferred by these various forms of vitamin
E against UV-light induced oxidative stressl8.
This paper reviews our recent findings concerning
the tissue distribution of vitamin E homologues in hairless mouse
tissues. We also present our findings on the protective effects of
topically applied TRF to hairless mouse skin.
Highest purity solvents and reagents were used. Tocopherol
standards (Covitol) were from Henkel Corporation (LaGrange, IL). TRF
was kindly provided by Palm Oil Research Institute of Malaysia (PORIM
Kuala Lumpur, Malaysia). Tocotrienols for use as standards were purified
from TRF by Dr Asaf A Qureshi, University of Wisconsin (Madison, WI).
Ubiquinone-9 and 10 standards were a gift from Nisshin Flour Milling
Co, Ltd (Tokyo, Japan).
Handling and housing. Experimental procedures for animal handling were approved by the Animal
Care and Use Committee of the University of California, Berkeley.
Female hairless mice (SKH1, 8-12 weeks old) were purchased from Charles
River Laboratories (Wilmington, MA, USA) and were kept under standard
light and temperature conditions. Food (Harlan Teklad Rodent Diet
8656, WI, USA) and water were provided ad libitum. Tissues were obtained
from three mice, which were anaesthetised and killed by cervical dislocation.
TRF application to skin. Mice were anaesthetised by an intraperitoneal injection of sodium pentobarbital
(50 mg/kg body weight) and remained anaesthetised during the entire
experimental period. Four polypropylene plastic rings (1 cm2)
were glued onto the animals backs, then 20 mL of a 5% w/v mixture containing TRF in polyethylene
glycol-400 (PEG; Sigma, St. Louis, MO). TRF was applied to the skin
circumscribed by 2 rings or PEG alone to the other 2 rings. After
2 hours, the skin was washed as described by Dupuis et al19,
the position of the application site was marked, the plastic rings
removed, and the mice exposed to UV-irradiation. Skin studies were
carried out in 19 mice18.
UV-irradiation. The mice were placed under an Oriel 1000W solar simulator (Oriel, Stratford,
CT) with an output of 2.8 mW/cm2 of UVA and UVB light (290-400
nm) and irradiated for 29 minutes (corresponding to 3 MED) on either
the upper or lower back, while the other part was shielded from UV-light
by covering the unexposed regions of the skin with paper and aluminium
foil. After exposure, the mice were killed by neck dislocation, and
the skin with subcutaneous fat were excised from the 4 exposure sites
and the samples immediately frozen in liquid nitrogen. All tissues
were extracted as described by Burton et al20, with
the exception of skin and diet samples, which were handled as described7.
Figure 1. Percent distribution of a-tocopherol, g-tocopherol, a-tocotrienol, and g-tocotrienol in various hairless
The fraction of the total vitamin E represented by each of the various
vitamin E homologues is shown. Mice were fed chow diets.
The details of the method are reported elsewhere7.
The HPLC system consisted of a Hewlett Packard 1050 series gradient
pump, a SCL-1OA Shimadzu system controller with a SILIOA autoinjector
with sample cooler, a Beckman Ultrasphere ODS C-18 column, a Hewlett
Packard 1050 diode array detector and an Bioanalytical Systems LC-4B
amperometric electrochemical detector with a glassy carbon electrode
(0.5 V potential, full recorder scale at 50 nA). The detectors were
setup in line, the eluent passing first through the diode array detector
(275 nm). The mobile phase consisted of a mixture of A (80/20 v/v
methanol/water and 0.2 percent w/v lithium perchlorate) and B (ethanol,
reagent grade with 0.2 percent w/v lithium perchlorate) at a flow
rate of 1 mL/min. The initial composition was 61% B and 39% A, after
16 minutes the mobile phase was changed linearly over a 2 min. to
100% B, which was continued for 10 min., then was changed linearly
over a 2 min. to the initial composition; total run time was 40 minutes.
Quantitation was carried out by comparison of peak
areas to the area of standard curves obtained with authentic compounds.
For vitamin E, a- and g-tocopherols were used as standards because the chromanol nucleus is
the same in a-tocopherol and a-tocotrienol, and in g-tocopherol
Evaluation of statistical significance was carried
out using SuperAnova for the Macintosh (Berkeley, CA). A p-value <0.05
was considered statistically significant.
Vitamin E homologue concentrations were measured in
various mouse tissues and in diet. In all tissues, a-tocopherol was the major form of
vitamin E. As shown in Figure 1, the brain contains 99.8% a-tocopherol,
while skin contains nearly 15% tocotrienols and 1% g-tocopherol. The associated subdermal
fat was not the source of these vitamin E forms because in skin samples
which had the fat removed, the tocotrienol concentrations were actually
higher (compare skin with skin and subcutis). In other tissues (heart,
kidney, liver), each of these forms represents about 1% of the total.
The diet contained a-tocopherol (29.7 ± 6.2 mg/kg diet), g-tocopherol (10.3 ± 1.1), a-tocotrienol (3.1 ± 0.7) and g-tocotrienol
(7.4 ± 1.7). It is likely that the tocotrienols found in mouse skin
arise from the relatively low concentrations present in the diet.
Ubiquinol concentrations were highest in kidney (81
± 29 nmol/g) and in liver (42 ± 16 nmol/g). The liver was unique in
that ubiquinol-9 (42 ± 16) and ubiquinone-9 (46 ± 18) concen-trations
were nearly identical. Skin and brain had similar concen-trations
of both ubiquinols (2.2 ± 0.3 and 1.6 ± 0.1, respectively) and ubiquinone
9 (7.6 ± 1.9 and 10.2 ± 0.5, respectively); with ubiquinols representing
around 20% of the total coenzyme Q. The highest ubiquinone-9 concentrations
were found in heart (245 ± 22) and kidney (302 ± 124), which contain
5 to 10-fold higher amounts than did the other tissues. These ubiquinone
concentrations were far greater than their respective ubiquinol concentrations.
absorption of tocopherols and tocotrienols following topical application
TRF treatment resulted in significant increases in
vitamin E concentrations; fractional increases were greater in those
forms which were present at low initial concentrations. Thus, TRF-treatment
resulted in a 28 ± 16-fold increase in a-tocopherol, a 80 ± 50-fold increase
in a-tocotrienol, a 130 ± 108-fold increase in g-tocopherol and a 51± 36-fold increase
in g-tocotrienol in the skin.
To evaluate the protection by vitamin E against oxidative
damage caused by UV-irradiation, the concentrations of the various
vitamin E forms present in the tissue before and after UV-irradiation
were measured (Figure 2). After UV-irradiation, the concentrations
of all forms of vitamin E in the PEG treated-skin decreased significantly
(all least square mean comparisons were p<0.01, except p<0.04
for g-tocopherol; Figure 2, left). They
also decreased significantly (p<0.001) after UV-irradiation as
compared with non-irradiated in the TRF-treated skin (Figure 2, right).
Notably, after UV-irradiation, the vitamin E homologue concentrations
were significantly higher in the TRF-treated, irrad-iated skin than
in the PEG-treated, non-irradiated skin (p<0.01).
To evaluate whether the decrease in vitamin E forms
in the TRF-treated samples was due to direct photodestruction of vitamin
E, the effect of UV-irradiation of the TRF solution was determined
in vitro. The percent remaining after UV-irradiation were:
86% for a-tocopherol, 83% for g-tocopherol,
83% for a-tocotrienol, and 84% for g-tocotrienol. These data suggest that direct
photodestruction was similar for all of these vitamin E forms.
of endogenous antioxidants.
To evaluate the protective effects of TRF on antioxidants
that were not applied topically, ubiquinol and ubiquinone were quantitated.
Ubiquinol concentrations were significantly (p<0.002) lower in
the TRF-treated skin (1.2 ± 0.7) compared with PEG-treated skin (0.8
± 0.6), but these differences may not be physiologically relevant
because the concentrations were low with large variances. Following
UV-irradiation, ubiquinol concentrations in both PEG-treated and TRF-treated
skin decreased 5-fold (p<0.001). Ubiquinone-9 and total Q (ubiquinone-9
+ ubiquinol-9) were similar in the PEG-treated and TRF-treated skin,
respectively. After UV-irradiation, both ubiquinone and total Q decreased
significantly (p<0.001) in PEG-treated and TRF-treated skin. Thus,
UV-irradiation resulted in statistically significant decreases in
ubiquinol, ubiquinone and total Q, which were not prevented by TRF
A unique distribution of tocopherols and tocotrienols,
and of coenzyme Q was found in mouse tissues. These suggest that tissues
have specific mechanisms for accumulating different amounts of these
antioxidants. It should be noted that the tissues analysed were obtained
from mice that had been fed standard mouse chow, and were not fed
diets specifically enriched in unique vitamin E forms. Hayes et
al21 demonstrated that tocotrienols represent only
a small proportion of vitamin E in tissues from hamsters fed tocotrienol-enriched
diets. The relatively high proportions of a- and g-tocotrienols in untreated mouse skin was
unexpected because 1) the mouse diets were not specially enriched
with tocotrienols, and 2) the liver discriminates against tocotrienols
in favour of a-tocopherol during repackaging of
dietary fats into very low density lipoproteins for secretion into
the circulation1,22. Suarna et al23
demonstrated that after feeding TRF to rats, all lipoprotein classes
contained tocotrienols. Apparently, transfer of tocotrienols to mouse
skin must take place following absorption and transport of dietary
vitamin E in chylomicrons during post-prandial chylomicron clearance
and delivery of tocotrienol-containing lipoproteins1,21,22.
Brain vitamin E is especially noteworthy because brain
was found to contain only a-tocopherol. The vitamin E content of brain
is spared in response to a vitamin E deficient diet24-29
and does not markedly increase in response to vitamin E supplementation30. Furthermore, feeding a diet deficient in a-tocopherol, but supplemented with
g-tocopherol, did not markedly enrich the brain with g-tocopherol31. Taken
together these data suggest that there may be specific transport mechanisms
for a-tocopherol through the blood/brain barrier.
Not only do the various vitamin E homologues have
different antioxidant capabilities, they may have important physiological
roles beyond their antioxidant activities32. For example,
skin has been suggested to be an important storage site for vitamin
E and a major excretory organ for this vitamin33. However,
skin vitamin E could also have a regulatory role in maintaining barrier
function. Skin contains a high proportion of tocotrienols, which could
inhibit cholesterol synthesis34. This is important because
cholesterol is a key component of the lipid barrier of the stratum
corneum35. In addition, vitamin E may enhance penetration
and resorption of skin lipids36. Taken together these data
suggest complex regulatory mechanisms for maintenance of skin vitamin
E content and composition.
Figure 2. a-tocopherol, a-tocotrienol, g-tocopherol and g-tocotrienol contents of murine
The left panels show the vitamin E concentrations
(mean ± SD, n= 19) in skin from non-irradiated or UV-irradiated hairless
mice following topical application of PEG (vehicle alone). The right
panels show the vitamin E concentrations in skin of hairless mice
before and after UV-irradiation following topical application of TRF
(in PEG). Note the different scales on the right and left y-axes.
Significant decreases in each vitamin E homologue were observed after
UV-irradiation both in PEG-treated and in TRF-treated skin. By least
square means comparisons: PEG verses PEG+UV for a-tocopherol, p<0.005; a-tocotrienol, p<0.0001; for g-tocopherol, p<0.000l; and g-tocotrienol,
p<0.0001. TRF verses TRF+UV for a-tocopherol, p<0.0001; a-tocotrienol, p<0.0001; for g-toocpherol, p<0.0001; and g-tocotrienol, p<0.0001.
After topical application of TRF, all the vitamin
E forms readily penetrated into the hairless mouse skin and were present
in concentrations far exceeding the baseline levels. Norkus et
al37 have also demonstrated that application of a-tocopheryl acetate onto hairless mouse skin results in penetration of
high concentrations into skin.
Tocopherols and tocotrienols in murine skin, applied
topically or derived from the diet, were significantly depleted by
UV-irradiation, indicating a protective antioxidant function (Figure
2). The similarity in the degree of depletion of the vitamins in response
to an oxidative stress, suggests that these vitamin E forms protect
similarly against UV-irradiation induced damage.
A larger percentage of the various vitamin E forms
remained after UV-irradiation of the PEG-treated compared with the
TRF-treated skin (Figure 2). This implies a greater destruction of
the various vitamin E forms in the TRF-treated skin. Whether this
is due to increased free radical scavenging remains to be clarified.
Localisation of TRF nearer to the upper epidermal layers in the TRF-treated
skin could allow increased destruction during UV-irradiation. Alternatively,
the TRF vitamin E may have penetrated the lipid components surrounding
cells and thus may not be accessible to aqueous antioxidants which
could recycle the vitamin E. Thus, the applied TRF may have a different
behaviour during UV-exposure than the vitamin E naturally present.
It should be emphasised that the skin was washed with ethanol and
dried before exposure to UV-light; therefore, the vitamin E forms
we have measured are not on the skin surface, but have penetrated
into the skin.
Ubiquinol is the first line of defence in response
to an oxidative stress5,38. It may readily react with the
tocopheroxyl radical and be oxidised, or it may react directly with
peroxyl radicals39. Tissues involved in detoxification,
both the liver and the kidney, have extraordinarily high concentrations
of ubiquinol, perhaps to protect them from radicals escaping from
p450. In addition, these tissues have high concentrations of mitochondria,
which could also account for their high coenzyme Q contents2.
Coenzyme Q (ubiquinone/ubiquinol) was chosen as a
marker for oxidative damage because ubiquinol is the most labile,
lipid soluble antioxidant5,38,40 and is not present in
TRF. Ubiquinol is oxidised prior to a-tocopherol during UV-irradiation
of skin and is substantially depleted before a-tocopherol concentrations are affected13.
The levels of ubiquinol detected in murine skin are low; nonetheless,
following UV-irradiation ubiquinol, ubiquinone and total Q all significantly
decreased. Regardless of TRF application, UV-irradiation caused a
loss in the total Q pool, thus depleting the skin of a vital component.
In summary, the data presented here give provocative
clues to the uptake and regulation of tissue lipophilic antioxidants.
This paper demonstrates not only that a variety of antioxidants are
present in skin, but that topical application provides an efficient
means of enriching the tissue in protective antioxidants, such as
vitamin E. Furthermore, these vitamin E homologues are consumed during
UV-light induced oxidative stress.
Beth Koh and Kenneth Tsang provided excellent technical
assistance. We gratefully acknowledge the efforts of Dr Asaf A Qureshi,
University of Wisconsin (Madison, WI), who isolated tocotrienols for
use as standards for this study. This study was supported by grants
from the NIH (CA 47597) and the Palm Oil Research Institute of Malaysia.
JT was supported by a fellowship of the Fritz Thyssen Stiftung, Germany
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Nutrition]. All rights reserved.
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