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Department of Physiology, Faculty of Medicine, University of Kuopio, 70211 Kuopio, Finland
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
ACKNOWLEDGEMENTS
FOOTNOTES
REFERENCES
ABSTRACT 
Sen, Chandan K., Mustafa Atalay, Jyrki Ågren,
David E. Laaksonen, Sashwati Roy, and Osmo Hänninen. Fish
oil and vitamin E supplementation in oxidative stress at rest and after
physical exercise. J. Appl. Physiol.
83(1): 189-195, 1997.
Fish oil supplementation and physical
exercise may induce oxidative stress. We tested the effects of 8 wk of
-tocopherol (vitamin E) and fish oil (FO) supplementation on resting and exercise-induced oxidative stress. Rats
(n = 80) were divided into groups
supplemented with FO, FO and vitamin E (FOVE), soy oil (SO), and SO and
vitamin E (SOVE), and for FOVE and SOVE they were divided
into corresponding exercise groups (FOVE-Ex and SOVE-Ex). Lipid
peroxidation [thiobarbituric acid-reacting substances
(TBARS)] was 33% higher in FO compared with SO in the liver, but
oxidative protein damage (carbonyl levels) remained similar in both
liver and red gastrocnemius muscle (RG). Vitamin E supplementation,
compared with FO and SO, markedly decreased liver and RG TBARS, but
liver TBARS remained 32% higher in FOVE vs. SOVE. Vitamin E also
markedly decreased liver and RG protein carbonyl levels, although
levels in FOVE and SOVE were similar. Exercise increased liver and RG
TBARS and RG protein carbonyl levels markedly, with similar levels in
FOVE-Ex and SOVE-Ex. FO increased lipid peroxidation but not protein
oxidation in a tissue-specific manner. Vitamin E markedly decreased
lipid peroxidation and protein oxidation in both FOVE and SOVE,
although liver lipid peroxidation remained higher in FOVE. Despite
higher levels of hepatic lipid peroxidation at rest in FOVE compared
with SOVE, liver appeared to be relatively less susceptible to
exercise-induced oxidative stress in FOVE.
polyunsaturated fatty acids; INTRODUCTION OXIDATIVE STRESS has been increasingly implicated in
atherosclerosis and numerous other diseases and conditions, including cancer, aging, and physical exercise (18, 35, 36). Fish oils (FO) also purportedly have a beneficial effect on
cardiovascular mortality as shown by several epidemiological studies (21), presumably via hypotriglyceridemic effects, increased membrane
fluidity, decreased platelet thromboxane production, and altered
leukocyte function (34). Not all studies show beneficial effects,
however (1). FO induce peroxisomal Manyfold increases in red cell membrane (3) and heart tissue (8)
vitamin E levels have been found with FO and vitamin E
cosupplementation compared with supplementation with vitamin E and
placebo oil. Such findings are in contrast to the observations in the
liver, kidney, and plasma (8, 24). Although most studies examining the
effect of FO and vitamin E cosupplementation have shown protection
against oxidative stress induced by FO, oxidative stress has remained
increased in vitamin E supplementation with FO relative to vitamin E
supplementation with placebo oil (24).
Increased free radical production during even moderate exercise can
overwhelm antioxidant defenses, resulting in oxidative tissue damage
(24, 35). The beneficial effects of regular exercise on cardiovascular
and overall mortality (30) may be decreased by exercise-induced
oxidative stress. This may be of particular concern in groups
predisposed to oxidative stress. Such groups include patients with
diabetes and coronary artery disease and may also include individuals
who consume large amounts of FO (24, 28, 33). Peroxisomal The effect of FO and vitamin E supplementation on exercise-induced
oxidative stress has not been previously reported. The aims of this
study were to assess the effect of FO and vitamin E supplementation
compared with soy oil (SO; placebo) and vitamin E supplementation on
physiological antioxidant defenses and resting and exercise-induced
oxidative stress in rat liver, heart, and skeletal muscle. A primary
aim was to assess whether FO cosupplementation with vitamin E could
actually decrease exercise-induced oxidative stress compared with
vitamin E supplementation with SO.
MATERIALS AND METHODS 
-oxidation; lipid peroxidation; protein oxidation; antioxidant
-Tocopherol (vitamin E) is a major lipid-phase, free radical chain-breaking antioxidant in the body (26). In detoxifying free radicals, vitamin E
itself becomes a less reactive free radical. Vitamin E can then be
regenerated by antioxidants such as vitamin C and glutathione (35).
Epidemiological studies have suggested a protective role of vitamin E
in reducing overall and cardiovascular mortality (32), and experimental
studies have demonstrated its efficacy in protecting against oxidative
stress (16, 26). However, the role of vitamin E supplementation in
slowing progression of atherosclerosis remains controversial (20, 39).
-oxidation, in which fatty-acyl
oxidation yields hydrogen peroxide
(H2O2)
as a normal by-product. Under normal conditions, up to 20% of cellular O2 consumption has, in fact, been
estimated to occur in the peroxisome (7). Furthermore, (n-3) fatty
acids making up FO are highly polyunsaturated. Thus concerns have been
raised regarding increased oxidative stress from FO intake (11, 24,
28).
-oxidation
may be a primary cause of FO-induced oxidative stress at rest.
Therefore, favorable effects of FO on leukocyte function and vitamin E
bioavailability could potentially decrease susceptibility to
exercise-induced oxidative stress, because the relative role of
peroxisomal -oxidation may decrease during exercise.
-tocopherol acetate (Table 1;
information provided by the manufacturer). All rats were
housed, four animals to a cage, at 22 ± 2°C room temperature with 10:14-h dark-light cycles. The study was approved by the University of Kuopio Animal Research Ethics Committee.
Table 1.
Composition of basal diet rat chow
Ingredient
%Total
Wheat
43.0
Barley
34.0
Wheat germ
5.0
Soy
5.0
Vitamins and minerals
4.5
Calcium powder
2.0
Monocalcium phosphate
1.0
Animal fat
0.9
Sodium chloride
0.5
Lysine
0.1
Other
4.5
-tocopherol added to protect against
oxidation. SO (Bio-Marin placebo, Pharma Nord) with similar vitamin E
content served as a control for FO supplementation. SO contains
predominantly linoleic acid [18:2(n-6)] and oleic acid to a
lesser degree. RRR--tocopherol (Bio-E-Vitamin, Pharma Nord) was
given intragastrically at a daily dose of 500 mg (750 IU)/kg body wt.
All supplementation was done 5 days/wk over an 8-wk period. At the end
of the supplementation period, the rats weighed on average 410.7 ± 38.8 g, with no significant difference between groups. Rats consumed on
average 26 g/day rat chow; average fat in the diet was ~6.1%, of
which the oil supplements were ~23%. Therefore, free
RRR--tocopherol administered with the FO and SO in the FO- and
SO-only groups was 6.0 mg/kg body wt. In addition, all rats consumed,
on average, 1.6 mg/day all-rac--tocopherol acetate present in the
diet. Thus baseline vitamin E consumption in all rats was high. We
chose to use high -tocopherol in the basal diet because of the
higher vitamin E requirements with diets high in polyunsaturated fatty
acids (12).
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70°C.
Fatty acid determinations.
Tissue lipids were extracted by the method of Folch et al. (14) and
methylated with 14% BF3 in methanol. The respective fatty acid methyl
esters were analyzed by using gas chromatography (HP 5890 series II;
Hewlett-Packard) equipped with a Hewlett-Packard FFAP capillary
column.
Vitamin E determinations.
Tissue vitamin E levels were determined by high-performance liquid
chromatography, where a series quaternary pump (HP 1050, Hewlett-Packard) was coupled to an ultraviolet detector
(Hewlett-Packard). Samples extracted in hexane and dried under nitrogen
gas were separated by using a LiChrosorb (Si60, 5 µM, Hibar, Merck,
Germany) column and hexane:t-butyl
methyl ether (95:5 vol/vol) as the mobile phase at a 1.5 ml/min flow
rate (22). The vitamin E peak was detected at 292 nm.
Thiobarbituric acid-reacting substances (TBARS) determinations.
Tissue homogenization for TBARS was carried out as described before
(36). After homogenization, the samples were were reacted with
thiobarbituric acid and assayed spectrophotometrically at 532 nm (36).
Protein carbonyl determinations.
Tissue homogenizations and protein carbonyl determinations were carried
out as described by Reznick and Packer (31), with modifications
reported by Yan et al. (40). Tissue protein was extracted in a
protease-inhibitor (0.5 µg/ml leupeptin, 0.7 µg/ml antipain, 0.5 µg/ml aprotinin, 40 µg/ml
phenylmethylsulfonylfluoride, 1 mM EDTA)-treated 0.1 M phosphate
buffer, pH 7.4. DNA was removed from samples with 1% streptomycin
treatment. The sample was then treated with 1 mM
2,4-dinitrophenylhydrazine. The protein was washed in ethyl
acetate-ethanol (1:1 vol/vol) and dissolved in 6 M guanidine
hydrochloride, pH 2.3. Tissue protein carbonyl content was quantitated
by scanning the samples from 320 to 410 nm in a spectrophotometer. The
peak absorbance was used to calculate protein carbonyl content
(extinction coefficient 22,000 l · mol
1 · cm1).
Using methods somewhat similar to this, Cao and Cutler (6) reported
difficulties in reliable determination of protein carbonyl content in
crude tissue extracts. After slightly different treatment with 1%
streptomycin and washing in ethyl acetate-ethanol, rat liver protein
carbonyl concentration had a coefficient of variation of
150-200%. In the present study, the relatively low SE, large decrease of tissue protein carbonyl content in response to vitamin E
supplementation, and large increase of skeletal muscle carbonyls in
response to exercise suggest that tissue protein carbonyl measurements in this study were reliable.
Statistical analyses.
Results are presented as means ± SE. Eicosapentaenoic acid and
vitamin E data for all tissues, heart (n-3) and (n-6) fatty acid
results, and liver protein carbonyl data were log transformed for
statistical analyses. The effect of FO supplementation and vitamin E
supplementation in the resting groups, and the effect of FO
supplementation and exercise in the exercise groups and their
corresponding resting groups, was assessed using two-way analysis of
variance (ANOVA). Interaction of vitamin E and FO refers to a combined
effect of FO and vitamin E different from the effects of vitamin E and
FO separately. Student's unpaired t-test with Bonferroni's correction
was used to further analyze differences between group pairs (i.e.,
FO-supplemented groups, vitamin E-supplemented groups, and exercise
groups). Statistical significance was defined as
P < 0.05.
RESULTS
0.036; in
liver, P = 0.088). The effect of vitamin E in lowering
docosahexaenoic acid content was not significant except in the RG
(P = 0.02), again seen mainly in FOVE
vs. SOVE (P = 0.02).
P < 0.001.
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-tocopherol (vitamin E) content. Bars and groups as in Fig.
1. Values are means ± SE. Effect of vitamin E supplementation, *** P < 0.001. Effect of
exercise, 
P < 0.01 and P < 0.001. Effect of FO supplementation,
P < 0.05.
Effect of exercise on tissue vitamin E levels. Exercise markedly decreased levels of vitamin E in all tissues in FOVE and SOVE, by ~10-20% in heart, 20-30% in liver, and 40% or more in the VL and RG compared with the resting groups (Fig. 2). There was no significant difference in the relative response to exercise between FOVE and SOVE. Effect of FO supplementation, vitamin E supplementation, and cosupplementation on tissue lipid peroxidation levels. FO supplementation remarkably increased mean TBARS levels in the liver (by 32-33% relative to the corresponding SO-supplemented groups, P = 0.002; Fig. 3). FO had no significant effect in the RG or superficial VL. Vitamin E supplementation lowered mean TBARS levels by 18-19% in the liver (P = 0.024) and by 33% in the FO- and 23% in the SO-supplemented groups in the RG (P = 0.002). Liver TBARS levels were ~32% higher in FOVE than SOVE (Student's t-test with Bonferroni's correction, P = 0.050). Neither FO nor vitamin E supplementation affected lipid peroxidation in the VL.
P < 0.01 and P < 0.001. Effect of FO supplementation,
P < 0.01.
Effect of exercise on tissue lipid peroxidation. Exercise markedly elevated TBARS content in the liver (30% in FOVE-Ex group, 69% in SOVE-Ex; P = 0.006) and the RG (64% in FOVE-Ex, 57% in SOVE-Ex; P < 0.001) compared with the corresponding resting groups, with similar TBARS levels in the exercise groups (Fig. 3). No effect of exercise was seen in VL. Effect of FO supplementation, vitamin E supplementation, and cosupplementation on tissue protein carbonyl levels. FO supplementation had no effect on protein carbonyl levels in the liver or RG (Fig. 4). In the VL, protein carbonyl levels were ~35% higher in FO than in the other groups (P = 0.025 for the effect of FO). Vitamin E supplementation led to a 33 and 20% decrease in mean protein carbonyl levels in the liver of FOVE and SOVE groups, respectively (P = 0.001). RG protein carbonyl content decreased by 41 and 56%, respectively, with vitamin E supplementation (P = 0.002). Vitamin E lowered VL protein carbonyl levels in FOVE only (interaction of FO and vitamin E, P = 0.055; further analysis of FOVE vs. FO with Student's unpaired t-test with Bonferroni's correction, P = 0.050).
P < 0.05. Effect of exercise,
P < 0.001
Effect of exercise on tissue protein carbonyl levels. Protein carbonyl levels in the RG were roughly threefold greater in the exercise groups (P < 0.001 for the effect of exercise; Fig. 4). In the VL, exercise increased carbonyl content by 83 and 69% in FOVE-Ex and SOVE-Ex, respectively (P < 0.001). In the liver, the effect of exercise only tended to significance (P = 0.096); however, by using one-way ANOVA, protein carbonyl content was significantly higher in SOVE than in the other groups (P = 0.05).
DISCUSSION
FO supplementation induced lipid peroxidation in a tissue-specific manner but, with the exception of VL, did not cause protein oxidative damage. High-dose vitamin E cosupplementation decreased FO-induced lipid peroxidation, despite elevated lipid peroxidation in the liver compared with SOVE supplementation. Although FOVE supplementation increased lipid peroxidation at rest compared with SOVE, at least in the liver, FOVE appeared to decrease relative susceptibility to exercise-induced oxidative stress.
FOVE supplementation at rest. FO-induced oxidative damage appeared to be largely limited to tissue lipids (except in the VL). Thus different mechanisms or factors possibly influenced oxidative damage to lipids and proteins. This is reinforced by our finding that although vitamin E feeding resulted in marked decreases of both tissue TBARS and protein carbonyl levels, there was no correlation between TBARS and protein carbonyl levels in any of the tissues. Protein oxidation has been suggested to be of greater significance in cell toxicity than lipid peroxidation or oxidative stress-associated vitamin E depletion (33). Findings of increased lipid peroxidation with FO supplementation have been previously reported in the liver (11, 24) and heart (24, 28). At rest, hepatic TBARS levels were ~30% higher in FOVE compared with SOVE, despite somewhat higher vitamin E levels. At least in the liver, vitamin E supplementation seemed to be inadequate in controlling FO-induced oxidative stress, in agreement with other studies (24). The more marked induction of lipid peroxidation in the liver and incomplete compensation of vitamin E supplementation in FOVE may be caused by the many metabolic and detoxification functions of the liver, making this organ more sensitive to FO-induced oxidative stress. Our findings are not consistent with the manyfold increase in vitamin E tissue levels induced by FO with or without vitamin E supplementation reported in some earlier studies (3, 8). In the present study, tissue levels of vitamin E increased only modestly, with a significant added effect of FO in the liver only. Leibovitz et al. (24) reported lack of significant changes in-tocopherol content in either the liver or
heart in 8-wk-old Sprague-Dawley rats with a diet supplemented with FO
(10% of diet) and vitamin E (180 mg/kg diet), although at lower levels
of vitamin E supplementation (35 mg/kg diet), liver -tocopherol
content was higher in the FO-supplemented group. Differences compared with our study may be because they used younger rats of a different strain (24). Berlin et al. (3) found manyfold increases in -tocopherol content in human red cell membranes in response to FO
supplementation. No other tissues were sampled, however,
and relatively smaller amounts of FO supplements were used. Chautan et
al. (8) found fourfold -tocopherol increases in heart membranes but
not in the liver, using the same rat strain as in the present study and
a 4-wk diet rather high in basal vitamin E content (~200 mg/kg diet;
5.2 mg/day, on average, assuming similar levels of diet consumption)
and fat content (17%). Differences in results may be caused in part by
the much higher dietary fat content in their study. Vitamin E
consumption does not seem to explain the discrepancy between our study
and that by Chautan et al., since the total vitamin E received in the
diet and with the oil supplements in the FO and SO only groups in
the present study did not differ greatly from their study.
Peroxisomal -oxidation of 20- and 22-carbon (n-3) fatty acids may
contribute to tissue lipid peroxidation (11). The (n-3)/(n-6) ratio in
the tissues of the FO group was two- to fourfold higher in all tissues
studied. FO supplementation is known to markedly induce peroxisome
activity (10, 11, 38), resulting in increased formation of
H2O2
as a by-product of -oxidation (10). An increased (n-3)/(n-6) ratio
markedly induced hepatic peroxisomal -oxidation and lipid
peroxidation in Wistar rats fed high-fat diets, even when the
unsaturation index was kept nearly constant in part through compensatory supplementation of polyunsaturated (n-6) fatty acids (28).
FO-induced oxidative stress has also been attributed to the membrane
incorporation of polyunsaturated fatty acids (24, 28) supplied through
FO supplementation. FO were efficiently incorporated into tissues at
the expense of membrane arachidonic and linoleic acids (37). An
increased unsaturation index in the liver of FO-fed rats could in part
explain increased lipid peroxidation in the liver. Vitamin E
supplementation had significant effects on tissue fatty acid profiles,
decreasing eicosapentaenoic acid concentration in all tissues and
docosahexaenoic acid concentration in the RG and increasing linoleic
acid concentration in the liver. These effects were primarily observed
in the FO-fed group. Berlin et al. (3) found similar but even more
striking effects of FOVE. They attributed the effects to more extended
FO supplementation, because the cosupplementation was followed by
further FO supplementation in their study (3), in contrast to the
present study. Because larger vitamin E supplements were used in the
present study than in most other studies not observing an effect of
vitamin E supplementation on tissue fatty acid profiles (24), our
observation could be related to the stabilizing effect of vitamin E in
the membranes (27).
Exercise and FO and vitamin E supplementation.
Exhaustive exercise markedly elevated TBARS and protein carbonyl levels
in the RG and TBARS level to a lesser degree in the liver of both
FOVE-Ex and SOVE-Ex. Despite higher resting levels of hepatic TBARS in
FOVE, liver TBARS increased with exercise in FOVE-Ex by less than
one-half that observed in SOVE-Ex, with no significant difference in
absolute TBARS levels. Although two-way ANOVA showed no significant
effect of FO or exercise on protein carbonyl content, with the use of
one-way ANOVA, protein carbonyl content was significantly higher only
in SOVE-Ex, suggesting increased exercise-induced oxidative stress in
that group.
A more minor role of peroxisomal -oxidation in total oxygen
consumption during exercise could decrease susceptibility of skeletal
muscle to exercise-induced oxidative stress in FO-supplemented groups.
This, coupled with increased vitamin E content in the liver, could
provide the FOVE group additional protection against oxidative stress
during exercise. During exercise at moderate intensity, skeletal muscle
mitochondrial fatty acid oxidation increases by approximately eightfold
(9). Studies involving peroxisomal oxidation have focused on its role
in the resting state (11, 28, 38). Meydani et al. (27)
have shown, however, that in men not receiving FO supplements,
docosahexaenoic and eicosapentaenoic acid levels relative to
arachidonic acid remain constant in exercised muscle. Because membrane
fatty acids undergo little change with exercise (15), peroxisomal fatty
acid metabolism appears to remain largely unaffected during exercise.
The immunomodulatory effects of FO could also lessen the relative
exercise-induced increase in oxidative stress. Exercise acutely induces
an immune response, similar to inflammatory or ischemia-reperfusion
reactions, in which reactive oxygen species (ROS) play a major role (2,
5). In long-lasting endurance events, this immune response may be an
important secondary source of ROS (5, 19). Despite unfavorable effects
at rest on lipid peroxidation (11, 24, 28), FO supplementation
decreases the release of proinflammatory cytokines such as
interleukin-1, interleukin-6, and tumor necrosis factor- (13);
attenuates neutrophil function, leukotriene chemotactic activity (23), and neutrophil superoxide generation (17); and inhibits arachidonic acid metabolism (23), cyclooxygenase activity, and prostaglandin synthesis (29). All the above-mentioned mechanisms can directly or
indirectly decrease ROS formation, perhaps more so in response to
exhaustive exercise (17).
Unlike in the RG, no effect of exercise on TBARS was seen in the VL,
which is mainly glycolytic. VL protein carbonyl levels, on the other
hand, were significantly elevated in the exercise groups, although the
relative increase was much less than in the RG. Exercise-induced
oxidative stress has been shown to be highest in active, oxidative
muscles (4, 35).
Exercise-induced depletion of vitamin E was seen in all tissues
measured, especially in skeletal muscle. Loss of tissue vitamin E
(probably because of enhanced consumption) in association with an acute
pro-oxidant stressor (25), including exercise (4, 27), has been
considered a marker of oxidative stress.
In summary, FO induced oxidative damage of lipids in a tissue-specific
manner. FOVE supplementation decreased tissue oxidative stress, as
measured by both TBARS and protein carbonyl levels, to below that seen
in non-vitamin E-supplemented animals, but hepatic lipid peroxidation
remained higher than in the SOVE-supplemented rats. Another novel
finding was that FOVE supplementation appeared to offset the relative
increase in exercise-induced oxidative stress in the liver compared
with SOVE supplementation, despite a higher oxidative stress state at
rest.
ACKNOWLEDGEMENTS
Vitamin E, fish oil, and soy oil supplements used in this study were a gift from Pharma Nord (Vojens, Denmark).
FOOTNOTES
Address for reprint requests: C. K. Sen, Dept. of Molecular and Cell Biology, 251 Life Sciences Addition, Univ. of California, Berkeley, Berkeley, CA 94720-3200 (E-mail: cksen{at}socrates.berkeley.edu).
Received 15 October 1996; accepted in final form 6 March 1997.
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