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Department of Animal Science, Cornell University, Ithaca, NY 14853 and * Department of Biomedical Science, College of Veterinary Medicine, Oregon State University, Corvallis, OR 97331
3To whom correspondence should be addressed.
 |
ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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-tocopheryl
acetate for 5 wk before an intraperitoneal injection of 50 mg paraquat/kg body weight. In Experiment 2, mice were fed the diet + 0 or
750 mg all-rac--tocopheryl acetate for 5 wk and were killed 1 or 3 h after an injection of diquat at 12, 24 or 48
mg/kg. In Experiment 1, all mice died of the injection and there were 8- to 15-fold differences (P < 0.001) in survival
times between the GPX1(-/-) and the WT mice. Although increasing tocopheryl acetate from 0 to 750 mg/kg extended the survival time of
the GPX1(-/-) mice for 2 h (P = 0.06), the highest tocopheryl acetate level resulted in a decrease
(P < 0.05) in survival time in the WT mice. The vitamin E–deficient GPX1(-/-) mice had the highest concentration of
hepatic thiobarbituric acid reacting substances. In Experiment 2, the diquat-induced formation of hepatic F2-isoprostanes was
accelerated (P < 0.05) by vitamin E deficiency and was also affected by the GPX1 knockout.
Diquat produced much greater (P < 0.01) dose-dependent increases in plasma alanine transaminase (ALT)
activities in the GPX1(-/-) than in the WT mice. Hepatic phospholipid
hydroperoxide GPX activities were decreased (P < 0.05) by the diquat injection only in the vitamin E–deficient
GPX1(-/-) mice. Despite a potent inhibition of hepatic lipid peroxidation, high levels of dietary vitamin E do not replace the
protection of GPX1 against the paraquat-induced lethality or the diquat-induced plasma ALT activity increase in mice.
KEY WORDS: • glutathione peroxidase • vitamin E • selenium • F2-isoprostanes • mice
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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). Because Se could prevent some, but not all of the
symptoms of vitamin E deficiency in various species (Levander 1997
, Scott 1980
), the biochemical mechanism of
the interactions between these two nutrients has remained a fascinating
question. Vitamin E is broadly considered an antioxidant, preventing
biological membranes and plasma lipoproteins from undergoing oxidative
stress because it is hydrophobic and can quench free radicals
(Traber and Sies 1996
). Although vitamin E has been
shown to inhibit paraquat-induced cell death and lipid peroxidation
in cultured rat hepatocytes (Watanabe et al. 1986
), it
plays only a limited role in protecting against diquat-induced
cytotoxicity (Eklow-Lastbom et al. 1986
, Sandy et al. 1988
). Supplementing vitamin E does not alleviate acute
oral paraquat lethality in chicks (Combs and Peterson 1983
), but exhibits a dose-dependent (25- to 250-fold of
daily needs) effect on endothelial vasodilator functions associated
with LDL oxidation in cholesterol-fed rabbits (Keaney et al. 1994
). Using the Se-dependent cellular glutathione
peroxidase (EC 1.11.1.9;
GPX1)4
knockout [GPX1(-/-)] mice, we have shown that GPX1 is the mediator
of body Se in protecting mice against the paraquat-induced
lethality, but -tocopheryl acetate at 20 mg/kg of diet does not
affect the responses of these knockout mice to that acute oxidative
stress (Cheng et al. 1998b
). It remains to be determined
whether higher levels of dietary vitamin E could replace the protection
of GPX1 against the oxidative stress induced by paraquat or other
prooxidants.
Paraquat and diquat are redox cycling bipyridyl herbicides. Both
utilize molecular oxygen to initiate superoxide and the subsequent
reactive oxygen species generation (Farrington et al. 1973
, Smith 1987
). Despite these
similarities, paraquat preferentially targets lung (Smith 1987
), whereas diquat causes primarily hepatic injuries
(Burk et al. 1995
). In consideration of the differences
in GPX1 expression (Behne and Wolters 1983
,
Christensen et al. 1995
) and vitamin E metabolism
(Liu and Huang 1996
) between these two organs,
challenging the GPX1(-/-) mice with paraquat and diquat may provide
us unprecedented models with which to assess the interaction of GPX1
and vitamin E in mice. In addition, phospholipid hydroperoxide GPX (EC
1.11.1.12; GPX4) is a membrane-associated selenoperoxidase that
reduces phospholipid hydroperoxides (Ursini et al. 1985
). Its expression is affected by testosterone
(Maiorino et al. 1998
). Thioredoxin reductase (EC
1.6.4.5; TR), a recently identified selenoprotein (Tamura and Stadtman 1996
), is capable of regenerating ascorbate
(May et al. 1998
), which could, in turn, regenerate
vitamin E from its radical form (Wefers and Sies 1988
).
Likely, these two selenoenzymes may be functionally related to vitamin
E, particularly in the GPX1(-/-) mice under oxidative stress.
Therefore, we fed the GPX1(-/-) and the wild-type (WT) mice
various levels of dietary vitamin E and challenged them with paraquat
or diquat. Our objectives were to determine whether high levels of
-tocopheryl acetate supplementation could achieve the following:
1) replace the protection of GPX1 against mouse
lethality, lipid peroxidation and liver injuries induced by paraquat or
diquat; 2) affect GPX4 and TR activities in lung and
liver of mice under the acute oxidative stress attack.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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The GPX1(-/-) mice were originally provided by Dr. Y.-S. Ho, Wayne
State University (Detroit, MI). These mice were generated from the
129/SVJ x C57BL/6 mice (Ho et al. 1997
). The
validity of this model has been established in previous experiments
(Cheng et al. 1997b
and 1998a
). Our study was approved
by the Institutional Animal Care and Use Committee at Cornell
University and conducted in accordance with the NIH guides for animal
care. All chemicals and materials were purchased from Sigma Chemical
(St. Louis, MO) unless otherwise indicated.
Dietary vitamin E treatments.
Weanling (3-wk-old) mice were fed the experimental diets for 5 wk
before being subjected to oxidative stress. The basal diet contained
30% torula yeast (Table 1
) and was the same as that described by Knight and Sunde (1987)
except that lard was replaced by tocopherol-stripped
corn oil (Dyets, Bethlehem, PA). The basal diet was supplemented with
0.4 mg Se/kg as sodium selenite to support adequate expression of TR
(Berggren et al. 1999
) and selenoprotein W (Yeh et al. 1997
), in addition to that of the other known
selenoproteins. Total Ca, P, Se, Fe, Cu, Zn and Mn concentrations in
the basal diet were analyzed as described by Stahl et al. (1999)
and are presented in Table 1
. In Experiment 1,
GPX1(-/-) and WT mice (n = 24/group) were fed the
diet containing 0, 75, 750 or 7500 mg
all-rac--tocopheryl acetate/kg. According to
Reeves et al. (1993)
, 75 IU/kg is considered
an adequate dietary vitamin E level for rodents. The two highest
dietary levels of vitamin E were used to compare the effect of this
nutrient at 10- and 100-fold of daily needs (Keaney et al. 1994
) and were within the range that produces linear increases
in circulating and tissue concentrations of
-tocopheryl in rodents (Barja et al. 1996
, Yang and Desai 1977
). In Experiment 2,
GPX1(-/-) and WT mice (n = 54/group) were fed the
same basal diet containing 0 or 750 mg
all-rac--tocopheryl acetate/kg. The vitamin E levels
were selected on the basis of the results of Experiment 1. Mice were
given free access to distilled water and diets, and housed in hanging
wire cages in a constant temperature (22°C) animal room with a 12-h
light:dark cycle.
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At the end of feeding, oxidative stress in mice was induced by an
intraperitoneal injection of paraquat (methyl viologen) or diquat
(dibromide monohydrate, Chem Service, West Chester, PA). The
preparation of both prooxidant solutions and the injection volume were
as described previously (Cheng et al. 1998b
). In
Experiment 1, all mice were injected with 50 mg paraquat/kg of body
weight and watched constantly except for a 6-h overnight interval. In
Experiment 2, mice from each of the treatment groups were injected with
diquat at 12, 24 or 48 mg/kg and killed 1 or 3 h after the
injection. Three mice from each of the four groups were injected with
0.9% saline and killed immediately; they served as the initial
controls (0 h and 0 mg/kg). Immediately after the death of mice in
Experiment 1 or after anesthetization with carbon dioxide in Experiment
2, blood was collected via heart puncture using a heparinized syringe.
Plasma was separated by centrifugation at 4°C (1400 x g for 15 min, Beckman GS-6KR, Palo Alto, CA). Fresh
tissue samples were collected, rinsed in ice-cold 0.9% saline,
frozen in liquid nitrogen and stored at -80°C before analyses; the
remaining tissues were fixed in situ in 10% buffered formalin for
histopathology (Cheng et al. 1998b
).
Biochemical analyses.
In Experiment 1, concentrations of liver thiobarbituric acid reacting
substance (TBARS) were measured (Cheng et al. 1997a
). In
Experiment 2, hepatic total F2-isoprostanes were determined
by an 8-isoprostane enzyme immunoassay kit (Cayman Chemical, Ann Arbor,
MI) according to the manufacturer's instruction. Lung and liver total
GPX and GPX4 activities were measured by the coupled assay of NADPH
oxidation (Lawrence et al. 1974
, Maiorino et al. 1990
). The substrate for the activity assay of total GPX was
hydrogen peroxide, and for GPX4 was phosphatidylcholine hydroperoxide.
The enzyme unit was defined as 1 nmol of reduced glutathione oxidized
per minute. Liver TR activity was measured using the method of
NADPH-dependent reduction of 5,5'-dithiobis-(2-nitrobenzoic acid)
(Holmgren and Björnstedt 1995
). The enzyme unit
was defined as 2 µmol 5'-thionitrobenzoic acid formed
at 30°C per minute. Plasma alanine transaminase (ALT) activity was
measured using an ALT 10 kit (Sigma Chemical). Protein concentration
was determined as described by Lowry et al. (1951)
.
Statistical analyses.
Data from Experiment 1 were analyzed by 2 x 4 factorial ANOVA
with mouse type and dietary levels of -tocopheryl acetate as the
main treatments. Data from Experiment 2 were analyzed by three-way
factorial ANOVA with mouse type, dietary vitamin E level and diquat
dose as the main treatments. Values from different diquat doses were
pooled if they had no effect or interaction with other treatments.
Effects of dietary vitamin E levels in Experiment 1 and diquat doses in
Experiment 2 on measures were also assessed by linear regression. The
Bonferroni t test was used for mean comparisons, and the
level of significance () was set at 0.05 unless otherwise indicated.
Before statistical analysis, data were examined for normality and
variance equality using the Bartlett test (Neter et al. 1990
). In cases of unequal variance, the transformed
(logarithmic) data were analyzed to confirm the conclusions from the
original data, and individual SE instead of pooled
SE were listed (Cheng et al. 1998b
). All
analyses were conducted using SAS (release 6.11, SAS Institute, Cary,
NC).
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RESULTS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Survival time and histopathology of mice.
Before paraquat injection, both GPX1(-/-) and WT mice remained
healthy and showed no difference in body weight gain during the feeding
period, irrespective of dietary vitamin E levels. All mice were killed
by the injection of 50 mg paraquat/kg. The mean survival times of
GPX1(-/-) mice were 6–11% (P < 0.001) of
those of WT mice (Fig. 1
). Although increasing tocopheryl acetate from 0 to 750 mg/kg resulted
in a marginally linear (P = 0.06) increase in survival
time of GPX1(-/-) mice, the extension was only 2 h. Compared
with other lower levels, tocopheryl acetate at 7500 mg/kg resulted in a
decrease (7 h, P < 0.05) in survival time of WT mice.
Furthermore, dietary vitamin E levels had no apparent effect on
histopathology in either group. Moderate-to-severe acute cellular
necrosis with associated alveolar changes in lung (100%) and vacuolar
changes or scattered acute necrosis of single cells in liver (25%)
were found only in WT mice. Renal epithelial necrosis of proximal
convoluted tubules was found in all treatment groups (86%). There was
no apparent lesion in lung and liver of GPX1(-/-) mice or in heart of
all mice.
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). Lung GPX activities in GPX1(-/-) mice exhibited a linear increase
(r = 0.60, P < 0.05) in response
to dietary tocopheryl acetate levels. Hepatic GPX activities in both
types of mice were higher (P < 0.05) at 7500 and/or
750 mg tocopheryl acetate/kg than those at 0 and 75 mg/kg. Hepatic GPX4
activities in both GPX1(-/-) and WT mice showed a linear increase
(r = 0.73 and 0.76, respectively, P
< 0.05) over dietary levels of tocopheryl acetate, which resulted
in apparent differences between the two lowest and the two highest
levels. At 7500 mg tocopheryl acetate/kg, WT mice had higher (28%,
P < 0.01) hepatic GPX4 activity than did
GPX1(-/-) mice. In contrast, neither the GPX1 knockout nor
the dietary vitamin E levels affected activities of GPX4 in lung. Mice
fed 0 mg tocopheryl acetate/kg had higher (P < 0.001)
hepatic TBARS concentrations than those fed the tocopheryl
acetate–added diets (Table 2
). Liver TBARS concentrations
in GPX1(-/-) mice were 32% (P = 0.09) and 98%
(P < 0.05) higher than those of WT mice at 0 and 75 mg
tocopheryl acetate/kg, respectively. Compared with WT mice, GPX1(-/-)
mice had higher plasma ALT activities (570 vs. 218 U/L,
SEM = 142, P = 0.08), which were not
affected by dietary levels of tocopheryl acetate (data not shown).
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Hepatic lipid peroxidation.
Initial hepatic F2-isoprostane concentrations
(Fig. 2
) tended to be higher (P = 0.07) in the mice fed 0 than
in those fed 750 mg tocopheryl acetate/kg. At 1 h after the
injection, all three doses of diquat resulted in elevated (P
< 0.05) formation of F2-isoprostanes in
liver of both GPX1(-/-) and WT mice fed 0 mg tocopheryl acetate/kg.
There was a difference (P < 0.05) in liver
F2-isoprostane concentrations between GPX1(-/-)
and WT mice at 12 mg diquat/kg and 0 mg tocopheryl acetate/kg. A
similar difference was also found between these two mouse groups at 48
mg diquat/kg and 750 mg tocopheryl acetate/kg. When mice were fed 750
mg tocopheryl acetate/kg, liver F2-isoprostane
concentrations in WT mice given various doses of diquat were not
different from the initial value (0 h and 0 mg diquat/kg). Under the
same condition, there was a linear (r = 0.87,
P < 0.01) rise of liver
F2-isoprostanes formation in GPX1(-/-) mice
over the diquat doses.
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), the increases in the WT mice were so small that their activities were
only 37 and 26% (P < 0.01) of those in GPX1(-/-)
mice at 24 and 48 mg diquat/kg, respectively. Dietary levels of
tocopheryl acetate did not affect plasma ALT activities in either
GPX1(-/-) or WT mice.
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). The GPX1 knockout affected total GPX but not TR activities
in liver. In the GPX1(-/-) mice fed 0 mg tocopheryl acetate/kg, the
injection of various doses of diquat reduced (P < 0.05) liver GPX4 activities over the initial value (Table 4
). No such reduction was seen in the WT or the GPX1(-/-) mice fed 750
mg tocopheryl acetate/kg. Thus, the vitamin E–deficient GPX1(-/-)
mice had lower (P < 0.05) liver GPX4 activities than
did the other three groups. Compared with the initial value, the
vitamin E–supplemented WT mice showed an induction (P
< 0.05) of liver GPX4 activities by 24 mg diquat/kg. At the same
time, there were also significant differences in the enzyme activities
between the two levels of dietary vitamin E in the WT mice.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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), this lethal dose of paraquat might
have killed the GPX1(-/-) mice so acutely by rapidly depleting NADPH
and other reducing equivalents because these knockout mice did not show
the typical lung injuries from paraquat. Presumably, this oxidative
stress, mainly aqueous, developed so drastically that vitamin E, as an
antioxidant in the lipid phase, had limited action. This is consistent
with the observation of Combs and Peterson (1983)
that
dietary vitamin E has little effect on acute oral paraquat toxicity in
chicks. Thus, GPX1 has an essential in vivo function in coping with the
acute, lethal oxidative stress, a function that cannot be replaced by
vitamin E. It is also interesting to note that supplementing tocopheryl
acetate at 7500 mg/kg resulted in a decrease in survival time of the WT
mice after the paraquat injection. Similarly, Keaney et al. (1994)
observed adverse effects of dietary vitamin E at
250-fold of daily needs in rabbits. Although vitamin E is considered
safe at large oral dosages (Kappus and Diplock 1992
),
the megavitamin E may act as a prooxidant (Bowry et al. 1992
, Maiorino et al. 1993
) when free radicals
are continuously generated, as under our experimental conditions.
Results from both Experiments 1 and 2 support the role of vitamin E as
a potent inhibitor of hepatic lipid peroxidation induced by paraquat or
diquat. Although we did not measure plasma or hepatic -tocopherol
levels because of the limited sample availability, it is well
established that circulating and tissue concentrations of vitamin E
increase linearly with dietary levels up to 10,000 IU/kg in
rodents (Barja et al. 1996
, Yang and Desai 1977
). Previously, we showed a two-fold difference in liver
-tocopherol concentrations between mice fed 0 and 20 mg
-tocopheryl acetate/kg (Cheng et al. 1998b
). More
importantly, responses of hepatic TBARS and
F2-isoprostane concentrations to the acute
oxidative stress in different groups clearly reflected their dietary
vitamin E treatments. In Experiment 1, we used liver of moribund
animals to determine TBARS because we needed to record the accurate
mouse survival time. Although these TBARS values might reflect simply
the final status of lipid peroxidation, we observed a predominant
effect of vitamin E and an additional inhibition of GPX1 at the two
lowest dietary tocopheryl acetate levels (0 and 75 mg/kg). The effect
of GPX1 on this paraquat-induced liver TBARS is similar to what we
reported earlier (Cheng et al. 1998b
). In Experiment 2,
we determined the formation of liver
F2-isoprostanes shortly after the injection of
various doses of diquat. Tissue F2-isoprostanes
are produced during the early stage of lipid peroxidation from
arachidonic acid and are considered a reliable marker of lipid
peroxidation in vivo (Morrow and Roberts 1996
). As shown
previously (Cheng et al. 1999
), the GPX1(-/-) and the
WT mice had similar concentrations of hepatic
F2-isoprostanes. Increasing dietary tocopheryl
acetate from 0 to 750 mg/kg remarkably suppressed the
diquat-induced formation of hepatic
F2-isoprostanes in both GPX1(-/-) and WT mice.
Similarly, a role of GPX1 in this process was also seen. When mice were
exposed to the lowest (12 mg/kg) dose of diquat, the vitamin
E–deficient GPX1(-/-) mice had significantly higher liver
F2-isoprostanes than did WT mice. Furthermore,
the protection of GPX1 against this lipid peroxidation became more
pronounced as the diquat dose increased from 12 to 48 mg/kg in those
mice fed diet + 750 mg tocopheryl acetate/kg. This type of oxidation
intensity–related protection of GPX1 was shown in our previous study
(Cheng et al. 1998b
). Despite its potent role in
attenuating the prooxidant-induced lipid peroxidation, vitamin E
had little effect on mouse mortality and survival time in this study.
Although lipid peroxidation has been suggested to be causative of
paraquat-induced lethality (Burk et al. 1980
,
Watanabe et al. 1986
), there is another view that
inhibition of lipid peroxidation by -tocopherol provides little or
no protection against diquat toxicity (Eklow-Lastbom et al. 1986
, Sandy et al. 1988
). Our results seem to
favor the latter view. As discussed above, the drastic oxidative stress
might kill these knockout mice by rapidly shifting redox status and
disrupting NADPH-dependent pathways. Likely, lipid peroxidation and
the inhibition of vitamin E are events that occur later in the cascade.
An interesting scenario in this study is that the high levels of
dietary vitamin E supplementation had no effect on the
prooxidant-induced rise of plasma ALT activities. In contrast, a
clear effect of the GPX1 knockout on the enzyme activity was
observed in both Experiments 1 and 2. The inhibition of GPX1 in the
rise in plasma ALT activity after the injection of prooxidants was not
affected by dietary tocopheryl acetate levels but was dependent on the
diquat dose. A temporal correlation between liver lipid peroxidation
and plasma ALT activity has been suggested, presumably due to the
damaged plasma membrane (Burk et al. 1995
). Despite an
active role in preventing lipid peroxidation, as mentioned above,
supplemental dietary vitamin E had no effect on the tissue ALT release
into plasma. Although the changes of plasma ALT activity in mice in
this study were relatively small compared with those showing the signs
of liver necrosis (Burk et al. 1980
and 1995
), the
biochemical cascade of lipid peroxidation, hepatic injury and plasma
ALT activity increases under acute oxidative stress, and the
involvement of GPX1 in the cascade warrants further study.
As shown by Whanger et al. (1977)
in sheep, there were
few effects of dietary vitamin E on liver or lung GPX activity in the
WT mice in this study. It is unclear why total GPX activities in liver
and lung of the GPX1(-/-) mice were enhanced by high levels of
dietary vitamin E in Experiment 1. May et al. (1998)
suggested that TR may interact with vitamin E through ascorbate, but we
did not see any effect of dietary tocopheryl acetate on hepatic TR
activity in this study. However, liver GPX4 activities and their
responses to either paraquat or diquat treatment were significantly
affected by dietary vitamin E levels. In Experiment 1, hepatic GPX4
activities in both GPX1(-/-) and WT mice showed a linear increase
(P < 0.05) with dietary levels of tocopheryl
acetate, indicating a sparing action or induction of GPX4 by vitamin E.
Because liver is the major site of body vitamin E metabolism
(Traber and Sies 1996
) and a good portion of cellular
GPX4 is membrane associated (Ursini et al. 1985
), the
two should be able to interact in liver. Ursini et al. (1984)
showed an enhanced activity of
"peroxidation-inhibiting protein," later identified as GPX4, by
adding tocopherol to peroxidizing microsomes. In Experiment 2, diquat
caused a significant decrease in liver GPX4 activities in the vitamin
E–deficient GPX1(-/-) mice, but not in the WT mice or the vitamin
E–supplemented GPX1(-/-) mice. Apparently, the GPX1
knockout had an effect on liver GPX4 activities when mice were vitamin
E deficient and were challenged with acute oxidative stress. Seemingly,
this diquat-associated loss of liver GPX4 activity could be
reversed by either high levels of dietary vitamin E and/or normal
GPX1 expression.
It is worth mentioning that the mineral mix formulation of our basal
diet is different from that of the AIN-93G diet (Reeves et al. 1993
). Although this formulation and the same basal diet have
been used successfully by other groups (Burk 1987
,
Knight and Sunde 1987
) in selenium research, one
particular concern is the lack of Zn in the mineral mix. Because of the
abundance of Zn in torula yeast, the basal diet contains 71.1 mg Zn/kg
by analysis, which is higher than the estimated minimal level (38
mg/kg) of the AIN-93G diet. More importantly, mice fed the diet exhibit
a normal appetite and growth. Similarly, concentrations (mg/kg) of Fe
(255.7), Cu (12.5) and Mn (66.0) in the diet are much higher than those
estimates of the AIN-93G diet (45, 6.0 and 10.0, respectively).
However, their concentrations relative to total dietary Ca are either
similar or closer than their absolute concentrations to those of the
AIN-93G diet. Nevertheless, it may not be prudent to exclude possible
effects of this mineral formulation on the responses of mice to the
GPX1 knockout and the oxidative stress.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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2 Supported by a National Institutes of Health grant DK53018 (to X.G.L.).
4 Abbreviations used: ALT, alanine aminotransferase; GPX, glutathione peroxidase; GPX1, cellular
glutathione peroxidase; GPX4, phospholipid hydroperoxide glutathione peroxidase; GPX1(-/-), cellular glutathione peroxidase knockout;
TBARS, thiobarbituric acid reacting substances; TR, thioredoxin reductase; WT, wild-type.
Manuscript received April 15, 1999. Initial review completed May 17, 1999. Revision accepted July 19, 1999.
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