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Department of Animal Science, Cornell University, Ithaca, New York 14853, USA
1Correspondence: Department of Animal Science, 252 Morrison Hall, Cornell University, Ithaca, NY 14853, USA. E-mail: XL20{at}cornell.edu
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Key Words: F2-isoprostanes • carbonyl • knockout • antioxidation • SOD
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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, and a large portion
of body Se is present in the form of cellular glutathione peroxidase
(EC 1.11.1.9, GPX1) (2
, 3)
. Although GPX1 was the
selenoenzyme first identified (4
, 5)
, its physiological
roles have been unclear. This is largely due to the difficulty in
distinguishing the specific role of GPX1 from the confounded effects of
other selenoproteins (6)
in the Se-deficient animal models
used typically and the lack of GPX1-specific inhibitors
(7
8
9)
. Consequently, there has been no exclusive evidence
for an in vivo antioxidative role of GPX1 until very
recently (10
, 11)
. Instead, GPX1 was proposed as a storage
form or a buffer of body Se (6
, 12)
, raising concerns
regarding using maximal GPX1 activity in tissues to determine dietary
Se requirement (13)
. The recently developed GPX1 knockout
mice [GPX1(-/-)] (14)
have provided us with an
unprecedented model to clarify the in vivo role of GPX1.
Using this model (10)
, we demonstrated that GPX1 was the
major metabolic form of body Se to protect mice against a pro-oxidant,
paraquat-induced lethality. The survival time of mice, after an
intraperitoneal (i.p.) injection of paraquat (50 mg/kg), was solely a
function of tissue GPX1 activity. de Haan et al. (ref 11)
also showed a similar protection of GPX1 against paraquat lethality
independently. Nevertheless, the biochemical mechanisms for this
protection of GPX1 were not apparent because there was no distinct
histopathology of paraquat toxicity in those GPX1(-/-) that died
acutely after the injection (10)
.
It is believed that paraquat initiates the formation of superoxide
radicals (O2·) through an oxygen- and
NADPH-dependent redox cycle, subsequently inducing oxidative
destruction of important biomolecules (16
, 17)
. Actually,
high doses of paraquat result in dramatic decreases in the ratio of
NADPH/NADP in lung of rats (18
, 19)
. Because there was no
tissue lesion in the GPX1(-/-) that died of the paraquat injection
acutely (10)
, we hypothesized that these mice, in the
absence of GPX1, were killed by paraquat through abrupt depletion of
NADPH and other reducing equivalents. Whereas lipids (7
, 17
, 20)
are presumably the main targets of the paraquat-induced
oxidative stress, the in vivo role of GPX1 in protecting
lipid peroxidation, as well as protein oxidation (21)
, was
not determined. In addition, an induction of total GPX activity in lung
of the wild-type mice (WT) by paraquat treatment was observed
(11)
. However, it was unclear whether this activity
increase was due to GPX1 exclusively or other selenoperoxidases.
Therefore, the present time course study was undertaken to examine
1) whether GPX1 protected mice against the paraquat-induced
depletion of NADPH and NADH and destruction of lipids and protein; and
2) how expression of GPX1 and other related antioxidant
enzymes responded to the acute oxidative stress of paraquat.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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and
characterized by completely undetectable GPX1 mRNA and 80 to 99% of
reduction in total GPX activities in various tissues compared with
those of WT (2
, 15)
. Our experiments were approved by the
Institutional Animal Care and Use Committee at Cornell University and
conducted in accordance with the NIH guidelines for animal care.
Mouse Se status, oxidative stress, and sample preparation
Seventy-two weanling (3-wk) GPX1(-/-) and 72 WT were divided
into two groups each: Se-deficient and -adequate. The Se-deficient
group was fed an Se-deficient torula yeast diet (< 0.02 mg/kg) whereas
the adequate group was fed that diet supplemented with 0.4 mg Se/kg as
sodium selenite. Both diets were supplemented with 75 mg of
all-rac-
-tocopheryl acetate/kg. The designated body Se
status was achieved by feeding these mice their assigned diets for 7 wk
prior to the challenging of an acute oxidative stress by paraquat. The
preparation of paraquat solution and the injection volume were the same
as described in our previous study (10)
. After the i.p.
injection of paraquat (50 mg/kg of body weight), six mice from each of
the four treatment groups were anesthetized with carbon dioxide and
killed by exsanguination at 0.5, 1, 2, 3, or 4 h, respectively.
Six mice from each of the four groups were injected with 0.9% saline
and killed immediately thereafter as the initial controls (0 h). Lung,
liver, and brain samples were collected immediately after death, rinsed
in ice-cold saline, frozen in liquid nitrogen, and stored at -80°C
before analyses.
Detection of pyridine dinucleotides
Concentrations of NADPH, NADH, NADP, and NAD in lung and liver
were assayed by high-performance liquid chromatography (a 501 pump, a
712 wisp, and a 490E UV detector with an interface module; Waters,
Milford, Mass.). Samples were prepared following the method of Kalhorn
et al. (22)
. Before injection, samples were passed through
a Millipore ultrafree Eppendorf filtration system (Millipore, Bedford,
Mass.). The pyridine dinucleotides were then separated in a Supelcosil
LC-18 C18 column (250 x 4.6 mm, 5 µM;
Supelco, Bellefonte, Pa.) preceded by a Supelguard LC-18 guard column
(Supelco). The mobile phase was 82% 0.2 M ammonium phosphate (pH 6.0),
17.87% methanol, and 0.13% tributylamine for the reduced forms, and
97% 0.2 M ammonium phosphate (pH 5.25) and 3% methanol for the
oxidized forms. Final concentrations of NADPH and NADH were estimated
by the absorbance at 340 nm, and those of NADP and NAD at 254 nm,
compared with their respective authentic standards. Concentrations of
the four dinucleotides were expressed as the relative percentages of
those in the Se-adequate WT injected with saline.
Detection of protein oxidation
Total carbonyl contents in liver were used as a biomarker of
protein oxidation (23)
. The contents were determined
spectrophotometrically (23
, 24)
and verified by an
immunodetection method (23)
. Briefly, tissue homogenates
(5 µg protein), after the 2,4-dinitrophenylhydrazine derivitization,
were separated by sodium dodecyl sulfate-polyacrylamide gel
electrophoresis (SDS-PAGE) (12%) and transferred to a Protran
nitrocellulose membrane (Schleicher & Schuell, Keene, N.H.). The
primary antibody was anti-2,4-dinitrophenol (DNP) developed in rabbit
(Sigma Chemical Co., St. Louis, Mo.) and used at a 1:1000 dilution. A
goat anti-rabbit immunoglobulin G conjugated with horseradish
peroxidase (Bio-Rad Laboratories, Hercules, Calif.) was used to
estimate the relative amount of protein oxidation, using an IS-1000
Digital Imaging System (Alpha Innotech Co., San Leandro, Calif.).
Equality of protein loading was checked in parallel gels stained with
Coomassie brilliant blue.
Detection of lipid peroxidation
Contents of total F2-isoprostanes, a
reliable and sensitive marker of in vivo lipid peroxidation
(25)
, in tissue homogenates (0.25 M sucrose, 0.1 M
Tris-HCl, pH 7.4) were determined by an 8-isoprostane enzyme
immunoassay kit (Caymen Chemical Co., Ann Arbor, Mich.) according to
the manufacturer's instruction. Selected samples were chosen to
validate this immunoassay by using GC/MS (model HP 5890A with a HP 5980
series mass selective ion monitoring, Hewlett-Packard, Palo Alto,
Calif.) as described previously (26
, 27)
.
Western blot analyses of GPX1 protein
Lung homogenates containing 100 µg of proteins were subject to
SDS-PAGE (12%), transferred to a Protran nitrocellulose membrane
(Schleicher & Schuell). The GPX1 protein was detected by an anti-human
GPX1 antibody (28)
(kindly provided by Drs. Q. Shen and
P. E. Newburger, University of Massachusetts Medical School,
Worcester) and quantified using the same secondary antibody as
described in the detection of protein oxidation.
Assays of enzyme activity
Lung and liver total GPX and GPX4 activities were measured by
the coupled assay of NADPH oxidation described previously (29
, 30)
. The enzyme unit was defined as 1 nmol of reduced
glutathione oxidized per minute. Lung total SOD activity was measured
using the competitive inhibition assay as described by Ukeda et al.
(31)
. The enzyme unit was defined as the amount of protein
that inhibits the rate of the XTT (31)
reduction by 50%
compared with the blank. Protein content was determined as described by
Lowry et al. (32)
.
Statistical analyses
Data were analyzed by two-way factorial (2 x 2) analysis
of variance with time-repeated measurement. The main effects were the
mouse type [GPX1(-/-) vs. WT] and body Se status (deficient vs.
adequate). The Bonferroni t test was used for mean
comparisons. All analyses were conducted using SAS (release 6.11, SAS
Institute, Cary, N.C.).
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RESULTS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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A) and NADH/NAD (Fig. 1B
) ratios decreased sharply
(P<0.05) 1 h after the injection of paraquat, these
two ratios were higher (P<0.05) in the Se-adequate WT than
in the other three groups at 2, 3, and 4 h. Thus, these two ratios
were significantly different (P<0.05) between the
Se-deficient and -adequate groups for the WT, but not for the
GPX1(-/-). Whereas the hepatic NADPH/NADP ratios remained steady in the
Se-adequate WT from 1 to 4 h, there were linear decreases
(P<0.05) in the other three groups over this period.
Pulmonary NADPH/NADP (Fig. 1C
) and NADH/NAD (Fig. 1D
) ratios were reduced (P<0.05) by 50–70%
only 0.5 h after the injection in all four groups, and thereafter
showed no further decrease or group difference.
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GPX1 protected against the paraquat-induced increases in liver
protein carbonyl contents
In the GPX1(-/-) and Se-deficient WT, the hepatic carbonyl
contents were significantly increased 1 h after the injection
(Fig. 2
A). These increased levels were maintained throughout the
time course. In contrast, the hepatic carbonyl contents in the
Se-adequate WT were not affected by the paraquat injection, and were
only 45–60% (P<0.05) of those in the other three groups
at each time point except for the initial one. Results from the Western
blot analysis of liver samples (Fig. 2B
) were in line with
the spectrophotometric data. Protein oxidation, measured as
protein-bound 2,4-dinitrophenylhydrazine, was evident in those samples
of the GPX1(-/-) and Se-deficient WT 4 h after paraquat exposure.
Meanwhile, these anti-DNP recognized bands in the paraquat-treated
Se-adequate WT were faint and not obviously different from those of the
untreated controls.
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GPX1 protected against the paraquat-induced lipid peroxidation in
both lung and liver
In the two GPX1(-/-) groups and the Se-deficient WT,
concentrations of F2-isoprostanes in lung were
elevated by more than threefold 1 h after the injection and
decreased to initial levels at 3 h (Fig. 3
A). In contrast, the increase at 1 h was much less
(P<0.05) in the Se-adequate WT, which had nearly identical
levels between 1 and 3 h. Peak increases of hepatic
F2-isoprostanes occurred within 1 h in the
Se-deficient GPX1(-/-), but were seen after 2 and 3 h in the
Se-deficient WT and the Se-adequate GPX1(-/-), respectively (Fig. 3B
). There was no increase or temporal change at all in the
Se-adequate WT. Consequently, the highest concentrations were shown in
the Se-deficient GPX1(-/-) at 1 and 2 h and in the Se-deficient WT
at 3 and 4 h. The concentrations in the Se-adequate GPX1(-/-) were
higher (P<0.05) than those of the Se-adequate WT at 2, 3,
and 4 h, but lower (P<0.05) than those of the
Se-deficient GPX1(-/-) at 1 and 2 h. There were significant
differences between the Se-adequate GPX1(-/-) and the Se-deficient WT
at 3 and 4 h. The two GPX1(-/-) groups had similar concentrations
at 3 h that were higher and lower (P<0.05) than that
of the Se-adequate and -deficient WT, respectively. The same was also
true at 4 h except that the two GPX1(-/-) groups were also
different (P<0.05). Unlike lung or liver, brain had no
significant change in F2-isoprostane
concentration due to either paraquat or the GPX1 knockout and
deficiency (Fig. 3C
).
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Expression of lung GPX1 and SOD was affected by the
paraquat-induced oxidative stress
Total GPX activities were different (P<0.001) between
the Se-deficient and -adequate WT in liver and lung, but not between
the two GPX1(-/-) groups (Table 1
). After the injection of paraquat, the Se-deficient WT had slightly
higher (P<0.05) lung GPX activity at 2, 3, and 4 h
than at 0 and 1 h. The Se-adequate WT had a linear increase
(P<0.05) in lung GPX activity between 0 and 2 h,
followed by a 16% decrease (P<0.05) at 3 and 4 h.
Based on the Western blot analysis of lung homogenates from the
Se-adequate WT, there was only one specific band of ~23 kDa that
cross-reacted with the anti-human GPX1 (Fig. 4
). The intensity of that band was increased from 0 to 2 h by 7%,
followed by a 28% (P<0.05) reduction at 3 and 4 h.
Lung and liver GPX4 activities were higher in the Se-adequate mice than
the Se-deficient ones. Throughout the 4 h period, there was no
induction of GPX4 activity in either tissue by paraquat or any
difference between the GPX1(-/-) and WT at the same body Se status.
Total SOD activities in lung decreased (P<0.01) by
22–34%, compared with the initial values, 1 h after the
injection in the Se-deficient WT and the two groups of GPX1(-/-)
(Fig. 5
). Although the Se-adequate WT also showed a slightly linear decrease
(P<0.03) of this activity in lung over time, their SOD
activities were higher (P<0.05 or P<0.08 at
3 h) than those of the GPX1(-/-) groups from 1 to 4 h and
those of the Se-deficient WT at 3 and 4 h. There were no
significant differences in lung SOD activities between the Se-deficient
WT and the GPX1(-/-) groups.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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. This unforeseen
observation led us to consider a possible role of GPX1 in protecting
redox status from acute oxidative stress. In the present study, we have
demonstrated a sharp decrease of NADPH/NADP and NADH/NAD ratios in both
lung and liver of those mice after the injection of paraquat. Although
these abrupt decreases are not different from the earlier observations
in rats (18
, 19)
, our data offer the first experimental
evidence for a protection of GPX1 against the paraquat-induced
depletion of NADPH and NADH. Those mice deficient in GPX1, due to
either the GPX1 knockout or Se deficiency, had significantly lower
ratios of NADPH/NADP and NADH/NAD in liver from 2 h after the
injection than the Se-adequate WT with normal expression of GPX1.
Notably, the depletion profiles of these two ratios in these mice
paralleled their survival times under the same stress
(10)
. The three groups of GPX1-deficient mice that died
within 4–6 h exhibited a 30–50% reduction in NADPH/NADP ratio at
1 h, followed by linear decreases over time. In contrast, the
Se-adequate WT that survived for 3 days had only 30% reduction of the
ratio at 1 h and showed no further reduction thereafter. Clearly,
the GPX1 deficiency aggravates the paraquat-induced depletion of NADPH,
NADH, and perhaps other reducing equivalents. Subsequently, redox
status and many NADPH-dependent pathways are disrupted
(19)
, causing sudden death before the formation of tissue
lesions. However, effects of GPX1 knockout on the depletion of NADPH
and NADH in lung were not apparent because the depletion was
essentially maximized by 0.5 h in all groups. This is not totally
unexpected because 1) paraquat is preferentially transported
into lung cells through a diamine receptor (17)
, and
2) the drastic oxidative stress by the high dose of paraquat
exceeded the antioxidant capacity of even the Se-adequate WT. Using a
lower dose of paraquat might give us a better chance to see the effect
of GPX1 on these two ratios in lung.
Lipid peroxidation is generally considered a major target of cellular
oxidative injury (33)
. Tissue
F2-isoprostanes are a reliable and sensitive
biomarker of in vivo lipid peroxidation (25
, 34
35
36)
. Although Se was shown to protect against
paraquat-induced lipid peroxidation (7
, 16)
, it was
unclear whether the GPX1 mediates the protection. In this study we have
shown that GPX1 protects against the paraquat-induced formation of
F2-isoprostanes in a tissue-specific way. In
lung, all of the GPX1 knockout or deficient mice had a much higher
increase in F2-isoprostanes 1 h after the
injection of paraquat than that of the Se-adequate WT, indicating a
major protection of GPX1 against this induced lipid peroxidation in
this organ. In liver, such a protective role of GPX1 is additive with
other selenoproteins. Although the peak elevation of hepatic
F2-isoprostanes occurred within 1 h in the
Se-deficient GPX1(-/-) and started at 2 h in the Se-deficient WT,
no sharp increase was seen until 3 h in the Se-adequate GPX1(-/-),
which also had lower concentrations of
F2-isoprostanes than those of the Se-deficient WT
at 3 and 4 h. Apparently, other selenoproteins (37)
in the Se-adequate GPX1(-/-) might help delay the peak appearance of
lipid peroxidation. Nevertheless, the protective role of normal or
residual GPX1 expression is still obvious. In Se deficiency, hepatic
F2-isoprostane formation peaked earlier and was
greater at 1 and 2 h in the GPX1(-/-) than in the WT. In Se
adequacy, the GPX1(-/-) also had higher hepatic
F2-isoprostanes concentrations than the WT after
1 h. In brain, a small amount of
F2-isoprotanes was induced by the paraquat
treatment. Although brain may be better protected from paraquat
toxicity than other tissues (38)
, there may be different
susceptibilities among various regions of the brain to this oxidative
stress. Overall, the protection of GPX1 against in vivo
formation of F2-isoprotanes has
pathophysiological implications. Burk et al. (37)
suggested that a pro-oxidant such as diquat exerted its acute toxicity
in rats largely through lipid peroxidation. Thus, GPX1 mimic might be
used to remedy that type of toxicity (38)
. An increase of
F2-isoprotanes was shown in the brains of
Alzheimer's patients (39)
, indicating a possible
involvement of GPX1 in the pathogenesis. In addition, NADH and NADPH
affected vitamin E and Se deficiency-induced lipid peroxidation in
liver plasma membrane of rats (40)
. Seemingly, the effects
of GPX1 on the paraquat-induced depletion of NADPH or NADH and lipid
peroxidation are physiologically related.
In an earlier study (41)
, paraquat injection (50 mg/kg)
resulted in an increase of protein carbonyl contents in lung of
hamsters. Here we have shown not only the same inductive effect of
paraquat on protein oxidation in liver of mice, but also the protection
of GPX1 against this oxidation. Because ·OH and
O2·-induced protein oxidation could
be inhibited by excessive bilirubin or Trolox, a water-soluble analog
of vitamin E (42)
, the mechanism of this GPX1 protection
may attribute to its ability to eliminate
H2O2. Hepatic carbonyl
contents in the GPX1 knockout or deficient mice reached plateau just
1 h after the injection of paraquat. It is likely that the drastic
stress produced excessive oxidized proteins that could not be
metabolized timely (43)
.
Increases in GPX activities were shown in paraquat-resistant HL-60 and
HeLa cells (44
, 45)
. Recently, de Haan et al.
(11)
reported an induction of GPX activity in lung of WT
4 h after an injection of 30 mg paraquat/kg. But they did not
verify whether the increased GPX activity was exclusively from GPX1. In
the present study, we have detected responses of lung GPX1 protein and
GPX4 activity to paraquat treatment. Our data indicate that the
increase in total GPX activity in lung of the Se-adequate WT was
primarily due to pulmonary GPX1 expression, and contributions of other
GPX forms (46)
should be minimal. Furthermore, we have
observed a significant decrease of lung GPX activity immediately after
the linear increase between 0 and 2 h, a different temporal
pattern from that of de Haan et al. (11)
. Reduction of GPX
expression has been shown in mice treated with nafenopin
(47)
or paraquat and SOD inhibitor (48). The upstream
oxygen response element in the GPX1 gene (49)
may
conceivably allow its expression in lung affected by paraquat through
alteration of pulmonary O2 pressure. However, the
transcriptional induction of GPX1 promoter by paraquat is saturable
(11)
, and our data indicate that the regulation may not
necessarily be unilateral.
We found that lung SOD activity decreased in response to paraquat
injection and GPX1 knockout or deficiency augmented such an effect.
Because SOD catalyzes the dismutation of
O2· into
H2O2, the substrate of
GPX1, a balance between these two enzymes is important to prevent the
subsequent deleterious actions of
H2O2 (50)
.
This might be particularly true in the paraquat-challenged GPX1(-/-)
and Se-deficient WT because
H2O2 was generated
continuously by paraquat (16
, 17)
whereas
H2O2 removal was diminished
by the lack of GPX1. The accumulation of cellular
H2O2 would result in
formation of ·OH that leads to lethal injuries
(17
, 50)
. Thereby, the decrease of SOD activity, due to
either the feedback of its end product
H2O2 (51)
or
the inactivation by O2· (52)
, may
be viewed as a protective response under the circumstance
(53
54
55
56)
. With a normal expression of GPX1, the
Se-adequate WT had minimal change in tissue SOD activity in response to
paraquat. In conclusion, GPX1 plays critical roles in maintaining the
redox status of mice under acute oxidative stress and protects against
the paraquat-induced lipid peroxidation and protein oxidation in
vivo. Expression of GPX1 protein and activity in lung of the
Se-adequate WT is responsive to the acute oxidative stress of paraquat.
The GPX1 knockout or deficiency augments lung SOD activity loss in
response to that stress.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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Received for publication December 21, 1998.
Revision received March 9, 1999.
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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(PGF2) receptor. J. Biol. Chem. 272,27147-27154This article has been cited by other articles:
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Y. Fu, W.-H. Cheng, D. A. Ross, and X. g. Lei Cellular Glutathione Peroxidase Protects Mice Against Lethal Oxidative Stress Induced by Various Doses of Diquat Experimental Biology and Medicine, November 1, 1999; 222(2): 164 - 169. [Abstract] [Full Text]
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A linear decrease (P<0.01) from 1 to
4 h. The pooled SEM (df=8) are as
follows: A) liver NADPH/NADP ratio: 0 h, 23.34;
1 h, 7.94; 2 h, 7.95; 3 h, 8.83; 4 h, 8.49;
B) liver NADH/NAD ratio: 0 h, 14.58; 1 h,
7.40; 2 h, 8.98; 3 h, 6.85; 4 h, 4.38; C)
lung NADPH/NADP ratio: 0 h, 9.80; 0.5 h, 9.94; 1 h,
4.26; 2 h, 3.25; 3 h, 5.84; 4 h, 4.18; D)
lung NADH/NAD ratio: 0 h, 16.98; 0.5 h, 4.76; 1 h,
11.24; 2 h, 8.22; 3 h, 9.78; 4 h, 8.09.
