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The Journal of Nutrition Vol. 128 No. 8 August 1998,
pp. 1289-1295
Nutritional Sciences Program and * Department of Pathology
School of Medicine, University of Missouri, Columbia MO 65211
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ABSTRACT |
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Abstract
Introduction
Methods
Results
Discussion
References
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We have previously shown that changes in glutathione peroxidase-1 (GPX1; H2O2:oxidoreductase, EC 1.11.1.9), plasma thyroid hormone and glutathione-S-transferase were not associated with changes in growth observed in second-generation (F2) severely Se-deficient rats; we also found that liver phospholipid hydroperoxide glutathione peroxidase (GPX4; EC 1.11.1.12) activity falls in first-generation (F1) Se-deficient rats to 41% of levels in Se-adequate rats. The purposes of this study were to determine the effect of F2 Se deficiency on GPX4 and to detect early changes in Se parameters associated with growth after single, small Se injections. Se-deficient male F2 weanling rats were randomly divided into two groups and fed a Se-deficient crystalline amino acid (0.003 µg Se/g diet; 
Se) diet or that diet supplemented for 14 d with 0.2 µg Se/g diet (+Se) as Na2SeO3. Growth of Se rats was 55% of the rate of +Se rats. Liver Se, GPX1 activity, GPX4 activity and testis GPX4 activity in Se rats at 14 d were 1, 2, 23 and 13%, respectively, of levels in +Se rats. In a series of experiments, additional F2 male weanling rats were fed the Se diet for 14 d and then were given an intraperitoneal single saline injection of 0, 1 or 5 µg Se/100 g body weight (BW) as Na2SeO3 and killed 1 or 7 d later. Rats injected with 1 or 5 µg Se/100 g BW grew 36 or 48%, respectively, above the rate of saline-injected rats. Liver Se concentration increased 367% and testis GPX4 activity doubled in rats 1 d after injection of 1 µg Se/100 g BW compared with saline-injected rats; these parameters were further elevated with 5 µg Se/100 g BW injections. Increases in liver Se and testis GPX4 activity were the parameters best associated with improved growth after Se injection, but the molecular role for Se in growth remains unclear.
selenium deficiency ·
selenium repletion
We previously developed a second-generation (F2)5 severely Se-deficient weanling rat model (Thompson et al. 1995 Phospholipid hydroperoxide glutathione peroxidase (GPX4; EC 1.11.1.12) is a second intracellular Se-dependent peroxidase that is widely distributed in animal tissues (Ursini et al. 1982 The purpose of this study was to determine the effect of F2 Se deficiency on GPX4 activity. In addition, F2 Se-deficient rats were given single injections of 1 or 5 µg Se/100 g BW, and parameters of Se status, including growth, liver Se, GPX1 activity and GPX4 activity, were measured to detect early changes in Se status that were associated with the reversal of Se deficiency.
Animals and diets.
Weanling female rats (Holtzman Sprague Dawley, Madison, WI) were fed a Se-deficient torula yeast-based diet for at least 6 wk, resulting in F1 Se-deficient rats. The basal Se-deficient 30% torula yeast diet (Knight and Sunde 1987 Se deficiency experiment.
To determine the effect of F2 Se deficiency on GPX4 activity as well as growth and other parameters, 22 male F2 weanling rats from four litters were randomly divided into two groups and fed either the Se-deficient crystalline amino acid diet or that diet supplemented with 0.2 µg Se/g as Na2SeO3. Rats were weighed daily and killed on d 14.
Se injection experiments.
An additional 65 F2 male weanling rats from 11 litters were fed the Tissue analyses.
Rats were anesthetized with ether, blood was drawn and centrifuged at 1,000 × g for 15 min at 4°C using sodium heparin to prevent coagulation, and plasma was stored as described previously (Thompson et al. 1995 Statistical analysis.
Data analysis comparing two treatments ( Dietary F2 Se deficiency.
When F2 Se-deficient male weanling rats were fed the Se-deficient crystalline amino acid diet or supplemented with 0.2 µg Se/g for 14 d, growth rates were 3.65 and 6.68 g/d, respectively (Fig. 1). At d 14, liver Se concentration and GPX1 activity in Se-deficient rats were 1 and 2%, respectively, of the levels found in rats fed 0.2 µg Se/g diet (Figs. 2 and 3). The level of liver GPX1 activity when these F2 Se-deficient rats were repleted with 0.2 µg Se/g diet for just 14 d was 92% of the mean liver GPX1 activity found in male weanling rats fed 0.2 µg Se/g diet for 14 or 28 d (Lei et al. 1995
One-day repletion by Se injection.
When F2 Se-deficient male weanling rats were fed the Se-deficient amino acid diet for 14 d and then injected with 1 or 5 µg Se/100 g BW, growth the following day was 59 and 81% greater (0.1< P < 0.2 and P < 0.05, respectively) compared with saline-injected rats. Liver Se concentration increased significantly 1 d after 1 or 5 µg Se/100 g BW injections to 367 and 2800%, respectively, above the levels in saline-injected rats (Fig. 2, Table 1). Liver GPX1 and GPX4 activities were unaffected by 1 µg Se/100 g BW, but were significantly greater in rats injected with 5 µg Se/100 g BW compared with saline-injected controls (Fig. 3). The 1 and 5 µg Se/100 g BW injections also significantly elevated the plasma T3/T4 ratios (Fig. 5). On the bases of liver Se concentration and plasma T3/T4 levels, it is clear that Se status improved 1 d after 1 µg Se/100 g BW injection, but this injection was not sufficient to increase liver GPX1 and GPX4 activities.
Seven-day repletion by Se injection.
Growth of rats injected with 1 and 5 µg Se/100 g BW over the subsequent 7-d period was 36 and 48%, respectively, greater (P < 0.05) than that of saline-injected rats (Fig. 1), showing the dramatic effect on growth of as little as 1 µg (12.7 nmol) Se per 100 g BW. Liver Se concentration was raised significantly to 140 or 875% above saline-injected levels in rats injected with 1 or 5 µg Se/100 g BW, respectively (Fig. 2, Table 1). Neither 1 nor 5 µg Se/100 g rat significantly affected liver GPX1 and GPX4 activities 7 d after injection (Figure 3). T3/T4 ratios were not altered by 1 µg Se/100 g BW injection, but 5 µg Se/100 g BW significantly raised T3/T4 ratios 86% above ratios in saline-injected controls (Fig. 5). Of the 7-d Se parameters described thus far, liver Se concentration appeared to be the most sensitive to changes in Se because it was significantly affected in a graded fashion with 1 and 5 µg Se/100 g BW.
These studies were focused on the use of GPX4 activity to monitor alterations in Se status associated with changes in growth in the F2 Se-deficient rat. When 21-d-old weanling pups from Se-deficient dams were fed a Se-deficient crystalline amino acid diet, the rats grew at 55% of the rate of littermates supplemented with 0.2 µg Se/g diet over an initial 2-wk period. This depressed growth is similar to the 68 and 53% growth rates observed in our previous experiments with F2 Se-deficient rats fed the crystalline amino acid diet for 14 and 28 d, respectively (Thompson et al. 1995
INTRODUCTION
Abstract
Introduction
Methods
Results
Discussion
References
) based on the multiple-generation Se deficiency model of Behne and co-workers (1990) and the Se-deficient crystalline amino acid diet model of Beckett and colleagues (1987). In this model, Se-deficient male rats grow at 54-69% of the rate for rats supplemented with 0.2 µg Se/g diet. A single injection of as little as 1 µg Se/100 g body weight (BW) is sufficient to increase growth rate significantly without increasing liver glutathione peroxidase-1 (GPX1; H2O2:oxidoreductase, EC 1.11.1.9) activity. Plasma triiodothyronine (T3) levels are depressed in this F2 Se deficiency model (Thompson et al. 1995) as well as in first-generation (F1) Se-deficient models (Beckett et al. 1987); we found, however, that restoration of plasma T3 by continuous infusion did not restore growth. Thus we expanded our study to additional Se-dependent parameters that changed in association with Se-mediated restoration of growth.
and 1985). In F1 Se-deficient rats fed the crystalline amino acid diet, liver GPX4 activity decreases to only 41% of Se-adequate levels compared with decreases to 1% for GPX1 activity; approximately half as much dietary Se is required for maximal GPX4 activity as is required for maximal GPX1 activity (Lei et al. 1995). Furthermore, the level of rat liver GPX4 mRNA is little affected by Se deficiency, whereas the GPX1 mRNA level falls to 10% of the Se-adequate level (Sunde et al. 1993). In F1 Se-deficient thyroid, GPX4 activity is not reduced by Se deficiency, whereas GPX1 activity decreases to only 50% of Se-adequate levels (Bermano et al. 1996). Thus we hypothesized that F2 Se deficiency might result in further reductions in GPX4 activity and that these reductions in GPX4 in liver or other tissues might be associated with the impaired growth.
MATERIALS AND METHODS
Abstract
Introduction
Methods
Results
Discussion
References
) contained 0.007 µg Se/g diet by analysis, and was supplemented with 100 mg/kg all-rac-
-tocopheryl acetate to insure prevention of liver necrosis. F1 females were then bred to Se-adequate male rats to produce F2 severely Se-deficient rats, as described previously (Thompson et al. 1995). Each litter was culled to eight pups 5 d after birth. At weaning, F2 rats were fed the Se-deficient basal crystalline amino acid diet (0.003 µg Se/g; Se) (Thompson et al. 1995) supplemented with 150 mg/kg all-rac--tocopheryl acetate. Care and treatment of experimental animals was approved by the Institutional Animal Care and Use Committee at the University of Missouri. Unless otherwise indicated, all named chemicals were obtained from Sigma Chemical (St. Louis, MO).
Se diet; on d 14, each litter was randomly divided, and half the rats were given a single control intraperitoneal injection of phosphate-buffered saline (1 µL/g BW); the other half were given a single intraperitoneal injection of Se in PBS. Se was administered at a level of 1 or 5 µg Se/100 g BW as Na2SeO3, and rats were killed 1 or 7 d after injection. All rats were weighed twice weekly before injection and then daily after injection.
). Livers were perfused in situ with ice-cold 0.15 mol/L KCl and all tissues were kept on ice until frozen at 20oC. Tissues were homogenized in nine volumes of 0.25 mol/L sucrose, 20 mmol/L Tris-HCl and 0.1% peroxide-free Triton X-100, pH 7.4. Homogenates were centrifuged at 4oC (10,000 × g for 15 min) (J2-21M centrifuge, JA21 rotor, Beckman Instruments, Palo Alto, CA) to obtain supernatants. GPX4 activity was measured with a coupled assay procedure using 3 mmol/L GSH and 78 µmol/L phosphatidylcholine hydroperoxide as described previously (Lei et al. 1995). A GPX4 enzyme unit (EU) is one micromole GSH oxidized per minute under these conditions. GPX1 activity was measured with a coupled assay procedure (Lawrence et al. 1974) using 2 mmol/L GSH and 0.12 mmol/L H2O2. A GPX1 enzyme unit (EU) is one micromole GSH oxidized per minute under these conditions. Supernatant protein concentrations were assayed spectrophotometrically (Lowry et al. 1951). Plasma thyroxine (T4) and T3 were quantitated by immunoassay as described previously (Thompson et al. 1995).
) except that integrated peak areas were chosen by Interactive Peak Search software (Canberra/ND, Schaumburg, IL). Bovine liver (National Bureau of Standards, Gaithersburg, MD) was used for reference standards.
Se and +Se) was conducted using the unpaired student's t test, and P < 0.05 was considered significant. Slope analysis was performed by linear regression analysis, and significant differences in slopes were calculated using SAS (version 6.04, SAS Institute, Cary, NC) following the method of Steel and Torrie (1960). Values in the text are means ± SEM.
RESULTS
Abstract
Introduction
Methods
Results
Discussion
References
; data not shown), showing that the levels of Se-dependent parameters measured in the F2 rats fed the 0.2 µg Se/g diet for 14 d are good estimates of Se-adequate values. GPX1 activities in Se-deficient lung, thymus, testis and heart were 12, 18, 28 and 9%, respectively, of levels in rats fed 0.2 µg Se/g diet (Figs. 3 and 4, Table 1). Plasma T3/T4 ratios in Se-deficient rats at 14 d were 35% of the ratios in rats fed 0.2 µg Se/g diet (Fig. 5). The reduced growth, liver Se concentration, GPX1 activities and plasma T3/T4 ratio clearly show that the Se-deficient rats were severely Se-deficient.
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Fig 1.
Effect of dietary Se and Se injection on growth in second-generation Se-deficient male rats. Panel A: Male second-generation Se-deficient weanling rats (22 rats from 4 litters) were fed the Se-deficient ( Se) crystalline amino acid diet or that diet supplemented with 0.2 µg Se/g for 14 d. Growth rates of Se and 0.2 µg Se/g body weight (BW) were 3.65 ± 0.35 and 6.68 ± 0.53 g/d, respectively. Panel B: one litter of seven male second-generation Se-deficient weanling rats was fed the Se-deficient (Se) crystalline amino acid diet for 22 d. On day 15, Se rats were given a single intraperitoneal injection (Inj) of saline or 1 µg Se/100 g BW as Na2SeO3 and killed 1 or 7 d later. Growth rates of Se rats and rats injected with 1 µg Se/100 g BW were 6.33 ± 0.33 and 8.64 ± 0.18 g/d, respectively. Panel C: one litter of seven male second-generation Se-deficient weanling rats was fed the Se-deficient (Se) crystalline amino acid diet for 21 d. On day 14, Se rats were given a single intraperitoneal injection of saline or 5 µg Se/100 g BW as Na2SeO3 and killed 1 or 7 d later. Growth rates of Se rats and rats injected with 5 µg Se/100 g BW were 4.09 ± 0.43 and 6.07 ± 0.62 g/d, respectively. Values are means ± SEM.
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Fig 2.
Effect of Se injection on liver Se concentration in second-generation Se-deficient male rats. Male second-generation Se-deficient weanling rats were fed the basal Se-deficient ( Se) amino acid diet for 14 d or that diet supplemented with 0.2 µg Se/g. On d 14 or 15, additional groups of Se rats were given a single intraperitoneal injection of saline, 1 or 5 µg Se/100 g body weight (BW) as Na2SeO3 and killed 1 or 7 d later. Values are means ± SEM. *Indicates significant difference between the Se and corresponding +Se treatment. The dotted line represents the level of liver Se in rats supplemented with 0.2 µg Se/g diet for 14 d. The number of rats in each treatment from left to right is as follows: 0.2, n = 12; Se, n = 10; saline-injected 1 d, n = 10; 1 µg 1 d, n = 11; saline-injected 1 d, n = 15; 5 µg 1 d, n = 15; saline-injected 7 d, n = 3; 1 µg 7 d, n = 4, saline-injected 7 d, n = 3; and 5 µg 7 d, n = 4.
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Fig 3.
Effect of Se injection (inj) on glutathione peroxidase-1 (GPX1, upper panels) and phospholipid hydroperoxide glutathione peroxidase (GPX4, lower panels) activities in liver, lung and thymus of second-generation Se-deficient male rats. Treatments are as described in Figure 2. Values are means ± SEM. *Indicates significant difference between the Se and corresponding +Se treatment. The dotted line represents the level of tissue activity in rats supplemented with 0.2 µg Se/g diet for 14 d. In liver, the number of rats in each treatment from left to right is as follows: 0.2, n = 12; Se, n = 10; saline-injected 1 d, n = 10; 1 µg 1 d, n = 11; saline-injected 1 d, n = 15; 5 µg 1 d, n = 15; saline-injected 7 d, n = 3; 1 µg 7 d, n = 4, saline-injected 7 d, n = 3; and 5 µg 7 d, n = 4. In lung, the number of rats in each treatment from left to right is as follows: 0.2, n = 5; Se, n = 3; saline-injected 1 d, n = 6; 1 µg 1 d, n = 6; saline-injected 1 d, n = 6; 5 µg 1 d, n = 6; saline-injected 7 d, n = 3; 1 µg 7 d, n = 4, saline-injected 7 d, n = 3; and 5 µg 7 d, n = 4. In thymus, the number of rats in each treatment from left to right is as follows: 0.2, n = 5; Se, n = 3; saline-injected 1 d, n = 6; 1 µg 1 d, n = 6; saline-injected 1 d, n = 10; 5 µg 1 d, n = 10; saline-injected 7 d, n = 3; 1 µg 7 d, n = 4, saline-injected 7 d, n = 3; and 5 µg 7 d, n = 4.
View this table:
Table 1.
Selenium retention factors (Retf) in F2 Se-deficient rats, and selenium restoration factors (Restf) 1 or 7 d after Se injection1,2,3
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Fig 4.
Effect of Se injection on glutathione peroxidase-1 (GPX1, upper panel) and phospholipid hydroperoxide glutathione peroxidase (GPX4, lower panel) activities in testis of second-generation Se-deficient male rats. Treatments are as described in Figure 2. Values are means ± SEM. *Indicates significant difference between the Se and corresponding +Se treatment. The dotted line represents the level of testis activity in rats supplemented with 0.2 µg Se/g diet for 14 d. The number of rats in each treatment from left to right is as follows: 0.2, n = 12; Se, n = 10; saline-injected 1 d, n = 10; 1 µg 1 d, n = 11; saline-injected 1 d, n = 10; 5 µg 1 d, n = 10; saline-injected 7 d, n = 3; 1 µg 7 d, n = 4, saline-injected 7 d, n = 3; and 5 µg 7 d, n = 4.
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Fig 5.
Effect of Se injection on plasma triiodothyronine/thyroxine (T3/T4) ratio in second-generation Se-deficient male rats. Treatments are as described in Figure 2. Values are means ± SEM. *Indicates significant difference between the Se and corresponding +Se treatment. The dotted line represents the level of plasma T3/T4 in rats supplemented with 0.2 µg Se/g diet for 14 d. The number of rats in each treatment from left to right is as follows: 0.2, n = 12; Se, n = 10; saline-injected 1 d, n = 10; 1 µg 1 d, n = 11; saline-injected 1 d, n = 15; 5 µg 1 d, n = 15; saline-injected 7 d, n = 3; 1 µg 7 d, n = 4, saline-injected 7 d, n = 3; and 5 µg 7 d, n = 4.
, as the percentage of a parameter's value that is retained in Se deficiency relative to the level in Se-adequate rats. These values are shown in Table 1. Inspection showed that the Retf could be placed into three groups as follows: parameters with Retf <10%, indicating that these tissues had a low priority for Se retention, included liver Se, liver GPX1, heart GPX1 and muscle GPX4; parameters with Retf between 10 and 40%, indicating a modest priority for Se retention, included testis GPX1 and GPX4, lung GPX1 and GPX4, and thymus GPX1 and GPX4; parameters with Retf >40%, indicating that Se-adequate levels of these parameters were retained preferentially during Se deficiency, included cerebrum GPX4, plasma T3, cerebrum GPX1, muscle GPX1 and growth rate.
DISCUSSION
Abstract
Introduction
Methods
Results
Discussion
References
). In contrast, weanling pups from Se-adequate dams fed Se-deficient diets for 28 d in recent experiments did not show significant growth depression (Lei et al. 1995, Weiss et al. 1996), and experiments conducted several decades ago reported only typical 85% growth rates when pups of Se-adequate dams were fed Se-deficient diets (Hafeman et al. 1974, Hurt et al. 1971). Thus the dramatically impaired growth, resulting from a combination of F2 Se deficiency and use of the crystalline amino acid diet, can be used as a parameter to distinguish severely Se-deficient rats from more moderately deficient rats.
), F1 Se-deficient rats retained 41% of the liver GPX4 activity found in Se-adequate rats. Thus GPX4 activity can be further reduced with increasing severity of Se deficiency. In contrast, liver GPX1 activity is so low in F1 Se-deficient rats that there is effectively no further reduction in GPX1 activity associated with F2 Se deficiency. Liver Se concentration fell to 0.07 nmol Se/g in F2 Se-deficient rats in this study, similar to the 0.04-0.08 nmol Se/g we observed previously in F2 rats fed Se-deficient diets for 14-21 d (Thompson et al. 1995), and lower than the 0.16 nmol Se/g concentration we found in F1 Se-deficient rats (Lei et al. 1995). Thus liver Se can also be used to distinguish severely Se-deficient rats from moderately Se-deficient rats.
developed the Rf Se retention factor, calculated as the ratio of 75Se specific activity in Se-depleted vs. Se-supplemented rats. We defined a similar Retf Se retention factor so that we could compare the various Se-dependent parameters on the basis of apparent priority for Se during Se depletion. We used the levels of Se-dependent parameters measured in the F2 rats fed the 0.2 µg Se/g diet for 14 d as Se-adequate values in these calculations because these are aged-matched rats from the same litter and because liver GPX1 activity is restored to the same level as found in F1 male weanling rats fed this diet for 14 d (Lei et al. 1995, data not shown). We found that liver Se, liver GPX1 and GPX4 activities, heart GPX1 and GPX4 activities, and muscle GPX4 activity had low or moderate Retf values. Behne et al. (1988) reported liver, heart and muscle as tissues with the lowest priority for 75Se retention. Se parameters with high Retf values and thus high priority for Se retention (>40%) include cerebrum GPX4, cerebrum GPX1, plasma T3 and growth. Thus the present experiments clearly support the hypothesis of Behne et al. (1988) that brain and endocrine organs have the highest priority for Se retention. The low Retf values for testis GPX1 and GPX4 activities in this study, however, do not at first glance support the inclusion of reproductive organs (Behne et al. 1988) with brain and endocrine tissues.
reported that brain had the highest retention of 75Se relative to the other organs examined, with a retention factor of 51.9%. We previously observed a 50% decrease in brain GPX1 activity in F2 Se-deficient rats fed the Se-deficient diet for 75 d compared with levels in rats supplemented with 0.1 µg Se/g diet (Thompson et al. 1995). This shows the relative resistance of brain to changes in selenoperoxidase activity compared with liver and other tissues.
). In this study, we found that 1 and 5 µg Se/100 g BW yielded significant 36 and 48% increases, respectively, in growth rate. In all of these experiments, the increased growth after Se injection is linear and starts within 24 h of the Se injection (see Fig. 1). Clearly biochemical changes occur within 24 h after Se injection that persist throughout the 7-d period. Thus we were most interested in detected changes that occurred within 24 h of Se injection of 1 µg Se/100 g BW. Our previous study eliminated circulating T3 as the causative agent, and thus we focused on other Se-parameters in this study.
). These changes in liver Se concentration suggest that increased Se in tissues other than liver is more likely responsible for the increased growth.
) of the reproductive organs in the group of tissues with high priority for Se. This apparent discrepancy likely occurred because rodent testis rapidly acquires Se ~40 d after birth (Behne et al. 1986, Evenson and Sunde 1988, Weitzel et al. 1990). Thus low Retf values for testis GPX4 activity are most likely not due to loss of testis Se in the Se-deficient rats but rather to rapid acquisition of Se in the testis during the 14 d of Se repletion in the +Se group.
) as well as castrated rats (Evenson and Sunde 1989). More likely, the elevated testis GPX4 activity indicates that Se levels, necessary for other Se-dependent processes in other tissues such as endocrine organs, were increased sufficiently in rats by the 1 µg Se/100 g BW injection to lead to increased growth. Reiter and Wendel (1984) found that 1 µg Se/100 g BW in mice was not sufficient to alter liver GPX1 activity, but was sufficient to alter nine hepatic drug metabolizing enzymes (some increase, some decrease). They concluded that this excluded stoichiometric involvement of Se, but instead suggested alterations in a Se-dependent mediator. Potential Se-dependent biochemical candidates could include partial restoration of plasma selenoprotein P, thioredoxin reductase, one of the selenium-dependent deiodinases or one or more of the other 30-50 uncharacterized selenoproteins (Arthur and Beckett 1994, Burk and Hill 1993, Sunde 1994 and 1997).
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FOOTNOTES |
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Se, selenium-deficient diet; +Se, selenium-supplemented diet; T3, triiodothyronine; T4, thyroxine.
Manuscript received 17 October 1997. Initial reviews completed 12 February 1998. Revision accepted 13 April 1998.
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ACKNOWLEDGMENTS |
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The authors thank Janice Vansciver for performing the T3 and T4 analyses. Selenium analyses were conducted at the Missouri University Research Reactor, and the authors thank Vickie Spate and J. Steven Morris for their cooperation in conducting those analyses.
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LITERATURE CITED |
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Abstract
Introduction
Methods
Results
Discussion
References
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II: independence of glutathione peroxidase and reversibility of hepatic enzyme modulations in deficient mice.
Biochem. Pharmacol.
1984;
33:1923-1928[Medline] structure, regulation and function. In: Selenium in Biology and Human Health (Burk, R. F., ed.), pp. 45-77. Springer-Verlag, New York, NY.This article has been cited by other articles:
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  M. S. Scimeca, D. J. Lisk, T. Prolla, and X. G. Lei Effects of gpx4 Haploid Insufficiency on GPx4 Activity, Selenium Concentration, and Paraquat-Induced Protein Oxidation in Murine Tissues Experimental Biology and Medicine, November 1, 2005; 230(10): 709 - 714. [Abstract] [Full Text] [PDF]
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 R. S. Esworthy, L. Yang, P. H. Frankel, and F.-F. Chu Epithelium-Specific Glutathione Peroxidase, Gpx2, Is Involved in the Prevention of Intestinal Inflammation in Selenium-Deficient Mice J. Nutr., April 1, 2005; 135(4): 740 - 745. [Abstract] [Full Text] [PDF]
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J. K. Evenson, A. D. Wheeler, S. M. Blake, and R. A. Sunde Selenoprotein mRNA Is Expressed in Blood at Levels Comparable to Major Tissues in Rats J. Nutr., October 1, 2004; 134(10): 2640 - 2645. [Abstract] [Full Text] [PDF]
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 E. Kumaraswamy, A. Malykh, K. V. Korotkov, S. Kozyavkin, Y. Hu, S. Y. Kwon, M. E. Moustafa, B. A. Carlson, M. J. Berry, B. J. Lee, et al. Structure-Expression Relationships of the 15-kDa Selenoprotein Gene. POSSIBLE ROLE OF THE PROTEIN IN CANCER ETIOLOGY J. Biol. Chem., November 3, 2000; 275(45): 35540 - 35547. [Abstract] [Full Text] [PDF]
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