![[Feedback]](/icons/banner/feedbackACT.gif){kind=icon}
![[For Subscribers]](/icons/banner/subscriberACT.gif){kind=icon}
![[Archive]](/icons/banner/archiveACT.gif){kind=icon}
![[Search]](/icons/banner/searchACT.gif){kind=icon}
![[Contents]](/icons/banner/tocACT.gif){kind=icon}
|
|
|
|
|
||
Department of Animal Science, Cornell University, Ithaca, NY 14853 and * Laboratory of Molecular Gerontology, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224
3To whom correspondence should be addressed. E-mail: XL20{at}cornell.edu.
 |
ABSTRACT |
|---|
 TOP ABSTRACT LITERATURE CITED |
|---|
KEY WORDS: • glutathione peroxidase-1 • selenium • signaling • oxidative stress • insulin resistance
The nutritional essentiality of Se (1) and cellular glutathione peroxidase (glutathione:H2O2 oxidoreductase, EC 1.11.1.9, GPX1)4 (2), 2 important discoveries in 1957, were linked by the identification of GPX1 as an Se-containing enzyme in 1972 (3,4). Subsequent biochemical characterizations of GPX1 indicated that Se exists in the protein as selenocysteine, and expression of GPX1 is regulated by Se (5). Chambers et al. (6) cloned the first gpx1 gene from mice and unveiled UGA, a stop codon, coding for selenocysteine. Shen et al. (7) dissected the mechanism of Se incorporation into the GPX1 protein, a process that requires a stem-loop structure in the 3'untranslated region of mRNA of all selenoproteins for translating the UGA codon into selenocysteine (8).
As a large portion of body Se (9), tissue GPX1 protein and activity are more prone to Se deficiency than those of other selenoproteins (10,11). Thus, changes of GPX1 activity in erythrocytes or tissues are a sensitive and convenient assessment of body Se status. However, the rapid responsiveness to Se fluctuation, along with its abundance, argues against an important housekeeping function for GPX1 in vivo. Consequently, the role of GPX1 was proposed to be "a buffer or storage of body Se" (12,13), similar to that of ferritin as the storage of body iron. The lack of exclusive evidence for a specific metabolic role of GPX1 in vivo made the "Se buffer" hypothesis appealing for a period of time. Although cell research with altered GPX1 expression (14–16) and animal experiments employing Se mimics or GPX inhibitors (17,18) suggested possible antioxidant roles of GPX1, results from these studies were not physiological or were confounded by effects of other selenoproteins. To overcome these problems, GPX1 knockout (GPX1–/–) mice (19–21) and mice overexpressing GPX1 (GPX1+) (22,23) were developed.
GPX1–/– and GPX1+ as specific models. Compared with the Se-adequate wild-type (WT) mice, knockout of GPX1 resulted in 60% reduction in liver Se concentration (24,25). However, knockout or overexpression of GPX1 did not alter expressions of GPX3, GPX4, thioredoxin reductase, and selenoprotein P in various tissues of mice fed Se-deficient, -adequate, or -excessive diets up to 21 wk of age (23–25). The independent expression of GPX1 from other selenoproteins not only ensures the specificity of these models for studying the physiological functions of GPX1, but also suggests that GPX1 does not affect body Se partitioning for synthesis of other selenoproteins.
Paraquat and diquat are able to produce reactive oxygen species (ROS) in vivo (26,27) and have been used to study the antioxidative role of Se in several species (28–30). Specifically, these 2 prooxidants utilize molecular oxygen to generate the superoxide anion, which is converted by superoxide dismutase into hydrogen peroxide, a substrate of GPX1. This metabolically-derived hydrogen peroxide formation offers an opportunity to test the physiological importance of the GPX1 function. The primary target organ is liver for diquat, and Se deficiency shifts the target organ for paraquat from lung toward liver (27). Earlier work in Se-deficient rats showed that an i.p. injection of Se before diquat injection prevented diquat-induced hepatic lipid peroxidation and liver necrosis (31). Based on repletion profiles of selenoproteins after Se injection (31,32), the researchers ascribed the Se protection to an increased expression of selenoprotein P, but not GPX1. Although the proposed role of selenoprotein P in diquat-mediated oxidative stress remains to be tested using the recently developed selenoprotein P null mice (33), GPX1–/– and GPX+ mice have already given us much better models than Se-deficient rodents with which to accurately assess the GPX1 role in this type of event.
Role of GPX1 in acute, lethal, oxidative stress. After an i.p. injection of paraquat at a dose of 50 mg/kg body weight, Se-adequate WT mice survived longer (P < 0.05) than Se-deficient WT mice (34). The survival time of GPX1–/– mice, regardless of their body Se status, was similar to that of the Se-deficient WT mice. This resulted in a linear relation between mouse survival time and tissue GPX1 activity. Because the same trend also occurred in mice injected with diquat at a dose of 24 mg/kg (35), GPX1 is clearly the mediator of body Se in the protection of mice against lethality induced by these prooxidants. Consistently, overexpression of GPX1 extended mouse survival time by a factor of 10 (59 vs. 5.8 h) compared with that of the WT mice after an i.p. injection of paraquat at 125 mg/kg (34). However, supplementing GPX1–/– mice with high levels of dietary vitamin E (up to 100-fold of daily needs) did not offer the same protection as that provided by GPX1 (36).
To understand the biochemical mechanism of GPX1 protection, we determined tissue F2-isoprostanes (a sensitive marker of lipid peroxidation) and protein carbonyl (a widely used indicator of protein oxidation), after the prooxidant challenge. Responses of these 2 variables to paraquat peaked at 1 h after the injection in GPX1–/– mice, whereas the responses in the Se-adequate WT mice were markedly delayed and attenuated (37). The increases in liver F2-isoprostanes preceded a rise in plasma aminotransferase activity, an indicator of liver necrosis (35). Consistent with an earlier report (38), tissue NADPH:NADP and NADH:NAD ratios were sharply decreased by paraquat injection. Knockout of GPX1 aggravated the redox collapse (37). Likely, GPX1 deficiency potentiated the shift of redox status toward oxidation such that a collapse of the NADPH-dependent metabolic system led to the sudden death of mice. This helps explain why GPX1–/– mice died of a lethal dose of paraquat without showing signs of the histopathology found in Se-adequate WT mice that survived for 3 d (34),
Role of GPX1 in mild oxidative stress. Under Se-adequate conditions, the knockout of GPX1 did not sensitize mice to toxicity caused by a low dose of paraquat (12.5 mg/kg) (39). However, the Se-deficient GPX1–/– mice were more prone than the WT mice to liver aponecrosis, a mixed cell death of apoptosis and necrosis, caused by the same treatment (39). A single i.p. injection of Se (50 µg/kg as Na2SeO3) before the paraquat injection reduced mortality and the severity of liver aponecrosis to a greater extent in the WT mice than in the GPX1–/– mice (39). Also, the liver aponecrosis induced seemed to be more apoptotic in the GPX1–/– mice, but more necrotic in the WT mice (39). These genotype differences were attributed to a small increase in GPX1 activity (4% of the adequate level) after the Se injection in WT mice because this minute amount of GPX1 activity inhibited or delayed the paraquat-induced appearance of activated caspase-3, Bcl-Xs, and GADD45 proteins in liver (39), and modulated c-jun N-terminal kinase (JNK) phosphorylation and the associated p53 phosphorylation on Ser15 in liver (40). Importantly, we found that phosphorylations of endogenous or purified p53 on Ser15 by anti-JNK liver immunocomplexes were affected by GPX1 (40).
Role of GPX1 in coping with reactive nitrogen species (RNS) vs. ROS. Like ROS, RNS are constantly generated metabolically and are involved in many physiological and pathological events. Using a cell-free system, Sies et al. (41) reported that purified bovine GPX1 protected against peroxynitrite-mediated protein nitration. With the availability of GPX1–/– mice, we used diquat (a superoxide generator), S-nitroso-N-acetyl-penicillamine (a NO donor), 3-morpholinosydnonimine (a peroxynitrite generator), and peroxynitrite (a potent RNS) to compare the role of GPX1 in ROS- and RNS-mediated apoptosis measured by DNA fragmentation, cytochrome c release, and caspase-3 activation in primary hepatocytes. It is striking that the knockout of GPX1 rendered these cells susceptible to ROS-induced apoptosis, but resistant to RNS-induced apoptosis (42,43). However, stimulated macrophages isolated from GPX1–/– mice produced more NO than those from the WT mice, and GPX1 protected NO-associated protein carbonyl formation in these cells (44). Nevertheless, our results are in opposition to the notion that GPX1 was a peroxynitrite reductase (41), but are strongly supported by several recent animal studies using RNS-related drugs. Overexpression of GPX1 sensitized mice to acetaminophen-induced lethality and hepatic glutathione depletion (45), whereas knockout of GPX1 offered a partial protection against an increase in acetaminophen-induced plasma alanine aminotransferase activity (46) and a strong protection against kainic acid-induced mortality and seizures (47). Seemingly, GPX1 does not protect against, but rather may potentiate, RNS-related oxidative stress.
Role of GPX1 in insulin function. Contrary to the previously reported insulin-mimetic property of Se (48), we showed that GPX1+ mice actually develop hyperglycemia, hyperinsulinemia, elevated body fat accretion and plasma leptin, and insulin resistance (49). Compared with WT mice, these GPX1+ mice exhibited attenuated phosphorylations of Akt on Ser308 and Ser473 and the insulin receptor ß-subunit after insulin stimulation. It is possible that overexpression of GPX1 over-crunches or diminishes intracellular hydrogen peroxide, lifting the inhibition of phosphatase and subsequently accelerating dephosphorylation of proteins in the insulin cascade. A strong positive association between erythrocyte GPX1 activity increases and insulin resistance has been shown in humans during normal pregnancy (50). These results create a fascinating new field of GPX1 research, and alert us that potential detrimental effects of upregulating the expression of GPX1 or similar antioxidant enzymes should not be ignored.
In summary, using the GPX1–/– mice, other groups demonstrated the role of GPX1 in protecting against ischemia/reperfusion injury (51,52), virus-induced myocarditis (53), endotoxemia (54), and prooxidant-induced neurotoxicity (55,56). Although several in vitro or ex vivo studies (57,58) did not show the protection by GPX1 against ROS-related oxidative stress, evidence for such a role for GPX1 in vivo from whole-animal experiments is unequivocal. The physiological importance and biochemical mechanism of GPX1 in defending ROS-related stress vary with the insult level and body Se status (Fig. 1). It is striking that GPX1 protects against diquat-induced cell death, but promotes peroxynitrite-induced cell death. This depicts a contrasting role of GPX1 in coping with ROS vs. RNS (Fig. 2), and suggests that the antioxidant function of GPX1 is not a simple feature, but depends on the nature of the oxidants. The effects of GPX1 overexpression on insulin signaling and function extended GPX1 function from redox regulation to the pathogenesis of chronic diseases. It is important to elucidate the molecular mechanisms and signal pathways for these new roles of GPX1 at the genomic and proteomic levels. Endeavors in this exciting new area of research will presumably continue to benefit from the GPX1–/– and GPX1+ mouse models.
|
|
|
ACKNOWLEDGMENTS |
|---|
|
FOOTNOTES |
|---|
2 Supported in part by National Institutes of Health grant DK53018.
4 Abbreviations used: GPX1, glutathione peroxidase-1; GPX1–/–, GPX1 knockout; GPX1+, GPX1 overexpression; JNK, c-Jun N-terminal kinase; ROS, reactive oxygen species; RNS, reactive nitrogen species; WT, wild-type.
Manuscript received 16 June 2005.
|
LITERATURE CITED |
|---|
|
TOPABSTRACTLITERATURE CITED |
|---|
1. Schwarz K, Foltz CM. Selenium as an integral part of factor 3 against dietary necrotic liver degeneration. J Am Biol Soc. 1957 Jul;79(1):3292-3293.
2. Mills GC. Hemoglobin catabolism. I. Glutathione peroxidase, an erythrocyte enzyme which protects hemoglobin from oxidative breakdown. J Biol Chem. 1957 Nov;229(1):189-197.
3. Flohe L, Gunzler WA, Schock HH. Glutathione peroxidase: a selenoenzyme. FEBS Lett. 1973 May 15;32(1):132-134.
4. Rotruck JT, Pope AL, Ganther HE, Swanson AB, Hafeman DG, Hoekstra WG. Selenium: biochemical role as a component of glutathione peroxidase. Science. 1973 Feb 9;179(73):588-590.
5. Hoekstra WG. Biochemical function of selenium and its relation to vitamin E. Fed Proc. 1975 Oct;34(11):2083-2089.[Medline]
6. Chambers I, Frampton J, Goldfarb P, Affara N, McBain W, Harrison PR. The structure of the mouse glutathione peroxidase gene: the selenocysteine in the active site is encoded by the ’termination’ codon, TGA. EMBO J. 1986;5:1221-1227.[Medline]
7. Shen Q, Chu FF, Newburger PE. Sequences in the 3'-untranslated region of the human cellular glutathione peroxidase gene are necessary and sufficient for selenocysteine incorporation at the UGA codon. J Biol Chem. 1993 May 25;268(15):11463-11469.
8. Berry MJ, Banu L, Chen YY, Mandel SJ, Kieffer JD, Harney JW, Larsen PR. Recognition of UGA as a selenocysteine codon in type I deiodinase requires sequences in the 3' untranslated region. Nature. 1991 Sep 19;353(6341):273-276.
9. Behne D, Wolters W. Distribution of selenium and glutathione peroxidase in the rat. J Nutr. 1983;113:456-461.
10. Lei XG, Evenson JK, Thompson KM, Sunde RA. Glutathione peroxidase and phospholipid hydroperoxide glutathione peroxidase are differentially regulated in rats by dietary selenium. J Nutr. 1995;125:1438-1446.
11. Bermano G, Nicol F, Dyer JA, Sunde RA, Beckett GJ, Arthur JR, Hesketh JE. Selenoprotein gene expression during selenium-repletion of selenium-deficient rats. Biol Trace Elem Res. 1996;51:211-223.[Medline]
12. Burk RF. Molecular biology of selenium with implications for its metabolism. FASEB J. 1991 Jun;5(9):2274-2279.
13. Sunde RA. Intracellular glutathione peroxidases-structures, regulation, and functions. Burk RF eds. Intracellular glutathione peroxidases-structures, regulation, and functions. Selenium in biology and human health. :45-77 Springer-Verlag New York.
14. Mirault ME, Tremblay A, Beaudoin N, Tremblay M. Overexpression of seleno-glutathione peroxidase by gene transfer enhances the resistance of T47D human breast cells to clastogenic oxidants. J Biol Chem. 1991 Nov 5;266(31):20752-20760.
15. Hockenbery DM, Oltvai ZN, Yin XM, Milliman CL, Korsmeyer SJ. Bcl-2 functions in an antioxidant pathway to prevent apoptosis. Cell. 1993 Oct 22;75(2):241-251.
16. Taylor SD, Davenport LD, Speranza MJ, Mullenbach GT, Lynch RE. Glutathione peroxidase protects cultured mammalian cells from the toxicity of adriamycin and paraquat. Arch Biochem Biophys. 1993 Sep;305(2):600-605.[Medline]
17. Asahi M, Fujii J, Suzuki K, Seo HG, Kuzuya T, Hori M, Tada M, Fujii S, Taniguchi N. Inactivation of glutathione peroxidase by nitric oxide. Implication for cytotoxicity. J Biol Chem. 1995 Sep 8;270(36):21035-21039.
18. Muller A, Cadenas E, Graf P, Sies H. A novel biologically active seleno-organic compound-I. Glutathione peroxidase-like activity in vitro and antioxidant capacity of PZ 51 (Ebselen). Biochem Pharmacol. 1984 Oct 15;33(20):3235-3239.
19. Ho YS, Magnenat JL, Bronson RT, Cao J, Gargano M, Sugawara M, Funk CD. Mice deficient in cellular glutathione peroxidase develop normally and show no increased sensitivity to hyperoxia. J Biol Chem. 1997 Jun 27;272(26):16644-16651.
20. de Haan JB, Bladier C, Griffiths P, Kelner M, O’Shea RD, Cheung NS, Bronson RT, Silvestro MJ, Wild S, et al. Mice with a homozygous null mutation for the most abundant glutathione peroxidase, Gpx1, show increased susceptibility to the oxidative stress-inducing agents paraquat and hydrogen peroxide. J Biol Chem. 1998 Aug 28;273(35):22528-22536.
21. Esposito LA, Kokoszka JE, Waymire KG, Cottrell B, MacGregor GR, Wallace DC. Mitochondrial oxidative stress in mice lacking the glutathione peroxidase-1 gene. Free Radic Biol Med. 2000 Mar 1;28(5):754-766.
22. Mirochnitchenko O, Palnitkar U, Philbert M, Inouye M. Thermosensitive phenotype of transgenic mice overproducing human glutathione peroxidases. Proc Natl Acad Sci U S A. 1995 Aug 29;92(18):8120-8124.
23. Cheng WH, Ho YS, Ross DA, Han Y, Combs GF, Jr, Lei XG. Overexpression of cellular glutathione peroxidase does not affect expression of plasma glutathione peroxidase or phospholipid hydroperoxide glutathione peroxidase in mice offered diets adequate or deficient in selenium. J Nutr. 1997;127:675-680.
24. Cheng WH, Ho YS, Ross DA, Valentine BA, Combs GF, Lei XG. Cellular glutathione peroxidase knockout mice express normal levels of selenium-dependent plasma and phospholipid hydroperoxide glutathione peroxidases in various tissues. J Nutr. 1997;127:1445-1450.
25. Cheng WH, Combs GF, Jr, Lei XG. Knockout of cellular glutathione peroxidase affects selenium-dependent parameters similarly in mice fed adequate and excessive dietary selenium. Biofactors. 1998;7:311-321.[Medline]
26. Farrington JA, Ebert M, Land EJ, Fletcher K. Bipyridylium quaternary salts and related compounds. V. Pulse radiolysis studies of the reaction of paraquat radical with oxygen Implications for the mode of action of bipyridyl herbicides. Biochim Biophys Acta. 1973 Sep 26;314(3):372-381.
27. Smith LL. Mechanism of paraquat toxicity in lung and its relevance to treatment. Hum Toxicol. 1987;6:31-36.[Medline]
28. Burk RF, Lawrence RA, Lane JM. Liver necrosis and lipid peroxidation in the rat as the result of paraquat and diquat administration. Effect of selenium deficiency. J Clin Invest. 1980;65:1024-1031.
29. Cagen SZ, Gibson JE. Liver damage following paraquat in selenium-deficient and diethyl maleate-pretreated mice. Toxicol Appl Pharmacol. 1977 May;40(2):193-200.[Medline]
30. Mercurio SD, Combs GF, Jr. Selenium-dependent glutathione peroxidase inhibitors increase toxicity of prooxidant compounds in chicks. J Nutr. 1986;116:1726-1734.
31. Burk RF, Hill KE, Awad JA, Morrow JD, Kato T, Cockell KA, Lyons PR. Pathogenesis of diquat-induced liver necrosis in selenium-deficient rats: assessment of the roles of lipid peroxidation and selenoprotein P. Hepatology. 1995;21:561-569.[Medline]
32. Atkinson JB, Hill KE, Burk RF. Centrilobular endothelial cell injury by diquat in the selenium-deficient rat liver. Lab Invest. 2001;81:193-200.[Medline]
33. Hill KE, Zhou J, McMahan WJ, Motley AK, Burk RF. Neurological dysfunction occurs in mice with targeted deletion of the selenoprotein P gene. J Nutr. 2004;134:157-161.
34. Cheng WH, Ho YS, Valentine BA, Ross DA, Combs GF, Jr, Lei XG. Cellular glutathione peroxidase is the mediator of body selenium to protect against paraquat lethality in transgenic mice. J Nutr. 1998;128:1070-1076.
35. Fu Y, Cheng WH, Porres JM, Ross DA, Lei XG. Knockout of cellular glutathione peroxidase gene renders mice susceptible to diquat-induced oxidative stress. Free Radic Biol Med. 1999 Sep;27(5–6):605-611.[Medline]
36. Cheng WH, Valentine BA, Lei XG. High levels of dietary vitamin E do not replace cellular glutathione peroxidase in protecting mice from acute oxidative stress. J Nutr. 1999;129:1951-1957.
37. Cheng W, Fu YX, Porres JM, Ross DA, Lei XG. Selenium-dependent cellular glutathione peroxidase protects mice against a pro-oxidant-induced oxidation of NADPH, NADH, lipids, and protein. FASEB J. 1999 Aug;13(11):1467-1475.
38. Witschi H, Kacew S, Hirai KI, Cote MG. In vivo oxidation of reduced nicotinamide-adenine dinucleotide phosphate by paraquat and diquat in rat lung. Chem Biol Interact. 1977 Nov;19(2):143-160.[Medline]
39. Cheng WH, Quimby FW, Lei XG. Impacts of glutathione peroxidase-1 knockout on the protection by injected selenium against the pro-oxidant-induced liver aponecrosis and signaling in selenium-deficient mice. Free Radic Biol Med. 2003 Apr 1;34(7):918-927.
40. Cheng WH, Zheng X, Quimby FR, Roneker CA, Lei XG. Low levels of glutathione peroxidase 1 activity in selenium-deficient mouse liver affect c-Jun N-terminal kinase activation and p53 phosphorylation on Ser-15 in pro-oxidant-induced aponecrosis. Biochem J. 2003 Mar 15;370(Pt 3):927-934.
41. Sies H, Sharov VS, Klotz LO, Briviba K. Glutathione peroxidase protects against peroxynitrite-mediated oxidations. A new function for selenoproteins as peroxynitrite reductase. J Biol Chem. 1997 Oct 31;272(44):27812-27817.
42. Fu Y, Sies H, Lei XG. Opposite roles of selenium-dependent glutathione peroxidase-1 in superoxide generator diquat- and peroxynitrite-induced apoptosis and signaling. J Biol Chem. 2001 Nov 16;276(46):43004-43009.
43. Fu Y, Porres JM, Lei XG. Comparative impacts of glutathione peroxidase-1 gene knockout on oxidative stress induced by reactive oxygen and nitrogen species in mouse hepatocytes. Biochem J. 2001 Nov 1;359(Pt 3):687-695.
44. Fu Y, McCormick CC, Roneker C, Lei XG. Lipopolysaccharide and interferon-gamma-induced nitric oxide production and protein oxidation in mouse peritoneal macrophages are affected by glutathione peroxidase-1 gene knockout. Free Radic Biol Med. 2001 Aug 15;31(4):450-459.
45. Mirochnitchenko O, Weisbrot-Lefkowitz M, Reuhl K, Chen L, Yang C, Inouye M. Acetaminophen toxicity. Opposite effects of two forms of glutathione peroxidase. J Biol Chem. 1999 Apr 9;274(15):10349-10355.
46. Knight TR, Kurtz A, Bajt ML, Hinson JA, Jaeschke H. Vascular and hepatocellular peroxynitrite formation during acetaminophen toxicity: role of mitochondrial oxidant stress. Toxicol Sci. 2001 Aug;62(2):212-220.
47. Jiang D, Akopian G, Ho YS, Walsh JP, Andersen JK. Chronic brain oxidation in a glutathione peroxidase knockout mouse model results in increased resistance to induced epileptic seizures. Exp Neurol. 2000 Aug;164(2):257-268.[Medline]
48. Ezaki O. The insulin-like effects of selenate in rat adipocytes. J Biol Chem. 1990 Jan 15;265(2):1124-1128.
49. McClung JP, Roneker CA, Mu W, Lisk DJ, Langlais P, Liu F, Lei XG. Development of insulin resistance and obesity in mice overexpressing cellular glutathione peroxidase. Proc Natl Acad Sci U S A. 2004 Jun 15;101(24):8852-8857.
50. Chen X, Scholl TO, Leskiw MJ, Donaldson MR, Stein TP. Association of glutathione peroxidase activity with insulin resistance and dietary fat intake during normal pregnancy. J Clin Endocrinol Metab. 2003;88:5963-5968.
51. Yoshida T, Maulik N, Engelman RM, Ho YS, Magnenat JL, Rousou JA, Flack JE, III, Deaton D, Das DK. Glutathione peroxidase knockout mice are susceptible to myocardial ischemia reperfusion injury. Circulation. 1997;96(9 Suppl):II-20.
52. Crack PJ, Taylor JM, Flentjar NJ, de HJ, Hertzog P, Iannello RC, Kola I. Increased infarct size and exacerbated apoptosis in the glutathione peroxidase-1 (Gpx-1) knockout mouse brain in response to ischemia/reperfusion injury. J Neurochem. 2001 Sep;78(6):1389-1399.[Medline]
53. Beck MA, Esworthy RS, Ho YS, Chu FF. Glutathione peroxidase protects mice from viral-induced myocarditis. FASEB J. 1998 Sep;12(12):1143-1149.
54. Jaeschke H, Ho YS, Fisher MA, Lawson JA, Farhood A. Glutathione peroxidase-deficient mice are more susceptible to neutrophil-mediated hepatic parenchymal cell injury during endotoxemia: importance of an intracellular oxidant stress. Hepatology. 1999;29:443-450.[Medline]
55. Klivenyi P, Andreassen OA, Ferrante RJ, Dedeoglu A, Mueller G, Lancelot E, Bogdanov M, Andersen JK, Jiang D, Beal MF. Mice deficient in cellular glutathione peroxidase show increased vulnerability to malonate, 3-nitropropionic acid, and 1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine. J Neurosci. 2000;20:1-7.
56. Zhang J, Graham DG, Montine TJ, Ho YS. Enhanced N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine toxicity in mice deficient in CuZn-superoxide dismutase or glutathione peroxidase. J Neuropathol Exp Neurol. 2000;59:53-61.[Medline]
57. Nakamura K, Wright DA, Wiatr T, Kowlessur D, Milstien S, Lei XG, Kang UJ. Preferential resistance of dopaminergic neurons to the toxicity of glutathione depletion is independent of cellular glutathione peroxidase and is mediated by tetrahydrobiopterin. J Neurochem. 2000;74:2305-2314.[Medline]
58. Spector A, Ma W, Wang RR, Yang Y, Ho YS. The contribution of GSH peroxidase-1, catalase and GSH to the degradation of H2O2 by the mouse lens. Exp Eye Res. 1997;64:477-485.[Medline]
This article has been cited by other articles:
|
|
 |
|
  M. S. Martin-Gronert, J. L. Tarry-Adkins, R. L. Cripps, J.-H. Chen, and S. E. Ozanne Maternal protein restriction leads to early life alterations in the expression of key molecules involved in the aging process in rat offspring Am J Physiol Regulatory Integrative Comp Physiol, February 1, 2008; 294(2): R494 - R500. [Abstract] [Full Text] [PDF]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
, inhibition by GPX1.
, promotion by GPX1.