Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P30044 (antioxidant enzyme)
 8,037 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Cellular glutathione peroxidase (GPx-1), a selenocysteine-containing enzyme, plays a central role in protecting cells from oxidative injury. GPx-1 is ubiquitously expressed in eukaryotic cells where it reduces hydrogen and lipid peroxides to alcohols. Adenosine, which is released from stressed or injured cells, protects against ischemia/reperfusion injury and apoptosis. In this study, we hypothesize that the cytoprotective effect of adenosine involves an increase in the activity of GPx-1. Treatment of human primary pulmonary artery endothelial cells (HPAECs) with 50 micromol/L adenosine in the presence of 10 micromol/L erytho-9-(2-hydroxy-3-nonyl)adenine (EHNA), an adenosine deaminase inhibitor, for 48 hours increased GPx-1 mRNA levels 2-fold. GPx-1 protein and enzyme activity also increased approximately 2-fold after treatment. The induction of GPx-1 expression was found to be a consequence of increased mRNA stability and not an increase in transcription. Bisindolylmaleimide I (BIM), a protein kinase C signaling pathway inhibitor, significantly attenuated the induction of GPx-1 mRNA by approximately 36%. The adenosine/EHNA-treated cells were more resistant to hydrogen peroxide stress. Both pharmacological inhibition and siRNA knockdown of GPx-1 attenuated the protective affect of adenosine/EHNA treatment, indicating that the adenosine-induced increase in GPx-1 contributes to an increase in cellular protection against oxidative stress. These data suggest that adenosine may protect the cardiovascular system from ischemia/reperfusion injury, in part, by enhancing the expression of the central intracellular antioxidant enzyme, GPx-1.
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PMID:Adenosine-dependent induction of glutathione peroxidase 1 in human primary endothelial cells and protection against oxidative stress. 1580 13

Cellular glutathione peroxidase-1 (GPX1) is the first identified and the most abundant selenoprotein in mammals. Although GPX1 has been widely considered to be a major antioxidant enzyme, there has been no direct evidence for such role in vivo until GPX1 transgenic and null mice became available 10 y ago. Using these new models, we demonstrated that GPX1 protects against oxidative stress mediated by reactive oxygen species (ROS), and the physiologic importance of this protection varies with insult level and body Se status. Full expression of GPX1 is needed, and overexpression of GPX1 is beneficial for Se-adequate mice to defend against severe oxidative stress. This function of GPX1 is associated with attenuating the prooxidant-induced oxidation of NADPH, NADH, lipid, and protein in various tissues. In Se-deficient mice, a minute amount of GPX1 activity (4% of adequate levels) protects against hepatic aponecrosis induced by mild oxidative stress. In contrast, knockout of GPX1 renders mice and their hepatocytes resistant to oxidative stress related to reactive nitrogen species (RNS). More intriguingly, mice overexpressing GPX1 develop insulin resistance and obesity, accompanied by a downregulation of insulin-mediated phosphorylations of insulin receptor and Akt protein. In conclusion, GPX1 seems to play contrasting roles in coping with ROS vs. RNS, and its metabolic functions extend beyond redox regulation.
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PMID:New roles for an old selenoenzyme: evidence from glutathione peroxidase-1 null and overexpressing mice. 1617 85

Cellular glutathione peroxidase is a key intracellular antioxidant enzyme that contains a selenocysteine residue at its active site. Selenium, a selenocysteine incorporation sequence in the 3'-untranslated region of the glutathione peroxidase mRNA, and other translational cofactors are necessary for "read-through" of a UGA stop codon that specifies selenocysteine incorporation. Aminoglycoside antibiotics facilitate read-through of premature stop codons in prokayotes and eukaryotes. We studied the effects of G418, an aminoglycoside, on cellular glutathione peroxidase expression and function in mammalian cells. Insertion of a selenocysteine incorporation element along with a UGA codon into a reporter construct allows for read-through only in the presence of selenium. G418 increased read-through in selenium-replete cells as well as in the absence of selenium. G418 treatment increased immunodetectable endogenous or recombinant glutathione peroxidase but reduced the specific activity of the enzyme. Tandem mass spectrometry experiments indicated that G418 caused a substitution of l-arginine for selenocysteine. These data show that G418 can affect the biosynthesis of this key antioxidant enzyme by promoting substitution at the UGA codon.
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PMID:Aminoglycosides decrease glutathione peroxidase-1 activity by interfering with selenocysteine incorporation. 1635 66

Docosahexaenoic acid (DHA, a lipid of marine origin) has been found to enhance the activity of several anticancer drugs through an oxidative mechanism. To examine the relation between chemosensitization by DHA and tumor cells antioxidant status, we used two breast cancer cell lines: MDA-MB-231, in which DHA increases sensitivity to doxorubicin, and MCF-7, which does not respond to DHA. Under these conditions, reactive oxygen species (ROS) level increased on anthracycline treatment only in MDA-MB-231. This was concomitant with a decreased cytosolic glutathione peroxidase (GPx1) activity, a crucial enzyme for protection against hydrogen and lipid peroxides, while major antioxidant enzyme activities increased in both cell lines in response to ROS. GPx-decreased activity was accompanied by an accumulation of glutathione, the GPx cosubstrate, and resulted from a decreased amount of GPx protein. In rat mammary tumors, when a DHA dietary supplementation led to an increased tumor sensitivity to anthracyclines, GPx1 activity was similarly decreased. Furthermore, vitamin E abolished both DHA effects on chemotherapy efficacy enhancement and on GPx1 inhibition. Thus, loss of GPx response to an oxidative stress in transformed cells may account for the ability of peroxidizable targets such as DHA to enhance tumor sensitivity to ROS-generating anticancer drugs.
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PMID:Sensitization by docosahexaenoic acid (DHA) of breast cancer cells to anthracyclines through loss of glutathione peroxidase (GPx1) response. 1826 29

Workers exposed to benzene frequently suffer from toxicities of the bone marrow as well as the central nervous, immune, and reproductive systems. This toxicity most likely is a result of the oxidative metabolism of benzene to reactive products. As green tea possesses antioxidant effects, the objective of this study was to examine any amelioration of benzene-induced oxidative stress in pump workers drinking 6 cups (150 ml/cup) of freshly prepared tea daily. Sixty male non-smoking subjects, divided into four groups: no benzene exposure/no green tea; no exposure/tea; exposure/no tea; and, exposure/tea, were monitored after a 6 mo period. On the final day of the study, urine samples were collected for analyses of benzene, trans-trans muconic acid, and phenol. Blood was also collected at this time; plasma was assayed for total antioxidant activity, malondialdehyde (MDA), and glutathione (GSH) while erythrocytes were analyzed for activity of antioxidant enzymes glutathione peroxidase (GSHPX), superoxide dismutase (SOD), and catalase. The results demonstrated that urinary levels of benzene, trans-trans muconic acid, and phenol were elevated in all pump workers, and that this elevation was mitigated by consumption of green tea. The benzene exposures also led to significant reductions in plasma GSH levels and erythrocyte antioxidant enzyme activities; these effects were abrogated (to near-control levels) by the tea. Interestingly, among control subjects, tea ingestion itself caused significant increases in both GSHPX and catalase activities. Unlike with the other plasma parameters, while the benzene exposures also significantly increased plasma MDA levels and decreased total antioxidant activity, tea ingestion did not cause a near-total reversion to control values; the effects on these two endpoints were more like those noted with the urine parameters (mitigation, not abrogation). These studies demonstrate that drinking green tea during benzene exposure can reduce several parameters indicative of oxidative stress. As such, as a dietary supplement, green tea could represent a potential therapeutic agent in reducing certain aspects of benzene-induced toxicity.
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PMID:Green tea attenuates benzene-induced oxidative stress in pump workers. 1838 60

Oxidative stress has been implicated in the pathogenesis of preeclampsia. This study measured the relative mRNA expression of antioxidant proteins glutathione peroxidase 1 and 4, glutathione reductase, thioredoxin 1 and 2, thioredoxin reductase 1, thioredoxin peroxidase 3 and superoxide dismutase 1 and 2 in preeclamptic and non-preeclamptic placentae. Quantitative real-time PCR was conducted on placental mRNA isolated from preeclamptic and control patients. Cycle threshold numbers and fold differences were calculated as a measure of linear product amplification and used for comparison. The mRNA expression of glutathione reductase was significantly reduced (fold difference 0.41, p<0.05) in preeclamptic placenta when compared to controls while the expression of thioredoxin peroxidase 3 was significantly increased (fold difference 3.25, p<0.001) in the preeclamptic placentae. No significant difference in expression was observed for glutathione peroxidase 1 and 4, thioredoxin 1 and 2, thioredoxin reductase 1 and superoxide dismutase 1 and 2. These results suggest that it is the abnormal oxidative insult associated with preeclampsia not mRNA expression of antioxidant proteins that may be responsible for reduced antioxidant enzyme activity in preeclamptic placentae.
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PMID:Antioxidant gene expression in preeclamptic placentae: a preliminary investigation. 1839 94

The aim of the study was to determine the selenium (Se) requirement of guinea pigs as a species unable to synthesize ascorbic acid. Forty-nine male guinea pigs (average weight 208 +/- 3.5 g) were divided into an initial status group and six experimental groups. The animals received a Se deficient Torula yeast based basal diet (<0.02 mg Se and 26 mg alpha-tocopherol/kg) or a Se addition of 0.05, 0.10, 0.15, 0.20 and 0.25 mg/kg diet as sodium selenate for 10 weeks. There was no significant difference in weight gain (final weight 643 +/- 21 g) between the groups and no clinical symptoms of Se deficiency occurred. With the exception of the testes, there was an increasing Se concentration in liver, plasma and haemolysate dependent on supplementation level. Glutathione peroxidase was determined in the plasma and Se dependent glutathione peroxidase (GPx1) in haemolysate, liver, kidney, heart and lung. Thioredoxin reductase (TR) activity was measured in liver, kidney and heart and deiodinase activity in the liver. A phospholipid hydroperoxide reducing activity with Se influence was determined in liver, kidney, heart, testes and brain. With the exception of GPx1 activity in heart and haemolysate and TR activity in the kidney, all enzymes already reached their maximal activity at 0.05 mg Se/kg diet. The activities of GPx1 and TR were used as parameters for broken line analysis and a Se requirement of 0.080 mg Se/kg diet was derived as sufficient for growing guinea pigs adequately supplied with vitamin E.
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PMID:Estimation of the selenium requirement of growing guinea pigs (Cavia porcellus). 1866 58

Glutathione peroxidase (GPx-1) is regarded as one of the mammalian cell's main antioxidant enzymes inactivating hydrogen peroxide and protecting against oxidative stress. Using control, Parkinson's disease (PD), and dementia with Lewy bodies tissue (DLB) we have shown that GPx-1 is a 21-kD protein under reducing conditions in all tissues examined but is not in high abundance in human brain. Using immunohistochemistry we have mapped the cellular distribution of GPx-1 and have shown it to be in highest levels in microglia and with lower levels in neurons. Only a trace amount was detectable in astrocytes using immunofluorescence and GPx-1 was not detectable in oligodendrocytes. GPx-1 positive microglia were hypertrophied and more abundant in PD and DLB tissues and were seen to be making multiple contacts with neurons. In some cases neurons containing Lewy bodies were surrounded by microglia. Unstructured Lewy bodies were enveloped with a layer of GPx-1 that was partially colocalized with alpha-synuclein whereas concentric Lewy bodies had discrete deposits of GPx-1 around the periphery which appeared to be involved in the degradation of the Lewy bodies. These results suggest that abnormal alpha-synuclein as found in Lewy bodies produce hydrogen peroxide and these neurons are capable of directing antioxidant enzymes to regions of oxidative stress. These results also suggest that GPx-1 positive microglia are involved in neuroprotection in PD and DLB and that GPx-1 is an important antioxidant enzyme in neuronal defences.
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PMID:Cellular glutathione peroxidase in human brain: cellular distribution, and its potential role in the degradation of Lewy bodies in Parkinson's disease and dementia with Lewy bodies. 1885 69

Cancer cells produce high amounts of reactive oxygen species (ROS) and evade apoptosis. Hydroperoxides support proliferation, invasion, migration and angiogenesis, but at higher levels induce apoptosis, thus being pro- and anti-carcinogenic. Accordingly, glutathione peroxidases (GPxs) regulating hydroperoxide levels might have dual roles too. GPx1, clearly an antioxidant enzyme, is down-regulated in many cancer cells. Its main role would be prevention of cancer initiation by ROS-mediated DNA damage. GPx2 is up-regulated in cancer cells. GPx1/GPx2 double knockout mice develop colitis and intestinal cancer. However, GPx2 knockdown cancer cells grow better in vitro and in vivo probably reflecting the physiological role of GPx2 in intestinal mucosa homeostasis. GPx2 counteracts COX-2 expression and PGE(2) production, which explains its potential to inhibit migration and invasion of cultured cancer cells. Overexpression of GPx3 inhibits tumor growth and metastasis. GPx4 is decreased in cancer tissues. GPx4-overexpressing cancer cells have low COX-2 activity and tumors derived therefrom are smaller than from control cells and do not metastasize. Collectively, GPxs prevent cancer initiation by removing hydroperoxides. GPx4 inhibits but GPx2 supports growth of established tumors. Metastasis, but also apoptosis, is inhibited by all GPxs. GPx-mediated regulation of COX/LOX activities may be relevant to early stages of inflammation-mediated carcinogenesis.
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PMID:Glutathione peroxidases in different stages of carcinogenesis. 1928 49

Numerous studies characterizing the function of glutathione peroxidase 4 (GPx4) have demonstrated that this selenoenzyme is protective against oxidative stress. Herein, we characterized the function of this protein by targeting GPx4 downregulation using RNA interference. Partial knockdown of GPx4 levels resulted in growth retardation and morphological changes. Surprisingly, GPx4 knockdown cells showed virtually unchanged levels of intracellular ROS, yet highly increased levels of oxidized lipid by-products. GPx1, another glutathione peroxidase and a major cellular peroxide scavenging enzyme, did not rescue GPx4-deficient cells and did not reduce lipid peroxide levels. The data established an essential role of GPx4 in protecting cells against lipid hydroperoxide damage, yet a limited role as a general antioxidant enzyme. As oxidized lipid hydroperoxides are a characteristic of neurodegenerative diseases, we analyzed brain tissues of mice suffering from a model of Alzheimer's disease and found that oxidized lipid by-products were enriched, and expression of both GPx4 and guanine-rich sequence-binding factor, which is known to control GPx4 synthesis, was downregulated. Brain tissue from an Alzheimer's diseased human also manifested enhanced levels of one of the oxidized lipid by-products, 4-hydroxynonenal. These data suggest a role of GPx4 in neurodegenerative diseases through its function in removal of lipid hydroperoxides.
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PMID:Delineating the role of glutathione peroxidase 4 in protecting cells against lipid hydroperoxide damage and in Alzheimer's disease. 1976 63


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