Disease relevance of Gpx1

• Because genetic background affects tumor susceptibility, we have generated a B6 Gpx1/2-DKO colony and discovered that these mice have fewer inflammatory cells, milder ileocolitis, and low mortality, and only 2.5% of B6 mice developed tumors [1].
• Bacteria-induced intestinal cancer in mice with disrupted Gpx1 and Gpx2 genes [2].
• We have previously demonstrated that targeted disruption of both the Gpx1 and Gpx2 genes (GPX-DKO) results in a high incidence of ileocolitis in mice raised under conventional conditions, which include the harboring of Helicobacter species [non-specific-pathogen-free (non-SPF) conditions] [2].
• We further demonstrate that paraquat transcriptionally up-regulates Gpx1 in normal cells, reinforcing a role for Gpx1 in protection against paraquat toxicity [3].
• Further, they emphasize the need to elucidate the role of Gpx1 in protection against different oxidative stressors and in different disease states and suggest that Gpx1 (-/-) mice may be valuable for studying the role of H2O2 in neurodegenerative disorders [3].

Psychiatry related information on Gpx1

• Increased formation of reactive oxygen species, but no changes in glutathione peroxidase activity, in striata of mice transgenic for the Huntington's disease mutation [4].

High impact information on Gpx1

• Antioxidants that scavenge peroxides, N-acetylcysteine and glutathione peroxidase, countered apoptotic death, while manganese superoxide dismutase did not [5].
• Glutathione peroxidase activity and mRNA level, glutathione reductase activity, and reduced glutathione levels were all transiently increased in hydroxyurea-treated cells, whereas the increase in glutathione-S-transferase activity was sustained [6].
• In the hormonally stimulated mammary gland, increasing dietary Se to 2.0 ppm increased GSH-Px activity threefold and decreased mammary-gland-membrane-localized lipid peroxidation by 16% [7].
• These results indicate that GSH-Px activity does not correlate with the tumorigenic inhibitory effects of Se [7].
• Selenium-dependent glutathione peroxidase (GSH-Px) activity in the mammary glands of BD2F1 female mice decreased at 6 months of age and then increased to the highest levels at 9 months of age [7].

Chemical compound and disease context of Gpx1

• Glutathione peroxidase activities were elevated following irradiation but returned to control levels within 0.5 h for both doses, implicating hydroperoxide formation as an early event in hypericin phototoxicity [8].
• Both Se-deficient GPX1 knockout (GPX1(-/-)) and wild-type (WT) mice ( n =64) were pretreated with an intraperitoneal injection of Se (as sodium selenite, 50 microg/kg body weight) 6 h before an intraperitoneal injection of paraquat (12.5 mg/kg) [9].
• Kidney expression of glutathione peroxidase-1 is not protective against streptozotocin-induced diabetic nephropathy [10].
• Glutathione peroxidase 1 and glutathione are required to protect mouse astrocytes from iron-mediated hydrogen peroxide toxicity [11].
• There was no difference in body weight gain or apparent susceptibility to dietary vitamin E and Se deficiency between the GPX1(-) and control mice [12].

Biological context of Gpx1

• The mutation spectra analysis has shown that B6 Gpx1/2-DKO ileum had a 3-fold increase in small nucleotide deletions at mononucleotide repeats over control B6, which are a signature mutation associated with oxidative stress [1].
• The mutant frequency of a cII reporter gene was about 2- to 3-fold higher in 28-day-old Gpx1/2-DKO and 4-fold higher in 8-month-old Gpx1/2-DKO ileal mucosa than in controls in both genetic backgrounds [1].
• Increased levels of cell death were detected in cells lacking Gpx1 following the addition of exogenous H2O2 [13].
• Similarly, endogenous oxidative stress induced by cardiac ischemia/reperfusion injury led to greater apoptosis in heart tissue from the Sod2(+/-)/Gpx1(-/-) mice than in that from mice deficient in either MnSOD or Gpx1 alone [14].
• Therefore, our results suggest that the increased susceptibility of Gpx1-/- cells to H2O2-induced apoptosis can be attributed in part to diminished activation of Akt despite an up-regulation in the activation of the prosurvival NFkappaB [13].

Anatomical context of Gpx1

• Our results suggest that inflammation drives gene mutations, which leads to neoplastic transformation of intestinal epithelium in the B6.129 Gpx1/2-DKO mice but rarely in the B6 Gpx1/2-DKO mice [1].
• These experiments revealed that Gpx1 is highly expressed in both the mitochondria and the cytosol of the liver and kidney, but poorly expressed in heart and muscle [15].
• Fibroblasts derived from Gpx1 knockout mice display senescent-like features and are susceptible to H2O2-mediated cell death [16].
• Moreover, the liver mitochondria were found to release markedly increased hydrogen peroxide, a Gpx1 substrate, and have decreased mitochondrial respiratory control ratio and power output index [15].
• After 12 weeks of HFD, atherosclerotic lesions at the aortic sinus were of similar size in control and Gpx1-deficient mice [17].

Associations of Gpx1 with chemical compounds

• Unexpectedly, B6 Gpx1/2-DKO mice had fewer C to T transitions at CpG dinucleotides than the WT B6 (18.0% versus 40.1%; P < 0.001) [1].
• Fibroblasts isolated from Sod2(+/-)/Gpx1(-/-) mice were more sensitive (4- to 6-fold) to oxidative stress (t-butyl hydroperoxide or gamma irradiation) than fibroblasts from wild-type mice, and were twice as sensitive as cells from Sod2(+/-) or Gpx1(-/-) mice [14].
• Diabetic Gpx1+/+ and -/- mice with equivalent blood glucose levels (23 +/- 4 mM) were selected and examined after 4 mo of diabetes [10].
• Glutathione peroxidase-1 (Gpx1) is an antioxidant enzyme that is highly expressed in the kidney and removes peroxides and peroxynitrite that can cause renal damage [10].
• Wild-type (Gpx1+/+) and deficient (Gpx1-/-) mice were made diabetic by intraperitoneal injection of streptozotocin (100 mg/kg) on 2 consecutive days [10].

Physical interactions of Gpx1

• Subsequently, we have shown using gel-shift assays that DNA sequences located within the 5' flanking region of the gpx5 gene have the ability to bind specifically to the PEA3 protein [18].

Regulatory relationships of Gpx1

• This is the first report that a particular isotype of the glutathione peroxidase family is regulated by TCDD at both mRNA and protein levels. pGPx is expressed in various tissues in contact with body fluids, and detoxifies hydrogen peroxides and lipid hydroperoxides [19].
• Our results suggest that the increased susceptibility of Gpx1-/- neurons to H2O2-induced apoptosis and neuronal cell death in vivo following cerebral ischaemia-reperfusion injury can be attributed in part to diminished activation of Akt [20].
• These changes were associated with increased expression of the proinflammatory marker monocyte chemoattractant protein-1 in control mice but not in Gpx1-deficient mice [17].
• Altogether, these results strongly suggest that the PEA3 factor might participate in the transcriptional control of the murine epididymis caput-specific gpx5 gene [18].
• By using the same protocol, PAI-1 mRNA and protein levels were enhanced in GPX double-transgenic mice, and again this response was blunted by the addition of doxycycline [21].

Other interactions of Gpx1

• To test this possible mechanism, we transfected human cytosolic GPX cDNA into human glioma cells overexpressing MnSOD [22].
• Both catalase and glutathione peroxidase (GPx) activities were not markedly altered by MPTP in both systems [23].
• Previously, we demonstrated that a perturbation in the Sod1-to-Gpx1 ratio, as a consequence of Sod1 overexpression, leads to senescence-like changes [16].
• Nonsynonymous nucleotide polymorphisms were identified in all genes, except for Gpx1, Gpx3, and Gpx4 [24].
• The results showed greater oxidative stress in SAMP8 than in SAMR1, largely because of a decrease in GSH levels and to an increase in GSSG and TBARS with the subsequent induction of the antioxidant enzymes GPX and GR [25].

Analytical, diagnostic and therapeutic context of Gpx1

• Using a reverse transcription coupled to PCR amplification strategy, with degenerated primers localized in highly conserved domains of known glutathione peroxidase (GPX) proteins, we have generated, from mouse epididymal RNA, a cDNA fragment which was subsequently used to isolate a genomic clone encoding mouse plasma GPX (GPX3) [26].
• Overall, the relative expression of ADH and Zn-Cu SOD were higher in treatment groups than in positive controls; whereas, the relative expression of GPX5 was higher in positive control groups than in treatment groups [27].
• After tumor transplantation and treatment with the complexes, the activities of GSH-Px and GSH-R were significantly lowered while SOD and G6PD activities were increased in EAC cells compared to their levels in EAC cells harvested from saline-treated mice [28].
• Oral administration of Brahma Rasayana BR-50 mg/dose/mouse for 10 days and 30 days significantly enhanced the tissue levels of SOD, CAT, GST, GPX, serum and tissue GSH and significantly reduced the serum and tissue lipid peroxidation [29].
• 5. In situ hybridization indicated expression of GPx4 isoforms in all developing germ layers during gastrulation and in the somite stage in the developing central nervous system and in the heart [30].

References