Mice Deficient in Cellular Glutathione Peroxidase Develop Normally and Show No Increased Sensitivity to Hyperoxia

Abstract

Glutathione peroxidase, a selenium-containing enzyme, is believed to protect cells from the toxicity of hydroperoxides. The physiological role of this enzyme has previously been implicated mainly using animals fed with a selenium-deficient diet. Although selenium deficiency also affects the activity of several other cellular selenium-containing enzymes, a dramatic decrease of glutathione peroxidase activity has been postulated to play a role in the pathogenesis of a number of diseases, particularly those whose progression is associated with an overproduction of reactive oxygen species, found in selenium-deficient animals. To further clarify the physiological relevance of this enzyme, a model of mice deficient in cellular glutathione peroxidase (GSHPx-1), the major isoform of glutathione peroxidase ubiquitously expressed in all types of cells, was generated by gene-targeting technology. Mice deficient in this enzyme were apparently healthy and fertile and showed no increased sensitivity to hyperoxia. Their tissues exhibited neither a retarded rate in consuming extracellular hydrogen peroxide nor an increased content of protein carbonyl groups and lipid peroxidation compared with those of wild-type mice. However, platelets from GSHPx-1-deficient mice incubated with arachidonic acid generated less 12-hydroxyeicosatetraenoic acid and more polar products relative to control platelets at a higher concentration of arachidonic acid, presumably reflecting a decreased ability to reduce the 12-hydroperoxyeicosatetraenoic acid intermediate. These results suggest that the contribution of GSHPx-1 to the cellular antioxidant mechanism under normal animal development and physiological conditions and to the pulmonary defense against hyperoxic insult is very limited. Nevertheless, the potential antioxidant role of this enzyme in protecting cells and animals against the pathogenic effect of reactive oxygen species in other disorders remains to be defined. The knockout mouse model described in this report will also provide a new tool for future study to distinguish the physiological role of this enzyme from other selenium-containing proteins in mammals under normal and disease states.

Models of reactive oxygen species in cancer

“…It utilizes glutathione as a substrate to catalyze the reduction of H 2 O 2 and lipid peroxides. GPX1 knockout (PGX1 −/− ) and GPX1-overexpressing transgenic (GPX1 TG ) mice have been developed to study the in vivo role of GPX1 in coping with oxidative stress [36][37][38]. GPX1 −/− or GPX1 TG mice exhibited no significant alterations in mRNA expression or activity of thioredoxin reductase and other selenoproteins.…”

Changes in Expression of Antioxidant Enzymes Affect Cell-Mediated LDL Oxidation and Oxidized LDL–Induced Apoptosis in Mouse Aortic Cells

“…Homozygous Gpx1 Ϫ/Ϫ mice deficient in Gxp1 activity were healthy and fertile. 14 The Sod2 ϩ/Ϫ and Gpx1 Ϫ/Ϫ mice were identified by polymerase chain reaction and Southern blots, as described by Li et al 11 and Ho et al, 14 respectively. The wild-type controls used in the present study were the littermates of the aforementioned transgenic/knockout mice.…”

“…The Sod2 ϩ/Ϫ mice, which appeared normal and fertile, showed reduced Mn-SOD activity in all the tissues studied. 13 The Gpx1 knockout mice used in the present study were developed by disrupting the second exon of the Gpx1 gene with a neomycin resistance cassette 14 and were backcrossed to 57BL/6 for 12 generations. Homozygous Gpx1 Ϫ/Ϫ mice deficient in Gxp1 activity were healthy and fertile.…”

Molecular biology of glutathione peroxidase 4: from genomic structure to developmental expression and neural function

“…For GPx4 the hypothesis that highly ranked selenoproteins are of major biological relevance is supported by functional inactivation of gpx4 in mice. Stem cell knockout of gpx4 leads to early embryonic lethality (Imai et al, 2003;Yant et al, 2003), whereas GPx1 knockout mice develop normally and are fully viable (Ho et al, 1997;de Haan et al, 1998). Interestingly, GPx4 shows a unique cellular distribution in brain compared to GPx1 (Ho et al, 1997;Schweizer et al, 2004;Savaskan et al, 2007).…”