MICE DEFICIENT IN CELLULAR GLUTATHIONE-PEROXIDASE DEVELOP NORMALLY AND SHOW NO INCREASED SENSITIVITY TO HYPEROXIA

Glutathione peroxidase, a selenium-containing enzyme, is believed to p rotect cells from the toxicity of hydroperoxides. The physiological ro le 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 enz ymes, 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 overproduc tion 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 m ajor isoform of glutathione peroxidase ubiquitously expressed In all t ypes of cells, was generated by gene-targeting technology. Mice defici ent in this enzyme were apparently healthy and fertile and showed no i ncreased sensitivity to hyperoxia. Their tissues exhibited neither a r etarded rate in consuming extracellular hydrogen peroxide nor an incre ased content of protein carbonyl groups and lipid peroxidation compare d with those of wild-type mice. However, platelets from GSHPx-1-defici ent mice incubated with arachidonic acid generated less 12-hydroxyeico satetraenoic acid and more polar products relative to control platelet s 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 hype roxic insult is very limited. Nevertheless, the potential antioxidant role of this enzyme in protecting cells and animals against the pathog enic effect of reactive oxygen species in other disorders remains to b e 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.