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

Glutathione peroxidases have been thought to function in cellular anti oxidant defense. However, some recent studies on Gpx1 knockout (-/-) m ice have failed to show a role for Gpx1 under conditions of oxidative stress such as hyperbaric oxygen and the exposure of eye lenses to hig h levels of H2O2. These findings have, unexpectedly, raised the issue of the role of Gpx1, especially under conditions of oxidative stress. Here we demonstrate a role for Gpx1 in protection against oxidative st ress by showing that Gpx1 (-/-) mice are highly sensitive to the oxida nt paraquat. Lethality was already detected within 24 h in mice expose d to paraquat at 10 mg . kg(-1) (approximately 1/7 the LD50 of wild-ty pe controls). The effects of paraquat were dose-related. In the 30 mg . kg(-1)-treated group, 100% of mice died within 5 h, whereas the cont rols showed no evidence of toxicity. me further demonstrate that paraq uat transcriptionally upregulates Gpx1 in normal cells, reinforcing a role for Gpzl in protection against paraquat toxicity. Finally, we sho w that cortical neurons from Gpx1 (-/-) mice are more susceptible to H 2O2; 30% of neurons from Gpx1 (-/-) mice were killed when exposed to 6 5 mu M H2O2, whereas the wild-type controls were unaffected. These dat a establish a function for Gpx1 in protection against some oxidative s tressors and in protection of neurons against H2O2. Further, they emph asize the need to elucidate the role of Gpx1 in protection against dif ferent oxidative stressors and in different disease states and suggest that Gpx1 (-/-) mice may be valuable for studying the role of H2O2 in neurodegenerative disorders.