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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

1998; Elsevier BV; Volume: 273; Issue: 35 Linguagem: Inglês

10.1074/jbc.273.35.22528

1083-351X

Judy B. de Haan, Cécile Bladier, Peter Griffiths, Michael J. Kelner, Ross D. OʼShea, Nam Sang Cheung, Roderick T. Bronson, Mary J. Silvestro, Steven Wild, Shao Shan Zheng, Philip M. Beart, Paul J. Hertzog, Ismail Kola,

Glutathione Transferases and Polymorphisms

Glutathione peroxidases have been thought to function in cellular antioxidant defense. However, some recent studies on Gpx1 knockout (−/−) mice have failed to show a role for Gpx1 under conditions of oxidative stress such as hyperbaric oxygen and the exposure of eye lenses to high levels of H 2 O 2 . 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 stress by showing that Gpx1 (−/−) mice are highly sensitive to the oxidant paraquat. Lethality was already detected within 24 h in mice exposed to paraquat at 10 mg·kg −1 (approximately 1 7 the LD 50 of wild-type 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 controls showed no evidence of toxicity. We further demonstrate that paraquat transcriptionally up-regulates Gpx1 in normal cells, reinforcing a role for Gpx1 in protection against paraquat toxicity. Finally, we show that cortical neurons from Gpx1 (−/−) mice are more susceptible to H 2 O 2 ; 30% of neurons from Gpx1 (−/−) mice were killed when exposed to 65 μm H 2 O 2 , whereas the wild-type controls were unaffected. These data establish a function for Gpx1 in protection against some oxidative stressors and in protection of neurons against H 2 O 2 . 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 H 2 O 2 in neurodegenerative disorders.