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
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
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DOI：
10.1074/jbc.273.35.22528
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发表时间：
1998-08-28
影响因子：
4.8
通讯作者：
Kola, I
中科院分区：
文献类型：
--
作者：
de Haan, JB;Bladier, C;Kola, I
谷胱甘肽过氧化物酶被认为在细胞抗氧化防御中发挥作用。然而，最近对GPX1基因敲除(-/-)小鼠的一些研究未能表明GPX1在氧化应激条件下的作用，如高压氧和眼睛晶状体暴露在高水平的过氧化氢中。这些发现出人意料地提出了GPX1的作用问题，特别是在氧化应激条件下。在这里，我们展示了GPX1(-/-)小鼠对氧化剂百草枯高度敏感，从而证明了GPX1在对抗氧化应激中的作用。在暴露于10毫克百草枯的小鼠中，已经在24小时内检测到死亡。Kg(-1)(约为野生型对照LD50的1/7)。百草枯的作用与剂量有关。在30毫克。Kg(-1)处理组小鼠在5h内100%死亡，而对照组无明显毒性。我进一步证明，百草枯在转录上上调了正常细胞中的GPX1，加强了Gpzl在保护百草枯毒性中的作用。最后，我们发现来自GPX1(-/-)小鼠的皮层神经元对过氧化氢更敏感；来自GPX1(-/-)小鼠的神经元在暴露于65muM的过氧化氢时30%的神经元被杀死，而野生型对照没有受到影响。这些数据确定了GPX1在保护某些氧化应激源和保护神经元免受过氧化氢影响方面的功能。此外，他们强调有必要阐明GPX1在不同氧化应激源和不同疾病状态下的保护作用，并建议GPX1(-/-)小鼠可能对研究过氧化氢在神经退行性疾病中的作用有价值。
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 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 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 LD50 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. me further demonstrate that paraquat transcriptionally upregulates Gpx1 in normal cells, reinforcing a role for Gpzl in protection against paraquat toxicity. Finally, we show that cortical neurons from Gpx1 (-/-) mice are more susceptible to H2O2; 30% of neurons from Gpx1 (-/-) mice were killed when exposed to 65 mu M H2O2, 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 H2O2. 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.