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

Abstract

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 mg⅐kg ؊1 (approximately 1 ⁄7 the LD 50 of wild-type controls). The effects of paraquat were dose-related. In the 30 mg⅐kg ؊1 -treated group, 100% of mice died within 5 h, whereas the controls showed no evidence of toxicity. We further demonstrate that paraquat transcriptionally upregulates 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 M 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.

Glutathione peroxidase-1 as a novel therapeutic target for COPD

“…52,53 In addition, these studies showed that Gpx-1 plays a protective role in the cell in situations of oxidative stress. 51 This hypothesis is confirmed by our study showing that Gpx-1 knockout mice are susceptible to oxidative stressors such as cigarette smoke. 54 Moreover, Gpx-1 has been implicated in the development and prevention of many common and complex diseases, including cancer and cardiovascular disease.…”

“…Recent studies using knockout mice have provided data about the function of the most abundant glutathione peroxidase, Gpx-1. Mice deficient in Gpx-1 are healthy and fertile and do not show any histopathologies (organs examined included lung, liver, brain, heart, and kidney) up to 15 months of age, 51 consistent with a limited role for Gpx-1 during normal development and under physiological conditions. 52,53 In addition, these studies showed that Gpx-1 plays a protective role in the cell in situations of oxidative stress.…”

Postprandial antioxidant gene expression is modified by Mediterranean diet supplemented with coenzyme Q10 in elderly men and women

“…GPx enzyme catalyzes the reduction of H 2 O 2 and scavenges organic hydroperoxides (de Haan et al 1998). Fasting Gpx1 mRNA levels were greater after participants consumed the SFA diet than when they consumed the other two diet period (p = 0.013; Fig.…”

Selenium in Biology: Facts and Medical Perspectives

“…By reduction of hydroperoxides to the corresponding alcohols, these enzymes can prevent the production of reactive oxygen radicals and thus may contribute to the protection of the Selenium in Biology 851 Ursini et al, 1982;Brigelius-Flohé et al, 1994 Plasma GPx (pGPx, GPx-3) Takahashi et al, 1987 Gastrointestinal GPx (GI-GPx, GPx-GI, GPx-2) Chu et al, 1993 Iodothyronine deiodinases 5Ј-deiodinase, type I (5ЈDI) Behne et al, 1990;Arthur et al, 1990 5Ј-deiodinase Lee et al, 1999;Watabe et al, 1999;Miranda-Vizuete et al, 1999;Gasdaska et al, 1999 Thioredoxin reductase homologs (SelZf1; SelZf2) Lescure et al, 1999 Selenophosphate synthetase-2 Guimaraes et al, 1996 Functionally undefined 15 kDa selenoprotein of T cells Gladyshev et al, 1998 Selenoprotein P 10 (SelP) Motsenbocker and Tappel organism's macromolecules and biomembranes against oxidation (Sies et al, 1972;Flohé, 1989;Ursini et al, 1995). The role of the cytoplasmic GPx as an 'emergency enzyme' to fight oxidative stress was verified by reverse genetics (Ho et al, 1997;Cheng et al, 1998;de Haan et al, 1998;Fu et al, 1999;Jaeschke et al, 1999) and, in this role, cGPx cannot be substituted by any of the other selenoproteins. Glutathione peroxidases, in particular the less ubiquitously distributed isozymes, are engaged in redox regulation of many metabolic processes (BrigeliusFlohé, 1999) and appear to be involved in peroxinitrite scavenging (Sies et al, 1997).…”