Cellular Glutathione Peroxidase Is the Mediator of Body Selenium To Protect against Paraquat Lethality in Transgenic Mice

Abstract

The antioxidative role of Se-dependent cellular glutathione peroxidase (EC 1.11.1.9, GPX1) in vivo has not been established. Our objective was to determine the effects of GPX1 knockout or overexpression on the susceptibility of mice to paraquat toxicity and the contributions of GPX1, compared with other selenoproteins and vitamin E, to body defenses against such acute oxidative stress. Four experiments were conducted using 111 GPX1 knockout or overexpressing mice and the respective controls. Mice were fed diets supplemented with Se (as sodium selenite) at 0–0.4 mg/kg and/or all-rac-α-tocopheryl acetate at 0–75 mg/kg before intraperitoneal injections of 12.5, 50 or 125 mg paraquat/kg body weight. All mice that received 50 or 125 mg paraquat/kg died spontaneously, and the survival time of mice was (independent of dietary levels of Se per se or α-tocopheryl acetate) solely a function of tissue GPX1 activity (P < 0.001). Severe acute pulmonary interstitial necrosis was found only in the GPX1 overexpressing mice and the controls that had extended survival time. Thiobarbituric acid reacting substances in postmortem liver inversely correlated with the tissue GPX1 activity and dietary levels of Se and/or α-tocopheryl acetate. In contrast, all mice that received 12.5 mg paraquat/kg survived and were killed 2 wk after the injection for tissue collection. Compared with the saline injection, this low dose of paraquat resulted in greater (P < 0.001) liver and lung F2-isoprostanes in both the GPX1 knockout mice and the controls. However, there was no difference in plasma alanine transaminase (EC 2.6.1.2) activity or overt injuries in liver, lung and kidney in either group. Our data indicate that GPX1 is the major, if not the only, metabolic form of body Se that protects mice against the lethal oxidative stress caused by high levels of paraquat; it seems less important, however, in protecting mice against the moderate oxidative stress by the low level of paraquat.