Knockout of cellular glutathione peroxidase gene renders mice susceptible to diquat-induced oxidative stress

Two experiments were conducted to determine the protection and the underlyi ng mechanisms of cellular glutathione peroxidase (GPX1) against lethal, acu te oxidative stress induced by an intraperitoneal injection of 24 mg diquat /kg body weight. In experiment 1, mortality and survival times were compare d among selenium (Se)-adequate or deficient GPX1 knockout mice [GPX1(-/-)] and wild-type mice (WT). In experiment 2, mice from these four groups were euthanized at 0, 1, 2, and 3 h after the injection of diquat to elucidate t he time course of oxidative events. The stress produced 100% mortality in a ll of the groups except for the Se-adequate WT, which were euthanized on da y 7 for analysis. The Se-deficient WT and the Se-adequate GPX1(-/-) had sim ilar survival times (4.1 and 3.9 h), which were longer (p < .05) than that of the Se-deficient GPX1(-/-) (2.4 h). However, these three GPX1-deficient groups had higher levels (p < .05) of hepatic F-2-isoprostanes and carbonyl contents and/or plasma alanine aminotransferase activities than those of t he Se-adequate WT. The diquat-induced formations of hepatic F-2-isoprostane s in these animals peaked at 1 h and preceded the rise of plasma alanine am inotransferase in the Se-adequate GPX1(-/-). Responses of hepatic superoxid e dismutase activities to the diquat treatment were affected by the GPX1 le vel. In conclusion, GPX1 is the major selenoprotein to protect mice against the lethal oxidative stress induced by diquat. (C) 1999 Elsevier Science I nc.