Knockout of cellular glutathione peroxidase gene renders mice susceptible to diquat-induced oxidative stress.
Two experiments were conducted to determine the protection and the underlying mechanisms of cellular glutathione peroxidase (GPX1) against lethal, acute oxidative stress induced by an intraperitoneal injection of 24 mg diquat/kg body weight. In experiment 1, mortality and survival times were compared 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 the time course of oxidative events. The stress produced 100% mortality in all of the groups except for the Se-adequate WT, which were euthanized on day 7 for analysis. The Se-deficient WT and the Se-adequate GPX1(-/-) had similar 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 F2-isoprostanes and carbonyl contents and/or plasma alanine aminotransferase activities than those of the Se-adequate WT. The diquat-induced formations of hepatic F2-isoprostanes in these animals peaked at 1 h and preceded the rise of plasma alanine aminotransferase in the Se-adequate GPX1(-/-). Responses of hepatic superoxide dismutase activities to the diquat treatment were affected by the GPX1 level. In conclusion, GPX1 is the major selenoprotein to protect mice against the lethal oxidative stress induced by diquat.
Fu
Y
Y
Department of Animal Science, Cornell University, Ithaca, NY 14853, USA.
Cheng
W H
WH
Porres
J M
JM
Ross
D A
DA
Lei
X G
XG
D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D002374:Catalase / Q000378:metabolism; D004178:Diquat / Q000494:pharmacology*; D005979:Glutathione Peroxidase / Q000235:genetics*; D008099:Liver / Q000187:drug effects / Q000201:enzymology; D051379:Mice; D018345:Mice, Knockout; D018384:Oxidative Stress / Q000235:genetics*; D011453:Prostaglandins / Q000378:metabolism; D011506:Proteins / Q000378:metabolism; D012643:Selenium / Q000172:deficiency; D051140:Selenoproteins; D013482:Superoxide Dismutase / Q000378:metabolism; D013997:Time Factors
D011453:Prostaglandins; D011506:Proteins; D051140:Selenoproteins; D004178:Diquat; D002374:Catalase; D005979:Glutathione Peroxidase; D013482:Superoxide Dismutase; D000410:Alanine Transaminase; D012643:Selenium