Impact of Cu, Zn-superoxide dismutase and Se-dependent glutathione peroxidase-1 knockouts on acetaminophen-induced cell death and related signaling in murine liver.
There is increasing evidence showing dual functions of antioxidant enzymes in coping with reactive oxygen species (ROS) versus reactive nitrogen species (RNS). The objective of this study was to compare the impacts of knockout of Cu, Zn-superoxide dismutase (SOD1) and Se-dependent glutathione peroxidase-1 (GPX1) on cell death and related signaling mediated by acetaminophen (APAP), a RNS inducer in liver. Two groups of young adult knockout mice (SOD1(-/-) and GPX1(-/-)), along with their wild types (WT), were killed 5 hrs after an ip injection of saline or APAP (300 mg/kg body wt). While the WT mice showed more hepatic necrosis and DNA breakage than the GPX1(-/-) mice, the SOD1(-/-) mice had essentially no positive response compared with their saline-injected controls. The APAP treatment activated liver c-jun N-terminal kinase (JNK) in the WT and GPX1(-/-) mice, but not in the SOD1(-/-) mice. The APAP-induced changes in other cell death-related signal proteins such as p21, caspase-3, and poly(ADP-ribose) polymerase (PARP) also were obviated in the SOD1(-/-) mice. In conclusion, knockout of GPX1 did not potentiate APAP-induced cell death and related signaling, whereas the SOD1 null blocked APAP-induced hepatic JNK phosphorylation and cell death.
Zhu
Jian-Hong
JH
Department of Animal Science, Cornell University, Ithaca, NY 14853, USA.
Zhang
Xiaomei
X
McClung
James P
JP
Lei
Xin Gen
XG
D000082:Acetaminophen / Q000633:toxicity*; D000818:Animals; D016923:Cell Death / Q000187:drug effects; D005979:Glutathione Peroxidase / Q000172:deficiency* / Q000235:genetics* / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology / Q000502:physiology; D048670:MAP Kinase Kinase 4 / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D012643:Selenium / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D013482:Superoxide Dismutase / Q000378:metabolism*; D000094765:Glutathione Peroxidase GPX1
D000082:Acetaminophen; D005979:Glutathione Peroxidase; D013482:Superoxide Dismutase; D048670:MAP Kinase Kinase 4; D012643:Selenium; D000094765:Glutathione Peroxidase GPX1; C000722068:Gpx1 protein, mouse