Mechanism of the protection by glutathione peroxidase-1 against oxidative stress in mice

Glutathione peroxidase-1 (GPX1) mediates body selenium to protect against lethal oxidative stress. Reactive oxygen species (ROS) can induce multiple signal cascades and apoptosis, and have been implicated in the pathogenesis of certain diseases. The mechanism by which GPX1 protects against various levels of ROS and its interaction with vitamin E are not clear. Three animal trials were conducted to determine how GPX1 protects against various levels of ROS induced by paraquat or diquat and whether such protection can be replaced by high levels of dietary vitamin E using GPX1 knockout (GPX−/− ) mice. Although high levels of dietary vitamin E (10- or 100-fold daily nutritional need) attenuated ROS-induced lipid peroxidation, it did not replace the protection by GPX1 against high levels of paraquat (50 mg/kg)-induced lethality and diquat (24 and 48 mg/kg)-induced plasma alanine transaminase (ALT) increase. The protection by GPX1 against acute oxidative stress was associated with an attenuation of NADPH and NADH oxidation, carbonyl and F ₂-isoprostane formation, and ALT release in various tissues. No signs of apoptosis were detected in mice that died from the high levels of the pro-oxidants. Adequate dietary Se seemed to be more important than GPX1 expression for mice to cope with low levels of oxidative stress induced by 12.5 mg paraquat/kg. However, 3% expression of GPX1 caused a decrease in the mortality rates and an extension of survival times in mice stressed with low level paraquat (12.5 mg/kg). The 3% GPX1 expression attenuated the onset of cell death, c-jun N-terminal kinase (JNK) activation, and accumulation of p53 and its phosphorylation at Ser-15. The phospho-JNK interacted with p53 and phospho-p53 (Ser-15) and could phosphorylate p53 at Ser-15. In conclusion, protection by GPX1 against lethal oxidative stress can not be replaced by dietary vitamin E. Protection by GPX1 is associated with the maintenance of redox balance and the integrity of lipids and proteins. A very low level of GPX1 expression is able to attenuate moderate oxidative stress-induced mouse death in association with an attenuation of p53 phosphorylation at Ser-15 by JNK in mice.