THE NATURE OF ANTIOXIDANT DEFENSE-MECHANISMS - A LESSON FROM TRANSGENIC STUDIES

Reactive oxygen species (ROS) have been implicated in the pathogenesis of many clinical disorders such as adult respiratory distress syndrom e, ischemia-reperfusion injury, atherosclerosis, neurodegenerative dis eases, and cancer. Genetically engineered animal models have been used as a tool for understanding the function of various antioxidant enzym es in cellular defense mechanisms against various types of oxidant tis sue injury. Transgenic mice overexpressing three isoforms of superoxid e dismutase, catalase, and the cellular glutathione peroxidase (GSHPx- 1) in various tissues show an increased tolerance to ischemia-reperfus ion heart and brain injury, hyperoxia, cold-induced brain edema, adria mycin, and paraquat toxicity. These results have provided for the firs t time direct evidence demonstrating the importance of each of these a ntioxidant enzymes in protecting the animals against the injury result ing from these insults, as well as the effect of an enhanced level of antioxidant in ameliorating the oxidant tissue injury. To evaluate fur ther the nature of these enzymes in antioxidant defense,gene knockout mice deficient in copper-zinc superoxide dismutase (CuZnSOD) and GSHPx -1 have also been generated in our laboratory. These mice developed no rmally and showed no marked pathologic changes under normal physiologi c conditions. In addition, a deficiency in these genes had no effects on animal survival under hyperoxia. However, these knockout mice exhib ited a pronounced susceptibility to paraquat toxicity and myocardial i schemia-reperfusion injury. Furthermore, female mice lacking CuZnSOD a lso displayed a marked increase in postimplantation embryonic lethalit y. These animals should provide a useful model for uncovering the iden tity of ROS that participate in the pathogenesis of Various clinical d isorders and for defining the role of each antioxidant enzyme in cellu lar defense against oxidant-mediated tissue injury.