Reactive oxygen species and free radicals are thought to contribute to many of the adverse effects associated with a number of human diseases and toxicities. Exposure of cells or tissues to reactive oxygen species often is characterized by the formation of glutathione disulfide and protein mixed disulfides, but oxidant cell damage appears to be more closely associated with the types of oxidations catalyzed by chemically reactive iron chelates. Although iron is absolutely essential for a wide range of biological functions, access to this iron is availability restricted by containment in enzymes or in storage proteins. Loss of homeostatic control of iron availability thus may represent a pivotal step in the initiation of tissue damage by reactive oxygen. Recent studies suggest that the reactive oxygen-mediated hepatic necrosis caused by diquat in Fischer-344 rats, and the resistance of Sprague-Dawley rats, may be a result of differences in control of iron metabolism. The greater sensitivity of Fischer-344 rats than of Sprague-Dawley rats to hyperoxic lung injury and the redistribution of lung nonheme iron in the hyperoxia-exposed Fischer rats further suggests the broader relevance of these animal models to the fundamental mechanisms of reactive oxygen- mediated tissue injury. The experiments described in the present application also will examine the contributions of glutathione reductase to antioxidant defense mechanisms through studies in cells in which reductase activity has been inhibited by antisense-oriented transfection of the human gene for glutathione reductase. The proposed studies also will test the hypothesis that thiol/disulfied shifts compartmentalized to the mitochondria contribute to oxidant cell injury in vivo, employing measurements of coenzyme A and its mixed disulfide with glutathione (CoASSG) in freeze-clamped tissues worked up in acid to minimize artifactual redox shifts during workup. Because the glutathione- dependent dose-threshold that prevents alkylation of protein and hepatic injury by therapeutic doses of acetaminophen may not be relevant to alkylation of DNA, the covalent binding to DNA in vivo of acetaminophen given at low doses will be examined, as will the chemical interactions with DNA of N-acetyl-p-benzoquinone imine, thought by many investigators to be a metabolite of acetaminophen responsible for cellular damage through alkylation and possibly through oxidation. Understanding the factors responsible for biological molecules, and the biochemical and pathophysiological consequences of the respective alterations represent important fundamental goal of biomedical research. These are the broad, long-term goals of the research described in the present application.
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