Chemically reactive intermediates cause the toxicities of a number of drugs and environmental chemicals and contribute to the pathogeneses of many human diseases through covalent modifications of biological molecules. Specific reactive oxygen and nitrogen species, radicals, free radicals, and other oxidant species exhibit different properties and reactivities, and efforts to prevent or treat the adverse effects of oxidant challenges require that we understand the properties of the reactive intermediates and the mechanisms by which they act. The principal goal of the research described in the present application is to elucidate these mechanisms. Previous studies implicated the loss of protein thiols in mechanisms of oxidant injury, but we have consistently not observed marked shifts in protein thiol status in toxicologically relevant models, particularly in vivo. In several models of oxidant cell killing, the data suggest that oxidations characteristic of those catalyzed by redox-active iron chelates correlate more closely with tissue damage than do thiol/disulfide redox shifts. Recent preliminary data indicate that reactive nitrogen species may contribute significantly to the mechanisms of injury in the primary models we study, and the relative contributions of these mechanisms need to be investigated.
Specific Aim 1 is to test the hypothesis that specific products of oxidation of hepatic proteins other than disulfides will provide biomarkers of the molecular (chemist definition of molecular) mechanisms responsible for oxidant-mediated hepatic necrosis in vivo. Despite the absence of global depletion of protein thiols in relevant models of oxidant tissue damage, several lines of evidence indicate that effects on protein thiols are important determinants of lethal cell injury, and the studies described in Specific Aim 2 are designed to test the hypothesis that compartmentalized and molecularly selective thiol/disulfide shifts and related changes contribute significantly to oxidant injury. The major models we employ are based on toxicities of diquat, acetaminophen, and furosemide in vivo and in vitro, and a limited set of model oxidants for studies in vitro. Therapeutic uses of acetaminophen and furosemide are extensive, and diquat and paraquat are widely used herbicides. Although most recognized human toxicities arise from acute exposures or overdoses, often intentional, emerging evidence suggests that chronic, low dose exposures to these agents may cause more adverse effects than are appreciated at the present time. However, our major interest in the study of the effects of these toxicants is to understand the fundamental principles and concepts of drug-induced cell death in vivo, with a primary focus on oxidant-induced hepatic necrosis. ? ? ? ?
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