Tissue hypoxia is a common manifestation of several clinically important conditions, e.g., chronic obstructive lung disease, anemias, and atherosclerosis. Drug therapy and exposure to environmental chemicals are common among individuals with tissue hypoxia. Recent studies have established that the toxicity of some chemicals is greatly enhanced by hypoxia, and other studies suggest that drug detoxication systems may be impaired during hypoxia. The purpose of this proposal is to measure directly the effects of hypoxia on the capabilities of mammalian cells to withstand toxic chemical injury. The focus will be to determine the effect of hypoxia on the function of glutathione-dependent detoxication systems. These systems normally function to detoxify reactive electrophilic compounds and to reduce peroxides generated by oxidative stress (e.g., hyperbaric oxygen, free radical-induced injury). Short-term in vitro experiments will determine the oxygen dependence of glutathione biosynthesis and transport and the ability of cells to maintain glutathione in the reduced state. Long-term experiments will determine the in vivo effects of chronic hypoxia on glutathione-dependent detoxication systems and the systems that maintain the cellular glutathione pool. The effect of chronic hypoxia on these systems will be further studied in primary cell cultures grown under varying 02 concentrations. Because of the ubiquitous importance of glutathione-dependent detoxication systems in protecting against chemical injury, detailed knowledge of their function during hypoxia will be valuable for several areas of medicine, i.e., to minimize potential injury from administration of therapeutic agents during hypoxia, to improve the selective killing of hypoxic tumor cells, to understand cellular sensitivity to post-ischemic reoxygenation injury, and to improve the reliability of the use of cultured mammalian cells for drug toxicity and carcinogenicity screening.
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