02 TOXICITY AND LUNG MICROSOMAL CYTOCHROME P-450 SYSTEM

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Lung tissue is exposed to a relatively high concentration of oxygen, compared with other tissues, and is a primary target for the deleterious effects of toxic O2 metabolites such as superoxide hydrogen peroxide (H2O2) or hydroxyl radical. Low levels of superoxide and H2O2 are scavenged by the protective enzyme systems superoxide dismutase (SOD) and catalase. However, enhanced production of these metabolites through increased levels of enzymes which fortuitously reduce O2 or through exposure to low molecular weight redox components, e.g. paraquat, may exceed the in situ scavenging abilities of SOD and catalase. The microsomal monooxygenase system (NADPH cytP-450 reductase, cytP-450) may be an important source of reduced O2 metabolites within the lung. The general aim of the proposal is to determine whether changes in the lung microsomal NADPH-cytP-450 reductase and cytochrome P-450 occur upon exposure of the animal to xenobiotics and whether O2 metabolite production changes concomitantly. Thus superoxide and hydrogen peroxide production in lung microsomes from control vs animal and animal exposed to phenobarbital, 3-methylcholanthrene, Arachlor or other xenobiotics will be measured. Rates of lipid peroxidation and alteration in Ca++ homeostasis will be measured as markers for potential tissue damage from the O2 metabolites.