P450 MEDIATED LUNG TOXICITY

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DESCRIPTION (Adapted from the Investigator's Abstract): Nononcogenic pulmonary diseases are the third leading cause of death in the US and are a major factor in morbidity and disability. Pulmonary cancer is the leading cause of cancer-related deaths. Although cigarette smoking is a major etiologic factor in these diseases, exposure to chemicals in the workplace and in the environment may be important as well. Numerous studies in laboratory animals have demonstrated the importance of the lung as a target for both inhaled and ingested chemicals. Because the studies in rodents have shown high variability in species and regional sensitivity within the lung to these chemicals, the applicability of studies in rodents for estimating the risks of exposure to humans is questionable. There is no understanding of how the factors thought to be critical for determining lung toxicity in rodents applies to the anatomically, cellularly, and metabolically distinct human lung. Among the factors likely to influence the susceptibility of the lung to toxic chemicals are the cellular distribution and catalytic activities of the key metabolic enzymes (cytochrome P450 monooxygenases) which bioactivate inert chemicals to reactive, lung toxic metabolites. These studies test the postulate that some rodent lung toxicants metabolically activated by P450 also produce focal injury in human lung. Three hypotheses will be tested: 1) the Rhesus macaque, which is anatomically and cellularly similar to humans, is an appropriate surrogate for humans in evaluating chemical-induced lung toxicity, 2) the cellular distribution of monooxygenases in human and primate lungs is highly focal making those cells particularly susceptible to cytotoxicants, and 3) the catalytic activities of pulmonary P450's in monkeys are similar to the human. The toxicity of three rodent lung toxicants, naphthalene (NA), 1-nitronaphthalene (NN) and 4-ipomeanol (IPO) will be evaluated in vitro in lungs of Rhesus monkeys, humans, and in sensitive rodent models (positive controls) and in vivo in monkeys. The cellular distribution of P450 isozymes responsible for the bioactivation of lung toxicants in rodents (CYP2B, CYP2E, CYP2F, CYP4B) will be defined in monkey and human lung. The catalytic activity of recombinant P450s (rodent, monkey and human) will be assessed with NA, NN and IPO. This work should provide a better understanding of the similarities and differences in the biologic response of lungs of rodents, monkeys, and humans to chemicals that undergo metabolic activation by the cytochrome P450 monooxygenase system.