Selective damage and cancer to pulmonary tissue from direct exposure to airborne contaminants or to circulating chemicals can be observed for a number of toxicants. Injury to lung cells from systemically circulated compounds such as naphthalene, butylated hydroxytoluene, and 3- methylindole (SMI) has been demonstrated to be a highly organ- and cell-selective process in a number of animal species. Studies on the mechanisms of SMI-mediated lung injury and cancer not only identify the risks of exposure to this toxicant from cigarette smoke, but provide an excellent prototypical toxicant to define the mechanisms of lung-selective damage by other chemicals. Lung tissue injury by SMI has been attributed to the selective bioactivation of this indole to 3- methyleneindolenine (3MEIN) by cytochrome P450 enzymes that are selectively expressed in lung cells. However, neither the specific molecular targets, DMA and proteins that are modified by 3MEIN, nor the cellular consequences of these modifications, have been elucidated. In addition, the precise mechanisms of cell death have not been identified. Therefore, the hypothesis of this research is: 3MI is both a potent lung carcinogen and acute cytotoxin to human lung tissues after cytochrome P450-mediated bioactivation of 3MI to 3MEIN, the proximal electrophilic intermediate; DNA alkylation by 3MEIN is the primary mechanism for initiation of both the mutagenic and pro- apoptotic processes in human lung cells. The specific goals of this application are to establish that SMI from cigarette smoke is a potent lung carcinogen through mechanisms of DNA modification, using both in vitro (human lung cells) and in vivo (mice) exposures, determine the identity and function of the proteins that are targeted by 3MEIN, establish the time- and concentration- dependency of protein alkylation events, and correlate and distinguish alkylation events as precursors to SMI-mediated human lung cell death via apoptotic pathways. The long-term goals of this research are to elucidate the mechanisms that control the species, organ, and cellular selectivity of xenobiotic-mediated pneumotoxicity and lung cancer, including the biochemical characterization of the P450 enzymes that control the bioactivation of SMI and other pneumotoxicants in lung cells, and to provide essential information about the basic biochemical and molecular mechanisms that control human susceptibilities to pneumotoxicants Principal Investigator/Program Director (Last, First, Middle): Yost, Garold S.
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