Humans are constantly exposed to 3-methylindole (3MI) from cigarettes, a variety of foodstuffs, and colonic production with subsequent absorption, but very little is known about the susceptibility of human lung tissues to 3MI-mediated insult. The selective damage to pulmonary tissues from direct exposure to airborne contaminants or to circulating chemicals can be observed for a number of pneumotoxicants. Injury to lung cells from systemically circulated compounds such as naphthalene, butylated hydroxytoluene, and 3MI has been demonstrated to be a highly organ- and cell-selective process in a number of animal species. Lung tissue injury by 3MI has been attributed to the selective bioactivation of this indole by cytochrome P450 enzymes that are selectively expressed in lung cells. However, the precise number and catalytic properties of the P450 enzymes that participate in the bioactivation of 3MI and other pneumotoxins have not been elucidated. In addition, the mechanisms responsible for the tissue-selective expression of the P450 genes in lung tissues or in specific lung cells are unknown. Despite substantial investigation, the chemical and biochemical pathways for the bioactivation and detoxication of 3MI have not been fully described. The major goal of this research is to precisely determine the mechanisms of pneumotoxicity of 3MI in animal and human tissues and cells, and to provide critical information about the P450 genes and their selective expression in pulmonary tissues. This goal will be realized through the following objectives: l) utilization of stable isotopes to evaluate the mechanisms of formation and the reactivity of electrophilic intermediates of 3MI as mediators of protein and/or DNA binding; 2) comparisons of the mechanisms of bioactivation and detoxication of 3MI in rabbit and human lung cells to correlate animal and human susceptibilities; 3) cloning pulmonary P450 genes to identify the genes whose products catalyze the bioactivation of 3MI; and 4) screening of human pulmonary tissues for the presence of transcripts to P450 genes by in situ hybridization to evaluate the cellular selectivity of gene expression in human tissues. The long-term objectives of this research are to determine the mechanisms of pneumotoxicity of the model pneumotoxicant 3MI to animals and man, and to provide essential information about the basic biochemical and molecular mechanisms that control human susceptibilities to circulating pneumotoxins.
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