Damage to human pulmonary tissues may occur through a variety of different routes and mechanisms. An increasing number of xenobiotics have been shown to be selectively pneumotoxic to animals after systemic circulations of the compounds, but the causative mechanisms for species, organ and cellular selectivities of these chemicals is largely unknown. The susceptibility of man to most of these pneumotoxins is also unknown. This research will address the basic biochemical, chemical, pathological, and molecular biological mechanisms for the pneumotoxicity of one such chemical, 3-methylindole (3MI), in animals. These results will be extrapolated to human exposures to 3MI and to the general mechanisms of human pneumotoxicities that are caused by systemically circulated toxins. 3MI is selectively toxic to Clara, and type II pneumocytes in several species, following the order ruminants > rodents > rabbits, and these differences can be exploited for susceptibility comparisons in animals. Lung injury is mediated by cytochrome P-450- dependent oxidative bioactivation of 3MI to produce electrophilic intermediates which are responsible for selective damage to the lungs. The major goal of this research is to determine the precise chemical and biochemical mechanisms of 3MI bioactivation and toxicities in susceptible and non-susceptible species, organs, and cells, and to relate these mechanisms to lung injury in humans. This goal will be realized through the following methods; 1) utilization of stable isotopes and metabolic profiles to determine the chemical mechanisms of bioactivation and detoxication; 2) separation and evaluations of lung cells from animals and man, including human lung tumor cell lines, to determine cellular and species differences in 3MI-mediated damage; 3) purification and characterization of pulmonary cytochrome P-450s from animal and human lung tissues to evaluate species differences; and 4) preparation, sequencing, and utilization of cDNA probes to animal and human genes that code for the activating P-450 isozymes to determine the genetic basis for differences in bioactivation of 3MI. 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 important information about the basic biochemical mechanisms that control human susceptibilities to circulating pneumotoxins.
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