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Our work is largely focused on the elucidation of the chemical, biochemical, and cellular mechanisms of toxicity to lung tissues that are caused by exposure to environmental pollutants. There are a number of chemicals that cause selective damage to lung tissues after inhalation or from ingestion followed by systemic exposure to circulating chemicals. One of the major compounds that we have studied is 3-methylindole (3MI) that is produced in animal and human digestive systems, and is also found in significant quantities in cigarette smoke or several different foods.

The toxicity caused by 3MI is specifically targeted to lung tissues and certain cells within the lungs of experimental animals. The specificity for lung damage by 3MI is observed despite the systemic circulation of this toxin to all organs, and much of the original work on the etiology of pneumotoxicity of 3MI was done in cattle where the fermentation of tryptophan produces 3MI. Mechanisms for the selective damage to lung tissues include selective bioactivation of 3MI by cytochrome P450 enzymes that are expressed only in lung cells and poor detoxication of reactive, toxic intermediates in lung cells. We have pursued both of these hypotheses in our work; our observations have led to the conclusion that both are operative, but specific P450-mediated bioactivation of 3MI is the most important mechanism for organ-selective toxicity of 3MI to lungs. We have used stable isotopes of hydrogen and oxygen to study the specific chemical transformations that take place in the bioactivation and detoxication of 3MI in animal and human lung tissues and specific lung cells. 3-Methylindole has proven to be a unique probe for the study of biotransformation enzymes.

Much of the recent work in our lab has centered on the cytochrome P450 genes that are selectively expressed in lungs of animals and man. We have cloned, sequenced, mutated and expressed several new P450 cDNAs. These cDNAs have been expressed in E. coli expressions systems to study the structure/function relationships of related genes within several subfamilies of P450 genes. In addition, the cDNAs have been expressed in viable human lung cell lines and the mechanisms of bioactivation of toxicants like 3MI and certain halogenated hydrocarbons have been assessed using these transfected cell lines. Our future studies will focus on the mechanisms that govern the organ-selective regulation of the P450 genes in animals and humans.

We have begun an extensive research initiative into the mechanisms responsible for human lung disease caused by particulate matter in air pollution. We have cloned, expressed, and characterized multiple "irritant receptors" that are expressed on human lung epithelial cells, and are activated by particulates in polluted air, and by capsaicinoids that are present in pepper sprays. This work has provided compelling evidence for the importance of these receptors in human lung disease.

Garold S. Yost
Professor of Pharmacology and Toxicology

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