THE ROLE OF XENOBIOTIC METABOLISM IN AIR-BORNE CHEMICAL MUTATION OF HUMAN CELLS

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The 5 year goal of this is to determine the identity of chemicals in urban air and indoor air which account for the mutagenicity of these samples in human cells expressing xenometabolic genes at levels found in human lungs. To achieve this broad goal we are (1) determining the primary mutagens in air samples from Los Angeles, Washington DC, Rochester NY and Woburn, Mass in the human diploid cell line h1A1v2 which expresses cytochrome P450 1A1 and is mutated by urban air samples, (2) determining expression a set of twelve xenometabolic genes in bronchial brush biopsies of Afro- and Euro Americans, males and females, smokers and nonsmokers and measuring the mutational load in the DNA of each sample, (3) constructing diploid human cell lines which express the xenometabolic patterns of the nonsmoking Afro- and Euro-American and smoker which show the highest lung cell mutational load and also constructing a line representing median enzyme levels for the whole population studied (4) using these lung surrogate lines to determine if an dhow the xenometabolic patterns effect the mutagenicity of the environmental air sample mutagens (5) using long term exposure of the lung surrogate cells to measure the mutational spectra of the environmental air samples at concentrations common to human experience. These data will allow air quality researchers to focus on chemicals with clear potential to cause genetic damage in human lungs and provide analytical geneticists with mutational spectra for which to search for cause and effect relationships between air-borne chemical exposure and cancer causing mutations in human lung cells.