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

这项工作的5年目标是确定城市中化学品的身份 空气和室内空气中这些样品的致突变性 在人类肺部发现的水平上表达异种代谢基因的人类细胞。 为了实现这一广泛的目标，我们正在(1)确定主要诱变剂 来自洛杉矶、华盛顿特区、纽约罗切斯特和马萨诸塞州沃本的空气样本 在表达细胞色素P450 1A1的人二倍体细胞系h1A1v2中 并被城市空气样本突变，(2)确定表达一组 非洲人和欧洲人支气管刷检中的12个异种代谢基因 美国人，男性和女性，吸烟者和不吸烟者，并测量 每个样本DNA中的突变负荷，(3)构建二倍体人 表达非吸烟者异种代谢模式的细胞系 非洲裔和欧洲裔美国人和吸烟者显示出最高的肺细胞 突变负荷和构建一条代表中位数酶的线 使用这些肺部替代物研究的全部人群的水平(4) 用于确定异种代谢模式是否影响 长期使用环境空气样品致突变剂(5)的致突变性 暴露于肺替代细胞以测量其突变谱 与人类相同浓度的环境空气样本 经验。 这些数据将使空气质量研究人员能够专注于具有 明确有可能导致人类肺部的遗传损害，并提供 具有要搜索的突变谱的分析遗传学家 空气中化学品暴露与空气污染之间的因果关系 导致人类肺细胞突变的癌症。

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.