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

该项目的5年目标是确定城市中化学品的特性， 空气和室内空气中的致突变性， 在人肺中发现的水平上表达异种代谢基因的人细胞。 为了实现这一广泛的目标，我们（1）确定主要诱变剂， 来自洛杉矶、华盛顿、纽约州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， 并通过城市空气样本进行突变，（2）确定一组 非洲人和欧洲人支气管刷检中12种异源代谢基因 美国人，男性和女性，吸烟者和不吸烟者， 每个样品的DNA中的突变负荷，（3）构建二倍体人 表达非吸烟者的异种代谢模式的细胞系 非裔和欧美人以及吸烟者，其肺细胞计数最高 突变负荷，并且还构建代表中值酶的线 使用这些肺替代物研究的整个人群的水平（4） 线，以确定如果一个独桅帆船的异种代谢模式影响， 环境空气样品诱变剂的致突变性（5）使用长期 暴露肺替代细胞以测量 环境空气样本中常见的浓度为人类 体验. 这些数据将使空气质量研究人员能够专注于化学品， 明确的可能性，造成人类肺部的遗传损伤，并提供 分析遗传学家的突变谱， 空气传播的化学品暴露与 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.