NEW APPROACHES IN PROTEIN-CARCINOGEN ADDUCTS

本申请的总目标是发现新方法 用于化学致癌物残留物的分析， proteins. 此类加合物已被证明可用于 人类暴露于环境致癌物的特征。 他们有 也被证明在识别个体间差异方面很有价值， 在调节个体对给定化学物质的反应方面发挥作用 挑战. 这些生物标志物在总体目标中的作用 然后，计划项目将作为环境之间的联系， 监测和健康影响。 这些新方法有望提供 定量分析的准确度和精确度得到显著提高， 已知加合物的分析以及分析的速度和成本。 改进定性分析也是一个目标，特别是在 因为它们将能够鉴定未知的加合物。 四个具体 目的是为了实现这些目标。 第一是制定一个 分离血清His（146）形成的加合物的一般方法 白蛋白。 该氨基酸位于具有广泛特异性的结合位点 并且预计会与许多致癌物质反应。 通过识别 加合物形成的残余物，将有可能阐明一些 环境中的化学物质被人类吸收， vivo. 第二个具体目标是扩大有用蛋白质的数量 对于目前使用的血红蛋白和血清白蛋白之外的生物监测， 特别强调那些具有较长寿命的， 可以描述更长期的暴露情况。 胶原蛋白和 选择核小体核心组蛋白进行研究。 激光 诱导荧光光谱将作为一种分析方法进行改进， 仪器系统，以补充质谱分析， 定量分析和结构鉴定。 最终的具体目标 是联合收割机在方法上结合各种发展和改进， 产生对至少一种致癌物的准确且低成本的测定， 苯并[a]芘，适合大规模应用。

The general objective of this application is the discovery of new methods for the analysis of chemical carcinogen residues covalently bound to proteins. Such adducts have been demonstrated to be useful in characterizing human exposure to environmental carcinogens. They have also proven valuable in identifying interindividual differences which may play a role in modulating the individual response to a given chemical challenge. The role of these biomarkers in the overall objectives of the Program Project then is to serve as a link between environmental monitoring and health effects. These new methods are expected to provide significant improvements in the accuracy and precision of the quantitative analysis of known adducts as well as in speed and cost of analysis. Improvements in qualitative analysis are also a goal, especially insofar as they will enable the identification of unknown adducts. Four specific aims are designed to accomplish these goals. The first is to develop a general procedure for isolating adducts formed by His(146) of serum albumin. This amino acid resides in a binding site of broad specificity and is expected to react with numerous carcinogens. By identifying adducts formed by this residue it will be possible to elucidate some of the environmental chemicals which are taken up by humans and activated in vivo. A second specific aim is to expand the number of proteins useful for biomonitoring beyond the currently used hemoglobin and serum albumin, with particular emphasis on those which have longer lifetimes so that longer term exposure scenarios can be described. Collagen and the nucleosome core histones have been chosen for investigation. Laser induced fluorescence spectroscopy will be refined as an analytical instrumentation system to complement mass spectrometry for both quantitative analysis and structure elucidation. The final specific aim is to combine a variety of developments and refinements in methodology to produce an accurate and low cost assay for at least one carcinogen, benzo[a]pyrene, suitable for large scale application.