NEW APPROACHES IN PROTEIN-CARCINOGEN ADDUCTS

这个应用程序的总体目标是发现新方法 用于分析共价结合的化学致癌物残留物 蛋白质。这种加合物已被证明对 人类暴露在环境致癌物质中的特征。他们有 在识别个体之间的差异方面也被证明是有价值的，这些差异可能 在调节个体对特定化学物质的反应中发挥作用 挑战。这些生物标记物在人类免疫系统总体目标中的作用 计划项目则是作为环境与环境之间的纽带 监测和健康影响。这些新方法有望提供 在定量的准确度和精密度方面有显著的改进 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，尤其是在 因为它们将能够识别未知的加合物。四个具体的 AIMS旨在实现这些目标。第一个是开发一种 分离血清His(146)形成加合物的一般方法 白蛋白。这种氨基酸位于一个具有广泛特异性的结合部位。 预计会与多种致癌物质发生反应。通过识别 由这种残基形成的加合物将有可能阐明一些 被人类吸收并激活的环境化学物质 活着。第二个具体目标是扩大有用蛋白质的数量。 用于目前使用的血红蛋白和血清白蛋白以外的生物监测， 特别强调那些寿命更长的，以便 可以描述更长期的暴露情景。胶原蛋白与 核小体核心组蛋白被选作研究对象。激光 诱导荧光光谱分析将作为一种分析 用于补充两者的质谱学的仪器系统 定量分析和结构解析。最终的具体目标 是将各种发展和改进方法结合起来，以 对至少一种致癌物质进行准确和低成本的检测， 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.