Metabolic Activation of N-Heterocyclic Aromatics

说明书(申请人提供)：N-杂环芳烃(NHA)是多环芳烃(PAH)的一个子族，多环芳烃(PAH)是在复杂混合物中发现的重要环境污染物。这项研究计划的总体目标是评估NHA在环境中多环芳烃混合物致癌中的作用。我们重点研究了二苯并[c，g]咔唑(DBC)和二苯并[a，j]吖啶(DBA)两种模型NHA的相对致癌性。我们发现，这些化合物的代谢有明显的差异，这对致癌性有很大的影响。我们现在开始了解DBC和DBA之间微小的结构和化学差异如何导致新陈代谢、器官趋向性和致癌性的巨大差异。根据这些结果和我们的经验，我们假设这两种化合物之间的结构和代谢差异将在致癌过程的多个阶段产生影响，包括DNA加合和修复、突变谱和全球基因表达。我们还假设，当在二元混合物中存在共同暴露时，这些结构和代谢差异将导致DBA和DBC与模型多环芳烃苯并[a]芘(BAP)发生不同的相互作用。研究DBC和DBA在小鼠皮肤、肝脏和人肝细胞中的代谢激活、DNA损伤和生物学效应：1)阐明DBC和DBA在体外和体内的激活机制。2)研究DBC和DBA对人肝细胞、小鼠肝和皮肤的DNA损伤类型，包括大块加合物、无嘌呤位点和氧化损伤。3)确定DBC和BaP或DBA和BaP的二元混合物对生物终点的影响，包括代谢、DNA加合物和ras突变谱。这种方法将提供有关NHA混合物的代谢激活和生物学后果的有价值的信息，并有助于更好地理解致癌机制(S)。在下一个研究阶段，一个重要的努力将是将我们在DBC和DBA结构中发现的差异与它们的生物效应联系起来，包括它们作为多环芳烃混合物的成分的表现。使用这种方法，我们将开始了解混合物各组分之间的相互作用。

DESCRIPTION (provided by applicant): N-heterocyclic aromatics (NHA) are a subgroup pf polycyclic aromatic hydrocarbons (PAH) which are environmentally important pollutants which are found in complex mixtures. The overall goal of this research program has been to evaluate the role of NHA in the carcinogenicity of PAH mixtures in the environment. We have focused on the relative carcinogenicity of two model NHA, dibenzo[c,g]carbazole (DBC) and dibenz[a,j]acridine (DBA). We have discovered that there are distinct differences in the metabolism of these compounds, which affects profoundly the carcinogenicity. We are now beginning to understand how small structural and chemical differences, between DBC and DBA, contribute to large differences in metabolism, organotropism and carcinogenicity. Building on these results and our experience, we hypothesize that the structural and metabolic differences between these two compounds will have an impact at multiple stages in the carcinogenic process including DNA adduction and repair, mutational spectra, and global gene expression. We also hypothesize that these structural and metabolic differences will cause DBA and DBC to interact differently with a model PAH, benzo[a]pyrene (BAP), when there is co-exposure in binary mixtures. These will be addressed by the following specific aims involving the characterization of the metabolic activation, DNA damage and biological effects of the lesions produced by DBC and DBA in mouse skin, and liver and in human liver cells: 1) Elucidate the mechanism of activation of DBC and DBA in vitro and in vivo. 2) Characterize the types of DNA lesions induced by DBC and DBA in human liver cells and in mouse liver and skin including bulky adducts, apurinic sites and oxidative damage. 3) Determine the effects of binary mixtures of DBC and BaP, or DBA and BaP on biological endpoints including metabolism, DNA adducts and ras mutational spectra. This approach will provide valuable information on the metabolic activation and biological consequences of mixtures of NHA and lead to a better understanding of the mechanism(s) of carcinogenesis. An important effort, in the next research period, will be to relate the differences we are discovering in the structure of DBC and DBA with their biological effects, up to and including, how each behave as components of PAH mixtures. Using this approach, we will begin to understand the interaction between components of mixtures.