Metabolic Activation of N-Heterocyclic Aromatics

描述（由申请人提供）：N-杂环芳烃（NHA）是多环芳烃（PAH）的一个亚组，多环芳烃是在复杂混合物中发现的重要环境污染物。本研究计划的总体目标是评估NHA在环境中PAH混合物致癌性中的作用。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存在明显差异，这对致癌性产生了深远的影响。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代谢、亲器官性和致癌性的巨大差异。基于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，这些结构和代谢的差异将导致DBA和DBC相互作用不同的模型PAH，苯并[a]芘（BAP），当有共同暴露在二元混合物。这些将通过以下具体目标来解决，这些目标涉及由DBC和DBA在小鼠皮肤、肝脏和人肝细胞中产生的病变的代谢活化、DNA损伤和生物学效应的表征：1）阐明DBC和DBA在体外和体内的活化机制。2)表征DBC和DBA在人肝细胞和小鼠肝脏和皮肤中诱导的DNA损伤类型，包括大体积加合物、脱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学终点的影响，包括代谢、DNA加合物和ras突变谱。这种方法将提供有关NHA混合物的代谢活化和生物学后果的有价值的信息，并导致更好地理解致癌机制。在下一个研究阶段，一个重要的努力将是将我们在DBC和DBA的结构中发现的差异与它们的生物学效应联系起来，包括它们各自作为PAH混合物组分的行为。使用这种方法，我们将开始了解混合物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.