METABOLIC ACTIVATION OF N HETEROCYCLIC AROMATICS

描述：含氮杂环芳香族化合物(NHA)是 重要的、可能致癌的环境污染物。而他们的 结构类似于更广泛研究的多环化合物 关于芳香烃，首席研究员已经证明 NHA化合物对强致瘤性和致突变性的代谢激活 在某些情况下，中间体可以通过不同的首选路径进行。 这个项目完全集中在两个结构上相关的N-杂环上 化合物，7H-二苯并[c，g]咔唑(DBC)和二苯并[a，j]吖啶(DBA)。 这两种化合物的不同之处仅在于它们的芳香性。 含氮环。DBC在小鼠的肺和皮肤中是一种强有力的致癌物，而 DBA是一种致癌物，仅存在于小鼠肺和皮肤中。具体目标是 小鼠代谢激活和DNA结合机制的研究 皮肤、肝脏和肺，并研究与 在这些组织中形成的共价DNA加合物。这将会实现的 通过表征肺中的NHA残留物和DNA靶基， 肝脏和皮肤。其他具体目标包括确定 肺癌ras癌基因点突变的频率和剂量依赖关系 相同的组织，并将这些发现与稳态相关联 急性和慢性粒细胞白血病ras基因DNA加合物及特异性加合物位点水平 DBC或DBA的慢性暴露实验。各种现有的 将采用实验技术来实现这些目标。这个 总体目标是更好地理解 与N-杂环芳香化合物相关的致癌作用。

DESCRIPTION: Nitrogen-substituted heterocyclic aromatic compounds (NHA) are important, potentially carcinogenic environmental pollutants. While their structures are similar to those of the more widely studied polycyclic aromatic hydrocarbons, the principal investigator has demonstrated that the metabolic activation of NHA compounds to potent tumorigenic and mutagenic intermediates can proceed, in some cases, by different preferred pathways. This project is focussed entirely on two structurally related N-heterocyclic compounds, 7H-dibenzo[c,g]carbazole (DBC) and dibenz[a,j]acridine (DBA). These two compounds differ from one another only in the aromaticity of the N-containing ring. DBC is a potent carcinogen in mouse lung and skin, while DBA is a carcinogen in mouse lung and skin only. The specific aims are to characterize the mechanisms of metabolic activation and DNA binding in mouse skin, liver, and lung, and to study the biological effects associated with the covalent DNA adducts formed in these tissues. This will be accomplished by characterizing the NHA residues, as well as the DNA target bases in lung, liver, and skin. Other specific aims include the determination of the frequencies and dose dependences of point mutations in the ras oncogene in the same tissues, and to correlate these findings with the steady-state levels of DNA adducts and specific adduct sites in ras genes in acute and chronic exposure experiments to DBC or DBA. A variety of existing experimental techniques will be employed to achieve these goals. The overall aim is to achieve a better understanding of the mechanisms of carcinogenesis associated with N-heterocyclic aromatic compounds.