METABOLIC ACTIVATION OF N HETEROCYCLIC AROMATICS

描述：氮取代的杂环芳族化合物（NHA）是 重要的、潜在致癌的环境污染物。 而他们的 结构类似于那些更广泛研究的多环 芳烃，主要研究人员已经证明， 代谢活化NHA化合物，以有效的致肿瘤和致突变 在某些情况下，中间体可以通过不同的优选途径进行。 该项目完全集中在两个结构相关的N-杂环 化合物，7 H-二苯并[c，g]咔唑（DBC）和二苯并[a，j]吖啶（DBA）。 这两种化合物彼此的不同之处仅在于 含氮环 DBC在小鼠肺和皮肤中是一种强致癌物， DBA仅在小鼠肺和皮肤中是致癌物。 具体目标是 表征小鼠代谢活化和DNA结合的机制 皮肤，肝脏和肺，并研究与 这些组织中形成的共价DNA加合物。 这将是完成 通过表征NHA残基，以及肺中的DNA靶碱基， 肝脏和皮肤。 其他具体目标包括确定 癌基因ras点突变的频率和剂量依赖性 相同的组织，并将这些发现与稳态 DNA加合物水平和ras基因的特异性加合位点在急性和 长期暴露于DBC或DBA的实验。 各种现有 将采用实验技术来实现这些目标。 的 总体目标是更好地了解 与N-杂环芳香族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.