MUTAGENICITY STUDIES WITH DIBENZ(A,H)ACRIDINE DERIVATIVE

苯并吖啶和二苯并吖啶是一类重要的环境污染物。 有毒物质，这是一个潜在的健康危害， 公众以及参与焦化和化石燃料转化的工人 运营 尽管这些化学物质具有潜在的致癌性， 关于它们的新陈代谢的信息非常有限， 作用机制。 拟议的研究旨在确定 二苯并（a，h）吖啶[DB（a，h）AC]的反应性代谢物， 参与这种化学物质的诱变/致癌作用。 一个主要 这项研究的目的是调查 多环芳烃致癌性的“海湾-区域”假说 芳烃（PAH）可以延伸到它们的氮杂类似物。 本研究的具体目标是：（1）综合几种 DB（a，h）AC的二醇环氧化物和二氢二醇衍生物，（2）以评估 DB（a，h）AC二醇环氧化物的内在致突变活性和代谢 DB（a，h）AC二氢二醇在体外致突变性试验中的活化， 鼠伤寒沙门氏菌，（3）与二醇的生物活性相关 环氧化物及其化学反应性和预测的电子性质 为了评估可计算的电子特性是否可用于 预测氮杂多环芳烃的二醇环氧化物的生物活性， 证明与某些多环芳烃，（4）评估氮杂取代的作用 以及氮在化学反应中的共轭效应， 海湾地区二醇环氧化物的致突变性/致癌性， 阐明影响致癌性的分子因素， 活性的二苯并吖啶和其他氮杂多环芳烃，和（5），以确定 DB（a，h）AC在大鼠肝脏中转化为二氢二醇的程度 微粒体 研究的长期目标是了解机制 参与多核氮杂芳香族化合物的致癌作用 芳香烃.

Benz- and dibenzacridines represent an important class of environmental toxicants which present a potential health hazard both to the general public and to workers involved in coking and fossil fuel conversion operations. In spite of the potential carcinogenicity of these chemicals, there is extremely limited information available on their metabolism or mechanism of action. The proposed research is aimed at identifying reactive metabolites of dibenz(a,h)acridine [DB(a,h)AC] which may be involved in the mutagenesis/carcinogenesis of this chemical. A major objective of the proposed research is to investigate whether the "bay-region" hypothesis proposed for the carcinogenicity of polycyclic aromatic hydrocarbons (PAHs) can be extended to their aza analogs. The specific aims of the proposed research are: (1) to synthesize several diol epoxides and dihydrodiol derivatives of DB(a,h)AC, (2) to assess the intrinsic mutagenic activity of DB(a,h)AC diol epoxided and the metabolic activation of DB(a,h)AC dihydrodiols in in vitro mutagenicity assays using Salmonella typhimurium, (3) to correlate the biological activity of diol epoxides with their chemical reactivity and predicted electronic properties in order to assess whether calculable electronic properties can be used to predict the biological activity of the diol epoxides of aza-PAHs, as demonstrated with certain PAHs, (4) to assess the role of aza substitution and the conjugative effect of nitrogens in the chemical reactivity and the mutagenicity/carcinogenicity of the bay-region diol epoxides, in an attempt to elucidate the molecular factors which influence the carcinogenic activity of dibenzacridines and other aza-PAHs, and (5) to determine the extent to which DB(a,h)AC is converted to its dihydrodiols by rat liver microsomes. The long-term aim of the research is to understand the mechanism(s) involved in the carcinogenesis of polynuclear aza-heteroaromatic hydrocarbons.