QUINOLINES AND CARBAZOLES: MUTAGENS AND CARCINOGENS

喹啉、咔唑和它们的甲基化衍生物被广泛地应用于 分布的环境污染物，并在实验室致癌 动物 这项研究计划的目的是确定 这些氮杂芳烃最终发挥其遗传毒性的机制 活动 我们的假设是喹啉被代谢转化为 能够与DNA和其它细胞相互作用的氧氮丙啶 形成加合物。 喹啉的亲电代谢产物 将使用放射性标记的喹啉研究体内形成的。 将通过分析 与谷胱甘肽和细胞大分子形成的加合物， 蛋白质RNA和DNA 这些生物化学研究将指导合成 在制备用于比较的参比标准品方面所做的努力 可疑亲电代谢产物相互作用产生的产物 与细胞大分子结合。 在肝癌活性方面存在主要的物种差异， 喹啉。 大分子加合物和代谢物在肝脏中形成， 将对大鼠、小鼠、仓鼠和豚鼠进行分析，以确定 可能与易感性有关。 形成的金属化合物和加合物 也将比较来自大鼠和人的肝细胞。 阐明 喹啉发挥其遗传毒性活性的机制是 特别重要的是，鉴于这些和物种的差异， 它的致癌活性，以及它在多大程度上存在于 环境保护 咔唑是第二个主要的致癌剂， 这个戒酒会这 我们的假设是，咔唑是在 体内9-羟甲基咔唑，最终形成亲电的9- 甲亚胺衍生物。 这一假设将由 表征代谢物和肝DNA加合物形成的 咔唑和9-甲基咔唑。 9-羟基咔唑和9- 乙酰氧基咔唑是S.鼠伤寒和广泛 在9-乙酰氧基咔唑孵育后观察到加合物形成 使用32 P后标记技术。 康贝特人将以 在小鼠肝脏中体内形成类似加合物的程度。

Quinoline, carbazole, and their methylated derivatives are widely distributed environmental pollutants and are carcinogenic in laboratory animals. The objective of this research program is to determine the mechanism(s) by which these aza-arenes ultimately exert their genotoxic activity. It is our hypothesis that quinoline is metabolically transformed to an oxaziridine capable of interacting with DNA and other cellular macromolecules to form adducts. The electrophilic metabolites of quinoline formed in vivo will be investigated using radiolabeled quinoline. Electrophilic metabolites will be identified through the analysis of the adducts formed with glutathione and cellular macromolecules including protein, RNA, and DNA. These biochemical studies will direct synthetic efforts in the preparation of reference standards for comparison with the products resulting from interaction of suspect electrophilic metabolites with cellular macromolecules. There are major species differences in the hepatocarcinogenic activity of quinoline. Macromolecular adducts and metabolites formed in the liver of rats, mice, hamsters, and guinea pigs will be analyzed to determine a possible correlation with susceptibility. Metabolites and adducts formed in hepatocytes from rats and humans will also be compared. Elucidation of the mechanisms by which quinoline exerts its genotoxic activity is of particular importance in view of these and species differences observed in its carcinogenic activity, as well as the extent to which it is present in the environment. Carbazole is the second principal carcinogenic agent targeted for study in this program. It is our hypothesis that carbazole is being transformed in vivo to 9-hyrdoxymethylcarbazole which ultimately forms an electrophilic 9- methiminium derivative. This hypothesis will be investigated by characterizing the metabolites and the liver DNA adducts formed from carbazole and 9-methylcarbazole in mice. 9-Hydroxycarbazole and 9- acetoxycarbazole are direct-acting mutagens in S. typhimurium and extensive adduct formation has been observed after incubation of 9-acetoxycarbazole with DNA using the 32P-postlabeling technique. We will determine the extent to which similar adducts are formed in vivo in mouse liver.