QUINOLINES AND CARBAZOLES: MUTAGENS AND CARCINOGENS

喹啉、咔唑及其甲基化衍生物广泛存在于 分布在环境中的污染物，在实验室中是致癌的 动物。这项研究计划的目标是确定 氮杂芳烃最终发挥其遗传毒性的机制(S) 活动。 我们的假设是，喹啉在代谢过程中转化为 能够与DNA和其他细胞相互作用的恶氮杂环 形成加合物的大分子。喹啉的亲电代谢物 在体内形成的将使用放射性标记的喹啉进行研究。 亲电代谢物将通过分析 谷胱甘肽和细胞大分子形成的加合物，包括 蛋白质、RNA和DNA。这些生化研究将指导合成 努力编制参考标准，以便与《公约》 可疑亲电代谢物相互作用产生的产物 用细胞大分子。 其致癌活性存在主要的种属差异。 喹啉。肝脏中形成的大分子加合物和代谢物 对大鼠、小鼠、仓鼠和豚鼠进行分析，以确定 可能与易感性相关。代谢物和加合物形成 在大鼠和人类的肝细胞中也将进行比较。澄清： 喹啉发挥其遗传毒性作用的机制是 鉴于观察到的这些和物种差异，特别重要 它的致癌活性，以及它在 环境。 咔唑是#年研究的第二种主要致癌剂 这个节目。我们的假设是咔唑正在转化为 体内到9-羟甲基咔唑，最终形成亲电的9-甲基咔唑。 甲基胺衍生物。这一假设将由 代谢产物和肝DNA加合物的表征 咔唑和9-甲基咔唑对小鼠的影响。9-羟基咔唑和9-羟基咔唑 乙酰氧基咔唑是鼠伤寒沙门氏菌的直接作用诱变剂，广泛存在于 在9-乙酰氧基咔唑孵育后观察到加合物的形成 用~(32)P-后标记技术与DNA结合。我们将确定 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.