QUINOLINES & BENZOQUINOLINES: MUTAGENS & CARCINOGENESIS

喹啉类

• 批准号: 3249713
• 负责人: EDMOND J LAVOIE
• 金额: $ 14.69万
• 依托单位: RUTGERS, THE STATE UNIV OF N.J.
• 依托单位国家: 美国
• 财政年份: 1988
• 资助国家: 美国
• 起止时间: 1988-03-01 至 1990-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3249713
• 关键词: DNA; alkyl group; binding proteins; bioassay; chemical addition; chemical carcinogen; chemical structure function; environment related neoplasm /cancer; environmental contamination; environmental toxicology; fluorescence spectrometry; guinea pigs; hamsters; high performance liquid chromatography; human subject; infrared spectrometry; ion exchange chromatography; laboratory mouse; laboratory rat; liver; liver neoplasms; mass spectrometry; microsomes; mutagen testing; mutagens; nuclear magnetic resonance spectroscopy; quinoline; scintillation counter; species difference; tissue /cell culture; toxicant interaction; toxicant screening; toxin metabolism; ultraviolet spectrometry

Quinoline, methylquinolines, and benzoquinolines are the major aza-arenes which have been detected as pollutants in the human respiratory environment. Our objective is to determine the mechanism(s) by which quinoline, methylquinolines, and benzoquinolines are metabolically activated to genotoxic agents. We will determine the mechanism by which quinoline is ultimately activated to a hepatocarcinogen in mice and rats. It is known that rat liver microsomes can metabolically activate quinoline to a mutagen. Our studies on the metabolism of quinoline will be extended to include the identification of all water-soluble metabolites formed using this activation system. Based upon our most recent studies, the oxaziridine of 1,2-dihydroquinoline and 3,4-epoxy-3,4-dihydroquinoline are the suspect ultimate genotoxic metabolites of quinoline. These electrophiles will be synthesized and their biological activities evaluated relative to quinoline. While mice and rats are known to be sensitive to the hepatocarcinogenic effects of quinoline, hamsters and guinea pigs are reported to be resistant. We will compare the DNA-adducts of quinoline formed in vivo in both mice and rats with those formed in hamsters and guinea pigs. We will structurally identify the major DNA adduct(s) of quinoline formed in vivo. Ultimately, we will compare the metabolites of quinoline and the DNA-adduct(s) of quinoline formed with human hepatocytes with those formed in rat hepatocytes. Benzo(f)quinoline has been shown to be a weak hepatocarcinogen in newborn mice. Bioassays are in progress to further evaluate the relative carcinogenic potential of quinoline, methylquinolines, and benzoquinolines. We will also examine the contribution of each of the major metabolites of benzo(f)quinoline, benzo(h)quinoline, and phenanthridine to their mutagenic activity. The major mutagenic metabolites of these aza-arenes will also be evaluated for their carcinogenic activity. These bicyclic and tricyclic compounds represent the major aza-arenes which are present in the human environment. This research is intended to increase our understanding of their genotoxic potential as well as the molecular basis for their biological activities.

喹啉，甲基喹啉和苯喹啉是主要的Aza芳烃 在人呼吸道中被发现为污染物 环境。 我们的目标是确定该机制 喹啉，甲基喹啉和苯喹啉是代谢的 激活为遗传毒性剂。 我们将确定喹啉最终激活的机制 到小鼠和大鼠的肝癌。 已知大鼠肝脏 微粒体可以代谢将喹啉激活至诱变剂。 我们的研究 关于喹啉的代谢，将扩展到包括 使用此的所有水溶性代谢物的识别 激活系统。 基于我们最近的研究 1,2-二氢喹啉和3,4-蛋白酶-3,4-二氢喹啉是可疑的 喹啉的最终基因毒性代谢产物。 这些电力将是 合成及其生物学活性相对于 喹啉。 虽然已知小鼠和大鼠对 喹啉，仓鼠和豚鼠的肝癌作用是 据报道具有抗性。 我们将比较喹啉的DNA-ADDUCTS 在小鼠和大鼠中与仓鼠形成的小鼠和大鼠形成 豚鼠。 我们将在结构上确定主要的DNA加合物 喹啉在体内形成。 最终，我们将比较 用人肝细胞形成的喹啉的喹啉和DNA-ADDUCT（S） 与大鼠肝细胞形成的那些。 苯并（F）喹啉已被证明是新生儿中的肝癌弱 老鼠。 正在进行生物分析以进一步评估亲戚 喹啉，甲基喹啉和 苯甲石。 我们还将研究每个人的贡献 苯并（F）喹啉的主要代谢产物，苯并（H）喹啉和 苯性具有诱变活性。 主要的诱变 这些AZA-ARENES的代谢物也将被评估 致癌活性。 这些双环和三环化合物代表 人类环境中存在的主要aza芳烃。 这 研究旨在增加我们对其遗传毒性的理解 潜力以及其生物活性的分子基础。