QUINOLINES & BENZOQUINOLINES: MUTAGENS & CARCINOGENESIS

喹啉、甲基喹啉和苯并喹啉是主要的氮杂芳烃 在人类呼吸道中被检测为污染物 环境 我们的目标是确定 喹啉、甲基喹啉和苯并喹啉是代谢性的 对遗传毒性物质有反应 我们将确定喹啉最终被激活的机制 在小鼠和大鼠中的肝癌原。 众所周知， 微粒体可以代谢活化喹啉成为诱变剂。 我们的研究 对喹啉代谢的影响将扩大到包括 鉴定使用该方法形成的所有水溶性代谢物 激活系统 根据我们最近的研究， 1，2-二氢喹啉和3，4-环氧-3，4-二氢喹啉是可疑的 喹啉的最终遗传毒性代谢物。 这些亲电体 合成，并评价其生物活性， 喹啉。 虽然已知小鼠和大鼠对 喹啉、仓鼠和豚鼠的致癌作用， 据报道有抗药性 我们将比较喹啉的DNA加合物 在小鼠和大鼠体内形成，在仓鼠体内形成， 豚鼠 我们将从结构上鉴定 喹啉在体内形成。 最终，我们将比较 喹啉和与人肝细胞形成的喹啉DNA加合物 与在大鼠肝细胞中形成的那些相同。 苯并（f）喹啉是一种弱的新生儿肝癌原 小鼠 生物测定正在进行中，以进一步评估相对的 喹啉、甲基喹啉和 苯并喹啉。 我们还将研究每个人的贡献， 苯并（f）喹啉、苯并（h）喹啉和 菲啶的诱变活性。 主要的诱变剂 还将评价这些氮杂芳烃的代谢物的 致癌活性 这些双环和三环化合物代表 存在于人类环境中的主要氮杂芳烃。 这 研究的目的是增加我们对它们的遗传毒性的理解， 潜力以及其生物活性的分子基础。

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.