QUINOLINES & BENZOQUINOLINES: MUTAGENS & CARCINOGENESIS

喹啉、甲基喹啉和苯并喹啉是主要的氮杂芳烃。 它们已被检测为人类呼吸道中的污染物 环境。我们的目标是确定(S)通过什么机制 喹啉、甲基喹啉和苯并喹啉在体内代谢 被基因毒剂激活。 我们将确定喹啉最终被激活的机制。 对小鼠和大鼠的一种致癌物质。众所周知，大鼠的肝脏 微粒体能代谢地将喹啉激活为诱变剂。我们的研究 关于喹啉代谢的研究将扩展到包括 用此方法形成的所有水溶性代谢物的鉴定 激活系统。根据我们最新的研究，恶氮杂环丙啶 可疑的有1，2-二氢喹啉和3，4-环氧基-3，4-二氢喹啉 喹啉的最终遗传毒性代谢物。这些亲电体将是 化合物的合成及其生物活性评价 喹啉。虽然已知小鼠和大鼠对 喹啉、仓鼠和豚鼠的致癌作用 据报道具有抗药性。我们将比较喹啉的DNA加合物 在小鼠和大鼠体内形成，与在仓鼠和 豚鼠。我们将对主要的DNA加合物(S)进行结构鉴定 喹啉在体内形成。最终，我们将比较 喹啉及其与人肝细胞形成的DNA加合物(S) 与在大鼠肝细胞中形成的那些。 苯并(F)喹啉已被证明是一种在新生儿中微弱的肝癌致癌物。 老鼠。生物检测正在进行中，以进一步评估亲属 喹啉、甲基喹啉和甲基喹啉的致癌潜力 苯并喹啉类药物。我们还将审查每一个 苯并(F)喹啉、苯并(H)喹啉的主要代谢产物 菲的诱变活性。主要诱变剂 这些氮杂芳烃的代谢物也将被评估其 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氮杂芳烃。这 研究旨在增加我们对它们的遗传毒性的了解 它们具有潜在的生物活性以及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.