Carcinogenicity of quinoline by drinking-water administration in rats and mice

Abstract

-The carcinogenicity of quinoline was examined by administrating quinoline in the drinking water to groups of 50 F344/DuCrj rats and 50 Crj: BDF1 mice of each sex. In rats, the doses of quinoline were 0, 200, 400, and 800 ppm for males and 0, 150, 300, and 600 ppm for females. In male rats, administration of quinoline was terminated at week 96 due to high mortality caused by tumors. There were significant increases of hepatocellular adenomas, hepatocellular carcinomas, hepatocellular adenomas and/or carcinomas (combined), and liver hemangiomas, hemangiosarcomas, hemangiomas and/ or hemangiosarcomas (combined) in both male and female rats, and nasal esthesioneuroepitheliomas and sarcoma NOS (not otherwise specified) in males. In mice, doses of quinoline were 0, 150, 300 and 600 ppm for both males and females. Administration of quinoline was terminated at week 65 in males and at week 50 in females due to high mortality caused by tumors. There were marked increases of hemangiomas, hemangiosarcomas, and hemangiomas and/or hemangiosarcomas (combined) in the retroperitoneum, mesenterium, and liver in males, and in the retroperitoneum, mesenterium, peritoneum, and subcutis in females. Additionally, histiocytic sarcomas were statistically increased in the livers of female mice. Thus the present studies provided clear evidence of carcinogenic activity of quinoline administered in the drinking water in both rats and mice.

Toluene Dioxygenase-Catalyzed cis-Dihydroxylation of Quinolines: A Molecular Docking Study and Chemoenzymatic Synthesis of Quinoline Arene Oxides

“…Identification of mammalian metabolites of quinoline 1 and their role in its mutagenicity and tumorigenicity, has been of interest for more than 40 years (Hollstein et al, 1978;Tada et al, 1980Tada et al, , 1982LaVoie et al, 1983;Agarwal et al, 1986Agarwal et al, , 1990Willems et al, 1992;Saeki et al, 1993;Reigh et al, 1996;Suzuki et al, 2000;Dowers et al, 2004;Hakura et al, 2007;Diaz Duran et al, 2015;Matsumoto et al, 2018). Several quinoline arene oxides, e.g., 20 and 27, were initially postulated as possible liver microsomal metabolites of quinoline 1 (Hollstein et al, 1978;Tada et al, 1980Tada et al, , 1982LaVoie et al, 1983), before 5,6-arene oxide 20 was finally confirmed as a major metabolite (Figure 8) (Agarwal et al, 1986).…”

“…Quinoline 1 is a mammalian hepatocarcinogen and a bacterial mutagen, with its metabolites binding covalently to DNA. Possible pathways responsible for these biological effects continue to be of interest (Hollstein et al, 1978;Tada et al, 1980Tada et al, , 1982LaVoie et al, 1983;Agarwal et al, 1986Agarwal et al, , 1990Willems et al, 1992;Saeki et al, 1993;Reigh et al, 1996;Suzuki et al, 2000;Dowers et al, 2004;Hakura et al, 2007;Diaz Duran et al, 2015;Matsumoto et al, 2018). Cytochrome P-450 (CYP-450) monooxygenases have been identified as responsible for catalyzing epoxidation and dearomatization of quinolines, during mammalian liver metabolism.…”