On the metabolism of quinoline and isoquinoline: possible molecular basis for differences in biological activities.
Quinoline is a hepatocarcinogen in mice and rats, a mutagen in Salmonella typhimurium, and induces unscheduled DNA synthesis in primary cultures of rat hepatocytes. In contrast, isoquinoline has not been shown to be genotoxic. The metabolites of quinoline and isoquinoline, as formed in vitro with rat liver homogenate, were identified to investigate possible molecular bases for the differences in their biological activity. The ethyl acetate extractable metabolites of quinoline and isoquinoline were analyzed directly by high pressure liquid chromatography and, after silylation, by capillary gas chromatography. The major metabolite of quinoline was 5,6-dihydroxy-5,6-dihydroquinoline. Lesser amounts of 2- and 3-hydroxyquinoline and quinoline-N-oxide were also identified as metabolites. 1-, 4- and 5-Hydroxyiso-quinoline and isoquinoline-N-oxide were detected as metabolites of isoquinoline. 5,6-Dihydroxy-5,6-dihydroiso-quinoline was detected as only a minor metabolite. This difference in the extent to which these isomers are ultimately metabolized to dihydrodiols may be associated with their differences in biological activity. Quinoline, 4-methylquinoline and 7-methylquinoline were bioassayed as tumor initiators on the skin of Sencar mice. While 4-methylquinoline was at least as potent a tumor initiator as quinoline, 7-methylquinoline was not significantly tumorigenic in this assay. These data are consistent with the hypothesis that formation of the 5,6-epoxide of quinoline is associated with its metabolic activation to a tumorigen.
D000818:Animals; D001711:Biotransformation; D002851:Chromatography, High Pressure Liquid; D005260:Female; D008401:Gas Chromatography-Mass Spectrometry; D007546:Isoquinolines / Q000378:metabolism*; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D008862:Microsomes, Liver / Q000378:metabolism*; D009374:Neoplasms, Experimental / Q000473:pathology; D011804:Quinolines / Q000378:metabolism*; D051381:Rats; D011916:Rats, Inbred F344; D011919:Rats, Inbred Strains; D012878:Skin Neoplasms / Q000139:chemically induced* / Q000473:pathology
D007546:Isoquinolines; D011804:Quinolines; C037219:quinoline; C039109:isoquinoline