title: [Anti-carcinogenic structural modification by fluorine-substitution in aza-polycyclic aromatic hydrocarbons].
abstract: One of the major goals of a series of our studies is to explore the availability of a method for anti-genotoxic modification of carcinogens by fluorine-substitution. Quinoline, a hepatocarcinogen, mutates bacterial tester strains in the presence of rat liver microsomal enzymes and induces GST-P (placental glutathione S-transferase)-positive foci in a medium-term bioassay system for hepatocarcinogenesis. On the other hand, 3-fluorinated quinoline (3-FQ) was neither mutagenic nor carcinogenic in the same assay system, whereas 5-fluoroquinoline (5-FQ) was mutagenic and carcinogenic. Quinoline, 3-FQ, and 5-FQ were also tested in an in vivo mutagenicity assay system using a lacZ-transgenic mouse (Muta Mouse). Mutation was induced by quinoline and 5-FQ only in the liver, the target organ of carcinogenesis by quinoline, but not in the other organs examined. 3-FQ was non-mutagenic in all of the organs. The results strongly indicate that fluorine-substitution at the position-3 of quinoline could be an anti-genotoxic structural modification of quinoline in a wide range of its genotoxic end-points. Additionally, seventeen mono- and di-fluorinated derivatives of 1,7-phenanthroline, 1,10-phenanthroline, benzo[h]quinoline, and benzo[f]quinoline were subjected to analysis of their structure-mutagenicity relationship. The results support that the enamine epoxide structure of the pyridine moiety, as well as the bay-region epoxide structure, is responsible for mutagenicity. These results suggest that the introduction of a fluorine atom to the molecule in question may be a useful tool to modify their mutagenic potency and to better understand the mechanism of mutation.
authors.affiliation: Faculty of Pharmaceutical Sciences, Nagoya City University, 3-1 Tanabe-dori, Mizuho-ku, Nagoya 467-8603, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Saeki
mesh_terms: D000818:Animals; D001372:Aza Compounds / Q000737:chemistry* / Q000633:toxicity; D002625:Chemistry, Organic / Q000379:methods*; D005461:Fluorine; D008114:Liver Neoplasms, Experimental / Q000139:chemically induced; D051379:Mice; D016296:Mutagenesis / Q000187:drug effects; D011084:Polycyclic Aromatic Hydrocarbons / Q000737:chemistry* / Q000633:toxicity; D011804:Quinolines / Q000737:chemistry / Q000633:toxicity; D051381:Rats
chemical_list: D001372:Aza Compounds; D011084:Polycyclic Aromatic Hydrocarbons; D011804:Quinolines; D005461:Fluorine