1989 Fiscal Year Final Research Report Summary
Deprivation of Genotoxicity of N-Containing Heteroaromatics: Effect of Fluorine Substitution
| Project/Area Number |
63571003
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| Research Category |
Grant-in-Aid for General Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Research Field |
Chemical pharmacy
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| Research Institution | Nagoya City University |
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Principal Investigator |
KAWAZOE Yutaka Nagoya City University, Faculty of Pharmaceutical Sciences, Professor, 薬学部, 教授 (80106252)
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| Co-Investigator(Kenkyū-buntansha) |
TAKAHASHI Kazuhiko Nagoya City University, Faculty of Pharmaceutical Sciences, Assistant, 薬学部, 助手 (40117833)
KAIYA Toyo Nagoya City University, Faculty of Pharmaceutical Sciences, Instructor, 薬学部, 講師 (10080201)
KOHDA Kohfuku Nagoya City University, Faculty of Pharmaceutical Sciences, Assistant Professor, 薬学部, 助教授 (60124286)
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| Project Period (FY) |
1988 – 1989
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| Keywords | Metabolism / Heteroaromatics / Carcinogenicity / Genotoxicity / Fluorine derivative / Metabolic activation / Microsomal enzyme / Quinolines |
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| Research Abstract |
Based on the concept that a halogen atom substituted on the aromatic ring blocks the oxidative metabolism at the site of the halogen-substitution in polycyclic aromatic hydrocarbons, it is expected that introducing a halogen atom at a putative site in the molecule would deprive the molecule of any genotoxic properties. Among halogens, F atom is sometimes ignored in the interactions with biomolecules, including enzymes. Therefore, F-substitution might possibly deprive the molecules of genotoxicity without affecting other biologcial activities of the parent molecules. The present study on the structure-mutagenicity relationship among quinoline derivatives revealed that 3-fluoro derivative of genotoxic quinoline was deficient in mutagenicity, whereas all the derivatives carrying a halogen at the 4-, 5-, 6-, or 8-position were mutagenic. It is noteworthy that the introduction of a fluorine on the position-3 deprived genotoxic quinoline molecule of its mutagenic, and probably carcinogenic, property. The present study also revealed that the metabolic activation of genotoxic quinoline proceeded through a microsomal oxidation of the pyridine moiety but not the benzene moiety. The ultimate structure is proposed to be the 2,3-epoxide of 1, 4-hydrated quinoline. The present result suggests that deprivation of genotoxic property of N-containing heteroaromatics might be accomplished in a wide variety of heteroaromatics such benzoquinolines by a fluorine substitution at the putative site for genotoxic epoxidation.
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