Activation mechanism of carcinogenic N-nitrosodialkyamines by chemical model for cytochrome P450
| Project/Area Number |
11672229
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Environmental pharmacy
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| Research Institution | Kyoritsu University of Pharmacy |
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Principal Investigator |
MOCHIZUKI Masataka Kyoritsu University of Pharmacy, Faculty of Pharmaceutical Sciences, Professor (10072414)
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| Co-Investigator(Kenkyū-buntansha) |
ISHIKAWA Satoko Kyoritsu University of Pharmacy, Faculty of Pharmaceutical Sciences, Research Associate (70223518)
INAMI Keiko Kyoritsu University of Pharmacy, Faculty of Pharmaceutical Sciences, Research Associate (00271247)
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| Project Period (FY) |
1999 – 2000
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| Project Status |
Completed (Fiscal Year 2000)
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| Budget Amount *help |
¥3,600,000 (Direct Cost: ¥3,600,000)
Fiscal Year 2000: ¥1,400,000 (Direct Cost: ¥1,400,000)
Fiscal Year 1999: ¥2,200,000 (Direct Cost: ¥2,200,000)
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| Keywords | N-nitrosodialkylamine / carcinogen / metabolic activation / metal porphyrin complex / oxidant / Fenton reagent / mutagen / 化学的酸化モデル系 / 変異原性 / 一酸化窒素 / DNAアルキル化 |
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| Research Abstract |
Carcinogenic and mutagenic N-nitrosodialkylamines exist in our environment. In order to study the biological and chemical properties of the activated form of carcinogenic N-nitrosodialkylamines, Fenton's reagent was used as an alternative chemical model for cytochrome P450. The Fenton's reagent containing an iron salt and hydrogen peroxide, supplemented with copper salts in acetate buffer (pH 4.5), has been used as an alternative metabolic system. The extract of the reaction mixture of N-nitrosodialkylamines in the presence of Fenton's reagent was mutagenic in S. typhimurium TA1535 and E.coi WP2 uvrA. Thus, the Fenton reagent activated the dialkylnitrosamines into direct-acting mutagens. The extract derived from N-nitroso-N-methylbutylamine (NMB) treated with Fenton's reagent showed the highest activity among N-nitrosodialkylamines tested. To identify structure of the direct-acting mutagen derived from NMB, the mutagen was isolated from the reaction mixture, and ^H-, ^<13>C-NMR, IR and MS were measured. The structure of the direct-acting mutagen was presumed to be 3-methyl-3-nitrito or nitro-Δ^1-pyrazoline 2-oxide originally, and 5-methyl-5-nitropyrazoline 1-oxide was finally identified. The activity of the mutagen was assayed using the S. typhimurium O^6-methylguanine methyltransferase-deficient strain YG7108, and the result was compared to that of the parent strain S. typhimurium TA1535. The mutagenicity increased in S. typhimurium YG7108, suggesting that the mutagenicity derived from NMB in the presence of the Fenton's reagent was due to DNA alkylation similar to the alkylation through α-hydroxynitrosamines.
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Report
(3 results)
Research Products
(22 results)
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[Publications] Chone Y,Kinouchi T,Yamada T,Suzuki Y,Kitaura K,Jiao Z,Minami T,Bando Y,Uehara H,Mochizuki M,Ohnishi Y,Izumi K: "Low susceptibility of Long-Evans Cinnamon rats to N-butyl-N-(4-hydroxybutyl)-nitrosamine-induced urinary bladder carcinogenesis and inhibitory effect of urinary copper"Jpn. J. Cancer Res.. 91. 16-24 (2000)
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