2002 Fiscal Year Final Research Report Summary
Mechanism of activation of carcinogenic N-nitroso compounds by reactive oxygen species
| Project/Area Number |
13672346
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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 College of Pharmacy |
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Principal Investigator |
MOCHIZUKI Masataka Kyoritsu College of Pharmacy, Professor, 薬学部, 教授 (10072414)
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| Co-Investigator(Kenkyū-buntansha) |
INAMI Keiko Kyoritsu College of Pharmacy, Research Associate, 薬学部, 助手 (00271247)
ISHIKAWA Satoko Kyoritsu College of Pharmacy, Research Associate, 薬学部, 助手 (70223518)
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| Project Period (FY) |
2001 – 2002
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| Keywords | N-nitrosodialkylamines / Fenton reagent / Fe^<2+> -Cu^<2+> -H_2O_2 system / mutagenicity / metabolic activation / reactive oxygen species |
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| Research Abstract |
N-Nitrosodialkylamines are metabolized by cytochrome P450, but the precise process of their activation is less well understood. The activation mechanism is quite important to elucidate a contribution of environmental N-nitrosodialkylamines to human cancer. In this study, N-nitrosodialkylamines were treated with hydroxyl radical generating system, ferrous ion -cupric ion- hydrogen peroxide system (defined as modified Fenton reagent), and mutagens formed in this system were analyzed to identify in order to investigate a novel metabolic pathway of N-nitroso compounds.
N-Nitroso-N-methylpentylamine was treated with modified Fenton reagent, and a candidate for mutagen was separated. The product was analyzed by X-ray crystallography, and its structure was determined as 5-ethyl-5-nitro-1-pyrazoline 1-oxide. The authentic compound was synthesized, but its mutagenic activity could not explain the overall mutagenicity of the Fenton-treated N-nitroso-N-methylbutylamine, was presumed in the same way, and corresponding 5-methyl-5-nitro-1-pyrazoline 1-oxide was synthesized. Mutagenicity of 5-methyl-5-nitro-1-pyrazoline 1-oxide was low as similar to its ethyl homologue, suggesting that the mutagens formed in the treatment of N-nitrosodialkylamines by modified Fenton reagent may be a novel metabolite. This study demonstrated that mutagenicity of the novel metabolite decreases during the purification process; the novel metabolite is not identical to the expected compound, mutagen X; there is a possibility that the novel metabolite converts to mutagen X, and overall mutagenicity decreases. Further research is necessary to identify the novel metabolite and the mechanism of its formation, and also to elucidate its contribution to the mutagenic activity expressed in N-nitroso compounds treated with reactive oxygen species.
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