2007 Fiscal Year Final Research Report Summary
Mechanism of hepatic toxicity induced by N-nitrosocompounds : Role of nitrogen monoxides and active oxygen
| Project/Area Number |
17590028
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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 |
Chemical pharmacy
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| Research Institution | National Institute of Health Sciences |
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Principal Investigator |
OKUDA Haruhiro National Institute of Health Sciences, Division of Organic Chemistry, Head (30160807)
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| Co-Investigator(Kenkyū-buntansha) |
FUKUHARA Kiyoshi National Institute of Health Sciences, Division of Organic Chemistry, Section Chief (70189968)
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| Project Period (FY) |
2005 – 2007
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| Keywords | N-nitrosocomnound / N-nitrsofenfluramine / fenfluramin / alkvlamine / reactive oxygen species / oxidative stress |
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| Research Abstract |
Many case of hepatopathy including deaths have frequently occurred after ingestion of Chinese dietary supplements for weight loss containing N-nitrosofenfluramine (N-fen), a nitroso derivative of fenfluramine (fen), which was used for the treatment of obesity in the United States. Since N-nitroso compound is reported to generate nitric oxide in the presence of cytocrome P450, oxidative damage of DNA, protein or lipid with reactive oxygen species (ROS) may contribute to the hepatopathy induced by N-fen.
When pBR322DNA was incubated with N-fen, no effect on DNA was observed. However, DNA cleaving reaction proceeded efficiently when Cu (II) was added in the reaction mixture of pBR322 and N-fen. The DNA cleavage is responsible for N-Nitroso structure in N-fen because no DNA damage was observed when fen was incubated with pBR322DNA. To confirm the generation of ROS, ESR spectrum was observed in the presence of DEPMPO, a spin trap for hydroxyl radical and superoxide, showing the typical signal of DEPMPO-OH that is formed by the reaction between DEPMPO and hydroxyl radical. These result suggested that N-fen is able to mediate Cu (II)-dependent DNA strand scission and the cleavage is more likely caused by a copper-peroxide complex as the reactive species. N-fen also generated nitric oxide in the presence of Cu (II), consisting from the result that the signal of carboxy PTI was observed in the mixture of N-fen and carboxy PTIO. As peroxynitrite is formed with nitric oxide and superoxide, peroxynitrite-mediated damage in pBR322DNA might also be proceeded as well as the Cu (II)-dependent DNA scission.
Finally, it was found that N-fen has an ability to generate copper-peroxide complex and nitric oxide in the presence of Cu (II), which result in DNA strand scission. Our result suggested that the mechanism with ROS generation leading to oxidative DNA damage might be important for understanding the toxicity of N-nitroso compound.
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