2000 Fiscal Year Final Research Report Summary
The method of safety evaluation of chemopreventive agents based on the ability of damaging human genes
| Project/Area Number |
10557040
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| Research Category |
Grant-in-Aid for Scientific Research (B).
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| Allocation Type | Single-year Grants |
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| Section | 展開研究 |
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| Research Field |
Hygiene
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| Research Institution | Mie University |
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Principal Investigator |
KAWANISHI Shosuke Mie University, Faculty of Medicine, Professor, 医学部, 教授 (10025637)
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| Co-Investigator(Kenkyū-buntansha) |
HIRAKAWA Kazutaka Mie University, Faculty of Medicine, Assistant, 医学部, 助手 (60324513)
OIKAWA Shinji Mie University, Faculty of Medicine, Assistant, 医学部, 助手 (10277006)
MURATA Mariko Mie University, Faculty of Medicine, Lecturer, 医学部, 講師 (10171141)
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| Project Period (FY) |
1998 – 2000
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| Keywords | Chemoprevention / DNA damage / Safety evaluation / Reactive oxygen species / Antioxidants / Carcinogenesis / β-Carotene / Flavonoids |
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| Research Abstract |
Cancer chemoprevention is very important in preventive medicine. Attempts have been made for cancer chemoprevention using antioxidants, such as vitamins and flavonoids, which have been believed to be promising chemopreventive agents. However, a recent epidemiological study revealed that the administration of β-carotene to male smokers caused an increase in the incidence of lung cancer. In this study, to develop the method for safety evaluation of antioxidants, we examined DNA damage induced by antioxidants using human cultured cells and ^<32>P-labeled DNA fragments obtained from the human c-Ha-ras protooncogene and the p16 and p53 tumor suppressor genes. We found that β-carotene metabolites, retinol and retinal, induced DNA damage by generating reactive oxygen species in the presence of Cu(II). In human cultured cells, these metabolites caused DNA cleavage and a significant increase in the formation of 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG), an oxidative product of guanine, at low concentrations. Vitamin E (α-tocopherol) and N-acetylcysteine were also capable of causing oxidative DNA damage. Among the flavonoids tested, quercetin caused oxidative DNA damage in cultured cells, whereas luteolin did not. Isothiocyanates also caused oxidative DNA damage through the formation of thiol compounds. Allyl isothiocyanate caused stronger DNA damage than benzyl isothiocyanate and phenethyl isothiocyanate. These finding indicate that antioxidants can serve as proxidants, capable of causing carcinogenesis via oxidative DNA damage. The present study provided insight into the development of a sensitive method to evaluate the safety of chemopreventive agents on the basis of their DNA-damaging ability.
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