Quantitative Approaches to Assess Key Carcinogenic Events of Genotoxic Carcinogens

Shoji Fukushima; Min Gi; Masaki Fujioka; Anna Kakehashi; Hideki Wanibuchi; Michiharu Matsumoto

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저자정보: Shoji Fukushima (Association for Promotion of Research on Risk Assessment) Min Gi (Osaka City University Graduate School of Medicine) Masaki Fujioka (Osaka City University Graduate School of Medicine) Anna Kakehashi (Osaka City University Graduate School of Medicine) Hideki Wanibuchi (Osaka City University Graduate School of Medicine) Michiharu Matsumoto (Japan Bioassay Research Center)

저널정보: 한국독성학회 Toxicological Research Toxicological Research Vol.34 No.4

발행연도: 2018.10

수록면: 291 - 296 (6page)

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Chemical carcinogenesis is a multistep process. Genotoxic carcinogens, which are DNA-reactive, induce DNA adduct formation and genetic alterations in target cells, thereby generating mutated cells (initiation). Subsequently, preneoplastic lesions appear through clonal proliferation of the mutated cells and transform into tumors (promotion and progression). Many factors may influence these processes in a dose-dependent manner. Therefore, quantitative analysis plays an important role in studies on the carcinogenic threshold of genotoxic carcinogens. Herein, we present data on the relationship between key carcinogenic events and their deriving point of departure (PoD). Their PoDs were also compared to those of the carcinogenesis pathway. In an experiment, the liver of rats exposed to 2-amino-3,8-dimethylimidazo-(4,5-f)quinoxaline (MeIQx) was examined to determine the formation of MeIQx-DNA adducts, generation of mutations at LacI transgene, and induction of preneoplastic glutathione S-transferase placental form (GST-P)-positive foci and tumors (benign and malignant). The PoDs of the above key events in the carcinogenicity of MeIQx were increased as the carcinogenesis advanced; however, these PoDs were lower than those of tumor induction. Thus, the order of key events during tumor induction in the liver was as follows: formation of DNA adducts ≪ Mutations ≪ GST-positive foci (preneoplasia) ≪ Tumor (adenoma and carcinoma). We also obtained similar data on the genotoxic and carcinogenic PoDs of other hepatocarcinogens, such as 2-amino-3,8-dimethylimidazo(4,5-f)quinoline. These results contribute to elucidating the existence of a genotoxic and carcinogenic threshold.

#Cancer risk assessment #Point of departure #Linear no-threshold carcinogenicity #Genotoxic carcinogen #MeIQx #IQ

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