Quantitative Approaches to Assess Key Carcinogenic Events of Genotoxic Carcinogens
Toxicol. Res. 2018;34:291−296
Published online October 15, 2018;  https://doi.org/10.5487/TR.2018.34.4.291
© 2018 Korean Society of Toxicology.

Shoji Fukushima1,2, Min Gi3, Masaki Fujioka3, Anna Kakehashi3, Hideki Wanibuchi3 and Michiharu Matsumoto2

1Association for Promotion of Research on Risk Assessment, Nakagawa, Nagoya, Japan
2Japan Bioassay Research Center, Hadano, Kanagawa, Japan
3Department of Molecular Pathology, Osaka City University Graduate School of Medicine, Abeno, Osaka, Japan
Shoji Fukushima, Association for Promotion of Research on Risk Assessment, 134 Arako 1-chome, Nakagawa, Nagoya 454-0869, Japan
E-mail: anhyohken@cloud-line.net
Received: July 23, 2018; Revised: August 20, 2018; Accepted: August 30, 2018
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
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.
Keywords : Cancer risk assessment, Point of departure, Linear no-threshold carcinogenicity, Genotoxic carcinogen, MeIQx, IQ


This Article

Cited By Articles
  • CrossRef (0)