title: Development of a Medium-term Animal Model Using gpt Delta Rats to Evaluate Chemical Carcinogenicity and Genotoxicity.
abstract: In this study, the potential for development of an animal model (GPG46) capable of rapidly detecting chemical carcinogenicity and the underlying mechanisms of action were examined in gpt delta rats using a reporter gene assay to detect mutations and a medium-term rat liver bioassay to detect tumor promotion. The tentative protocol for the GPG46 model was developed based on the results of dose-response exposure to diethylnitrosamine (DEN) and treatment with phenobarbital over time following DEN administration. Briefly, gpt delta rats were exposed to various chemicals for 4 weeks, followed by a partial hepatectomy (PH) to collect samples for an in vivo mutation assay. The mutant frequencies (MFs) of the reporter genes were examined as an indication of tumor initiation. A single intraperitoneal (ip) injection of 10 mg/kg DEN was administered to rats 18 h after the PH to initiate hepatocytes. Tumor-promoting activity was evaluated based on the development of glutathione S-transferase placental form (GST-P)-positive foci at week 10. The genotoxic carcinogens 2-acetylaminofluorene (2-AAF), 2-amino-3-methylimidazo [4,5-f] quinolone (IQ) and safrole (SF), the non-genotoxic carcinogens piperonyl butoxide (PBO) and phenytoin (PHE), the non-carcinogen acetaminophen (APAP) and the genotoxic non-hepatocarcinogen aristolochic acid (AA) were tested to validate the GPG46 model. The validation results indicate that the GPG46 model could be a powerful tool in understanding chemical carcinogenesis and provide valuable information regarding human risk hazards.
authors.affiliation: Division of Pathology, National Institute of Health Sciences, 1-18-1 Kamiyoga, Setagaya-ku, Tokyo 158-8501, Japan.
authors.forename: Kohei
authors.initials: K
authors.lastname: Matsushita
authors.forename: Aki
authors.initials: A
authors.lastname: Kijima
authors.forename: Yuji
authors.initials: Y
authors.lastname: Ishii
authors.forename: Shinji
authors.initials: S
authors.lastname: Takasu
authors.forename: Meilan
authors.initials: M
authors.lastname: Jin
authors.forename: Ken
authors.initials: K
authors.lastname: Kuroda
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Kawaguchi
authors.forename: Noriaki
authors.initials: N
authors.lastname: Miyoshi
authors.forename: Takehiko
authors.initials: T
authors.lastname: Nohmi
authors.forename: Kumiko
authors.initials: K
authors.lastname: Ogawa
authors.forename: Takashi
authors.initials: T
authors.lastname: Umemura
keywords: carcinogenicity; glutathione S-transferase placental form; gpt delta rats; in vivo genotoxicity; medium-term animal model