title: Detection of initiation activity of 1,2-dimethylhydrazine in in vivo medium-term liver initiation assay system using 4-week-old rats without hepatocellular proliferative stimuli during the test chemical treatment period.
abstract: We have developed an in vivo medium-term liver initiation assay system to detect initiation activities of chemicals on multi-organ carcinogenesis. However, cell proliferation stimuli during the test chemical treatment period, required in the previously used assay models using adult rats, are laborious; moreover, those cause decrease of hepatic metabolic enzymes and psychological and physical discomfort to animals resulting in inaccurate interpretation. Therefore, we investigated the utility of another in vivo medium-term liver initiation assay model using 4-week-old rats without the cell proliferation stimuli. In this study, we confirmed that 4-week-old and 4.5-week-old male rats have high hepatocyte proliferation activity and similar enzyme activities of hepatic Cytochrome P450 subtypes as compared with 8-week-old male rats. Next, the in vivo medium-term liver initiation assay model using 4-week-old rats without cell proliferation stimuli was evaluated for the detection of the initiation activity of 1,2-dimethylhydrazine (DMH), which is a well-known genotoxic carcinogen. Four-week-old rats were orally administered DMH (single dose, 4 or 16 mg/kg; or 4-day repeat, 1 or 4 mg/kg); subsequently, these rats were treated promotion treatment consisted of administration of 2-acetylaminofluorene and carbon tetrachloride. Four weeks after the first DMH administration, the glutathione S-transferase placental form (GST-P)-positive foci induced by DMH in the liver was measured immunohistochemically. The inductions of GST-P-positive foci in all DMH-treated groups were dose-dependent, duration-dependent and significantly higher than that in non-DMH-treated group. From these results, our assay model was detected the initiation activity of DMH simply, and would be useful to evaluate the carcinogenicity of chemicals.
authors.affiliation: Pathogenetic Veterinary Science, United Graduate School of Veterinary Sciences, Gifu University, Gifu, Japan.
authors.forename: Yoshiji
authors.initials: Y
authors.lastname: Asaoka
authors.forename: Hiroki
authors.initials: H
authors.lastname: Sakai
authors.forename: Akihiro
authors.initials: A
authors.lastname: Hirata
authors.forename: Jun
authors.initials: J
authors.lastname: Sasaki
authors.forename: Masanobu
authors.initials: M
authors.lastname: Goryo
authors.forename: Yohei
authors.initials: Y
authors.lastname: Miyamoto
authors.forename: Tokuma
authors.initials: T
authors.lastname: Yanai
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Masegi
authors.forename: Kosuke
authors.initials: K
authors.lastname: Okada
mesh_terms: D019813:1,2-Dimethylhydrazine / Q000633:toxicity*; D000818:Animals; D015197:Carcinogenicity Tests / Q000379:methods*; D049109:Cell Proliferation / Q000187:drug effects; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D022781:Hepatocytes / Q000187:drug effects / Q000502:physiology; D008114:Liver Neoplasms, Experimental / Q000139:chemically induced*; D008297:Male; D011230:Precancerous Conditions / Q000139:chemically induced*; D051381:Rats; D011916:Rats, Inbred F344
chemical_list: D003577:Cytochrome P-450 Enzyme System; D019813:1,2-Dimethylhydrazine