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
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概要
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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.
著者
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HIRATA Akihiro
Division of Oncological Pathology, Aichi Cancer Center Research Institute
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SAKAI Hiroki
Laboratory of Oncological Pathology, Aichi Cancer Center Research Institute
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SASAKI Jun
Department of Production Systems Engineering, Toyohashi University of Technology
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坂井 宏明
帯広畜産大学畜産学部獣医学科家畜内科学教室
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YANAI Tokuma
Laboratory of Veterinary Pathology, Faculty of Applied Biological Sciences, Gifu University
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MASEGI Toshiaki
Laboratory of Veterinary Pathology, Department of Veterinary Medicine, Faculty of Applied Biological
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ASAOKA Yoshiji
Pathogenetic Veterinary Science, United Graduate School of Veterinary Sciences, Gifu University
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YANAI Tokuma
Pathogenetic Veterinary Science, United Graduate School of Veterinary Sciences, Gifu University
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MASEGI Toshiaki
Pathogenetic Veterinary Science, United Graduate School of Veterinary Sciences, Gifu University
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GORYO Masanobu
Laboratory of Toxicology and Pharmacokinetics, Pharmaceutical Research Laboratories, Toray Industrie
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MIYAMOTO Yohei
Laboratory of Toxicology and Pharmacokinetics, Pharmaceutical Research Laboratories, Toray Industrie
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OKADA Kosuke
Laboratory of Toxicology and Pharmacokinetics, Pharmaceutical Research Laboratories, Toray Industrie
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SAKAI Hiroki
Pathogenetic Veterinary Science, United Graduate School of Veterinary Sciences, Gifu University
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SASAKI Jun
Pathogenetic Veterinary Science, United Graduate School of Veterinary Sciences, Gifu University
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OKADA Kosuke
Pathogenetic Veterinary Science, United Graduate School of Veterinary Sciences, Gifu University
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GORYO Masanobu
Laboratory of Toxicology and Pharmacokinetics, Pharmaceutical Research Laboratories, Toray Industries, Inc.
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HIRATA Akihiro
Division of Animal Experiment, Life Science Research Center, Gifu University
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MIYAMOTO Yohei
Laboratory of Toxicology and Pharmacokinetics, Pharmaceutical Research Laboratories, Toray Industries, Inc.
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