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ID 52431
フルテキストURL
著者
Fang, Xing Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University
Nunoshiba, Tatsuo International Christian University
Yoshida, Midori National Institute of Health Sciences
Nishikawa, Akiyoshi National Institute of Health Sciences
Nemoto, Kiyomitsu School of Pharmaceutical Sciences, University of Shizuoka
Degawa, Masakuni School of Pharmaceutical Sciences, University of Shizuoka
Arimoto, Sakae Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University
Okamoto, Keinosuke Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University
Takahashi, Eizo Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University
Negishi, Tomoe Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University
抄録
It remains uncertain why non-genotoxic compounds that result in liver hypertrophy cause liver tumors. In an effort to resolve this issue, we examined whether liver post-mitochondrial fraction (S9) prepared from rats treated with non-genotoxic compounds affected the genotoxicity of pro-mutagens. Known hepatotoxic compounds, such as piperonyl butoxide (PBO), decabromodiphenyl ether (DBDE), beta-naphthoflavone (BNF), indole-3-carbinol (I3C) and acetaminophen (AA), were orally administered to male and female F344 rats at doses sufficient to cause liver hypertrophy. Rats received diets containing each test compound for 3 days, 4 weeks or 13 weeks, and were then kept for 4 weeks without the test chemical. S9 prepared from the livers of each group was used for the Ames test with 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx), benzo[a]pyrene (BaP) and N-nitrosodimethylamine (NDMA). In both sexes, liver hypertrophy was observed following administration of all test compounds, and was then reversed to the control state when administration ceased. The mutagenicity of MeIQx, BaP and NDMA increased with the use of S9 derived from rats treated with non-genotoxic compounds other than AA. DBDE administration had a marked effect on the mutagenicity of BaP (over a 30-fold increase in females) and NDMA (about a 20-fold increase in males). To estimate the involvement of metabolic enzymes in the alteration of mutagenicity, we measured the activity of ethoxyresorufin-O-deethylase (EROD) and methoxyresorufin-O-demethylase (MROD) (phase I enzymes), and UDP-glucuronosyltransferase (UGT) and glutathione S-transferase (GST) (phase II enzymes) in each S9 sample. The activity of phase I enzymes increased, even at the 3rd day following administration, and then decreased gradually, except in the case of AA, while the activity of phase II enzymes increased slightly. These results suggest that non-genotoxic hepato-hypertrophic compounds may be partly involved in carcinogenesis by modulating the metabolism of pre-carcinogens incorporated from the environment, in a manner that is dependent on sex and pre-incorporated chemicals.
キーワード
liver hypertrophic compound
metabolism
mutation
Ames test
発行日
2014-02-28
出版物タイトル
Genes and Environment
36巻
1号
開始ページ
1
終了ページ
9
ISSN
1880-7046
資料タイプ
学術雑誌論文
言語
English
著作権者
© 2014 by The Japanese Environmental Mutagen Society
論文のバージョン
publisher
査読
有り
DOI