Altered expression of GADD45 genes during the development of chemical-mediated liver hypertrophy and liver tumor promotion in rats
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概要
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The purpose of our study was to examine the altered gene expression associated with nongenotoxic chemical-mediated liver hypertrophy and successive liver tumor promotion. Five-week-old male rats were fed a basal diet or a diet containing phenobarbital (PB) or clofibrate (CF) for 3 days, 4 weeks, and 13 weeks. Hepatic expression profiling of cell growth- and stress-related genes, as well as those involved in xenobiotic metabolism, was performed by DNA microarray and/or real time quantitative reverse transcription-polymerase chain reaction. The induction of liver hypertrophy and hepatic cytochrome P450 (CYP) isoforms (CYP2B1/2B2 for PB and CYP4A1 for CF) by PB and CF were clearly observed at all the treatment periods examined. Genes encoding DNA damage-inducible 45 (GADD45) family proteins, in particular GADD45g (GADD45 gamma) were down-regulated by treatment with either PB or CF for 4 and 13 weeks. The chemical-mediated development of liver hypertrophy, induction of hepatic CYPs, and suppression of hepatic GADD45g gene at week 13 disappeared at 4 weeks following cessation of the chemical treatment. Additionally, DNA microarray data indicated that cell cycle-related genes such as cyclins CCNB1 and CCNA2 and cyclin-dependent kinase inhibitor CDKN3 were also down-regulated by treatment with either PB or CF at 13 weeks. Since GADD45 functions as a chemical and radiation stress sensor by interacting with cyclins and cyclin-dependent kinase inhibitors, the decrease in the gene expression of GADD45g mRNA observed in this study, may be associated with nongenotoxic chemical-induced tumor promotion of hepatocarcinogenesis rather than liver hypertrophy.
- 日本トキシコロジー学会の論文
著者
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OZAWA Shogo
Department of Pharmacology, School of Medicine, Keio University
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Inoue Kaoru
Division Of Pathology National Institute Of Health Sciences
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Yoshida Midori
Division Of Pathology National Institute Of Health Sciences
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Nishikawa Akiyoshi
Division Of Pathology Biology Safety Research Center National Institute Of Health Sciences
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NEMOTO Kiyomitsu
Department of Molecular Toxicology and COE Program in the 21st Century, School of Pharmaceutical Sci
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Habano Wataru
Department Of Diagnostic Pathology Iwate Medical University
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Degawa Masakuni
Department Of Hygienic Chemistry Faculty Of Pharmaceutical Sciences Tohoku University
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Gamou Toshie
Department of Pharmacodynamics and Molecular Genetics, School of Pharmacy, Iwate Medical University
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