Altered expression of GADD45 genes during the development of chemical-mediated liver hypertrophy and liver tumor promotion in rats.
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.
Department of Pharmacodynamics and Molecular Genetics, School of Pharmacy, Iwate Medical University, Iwate, Japan. sozawa@iwate-med.ac.jp
Shogo
S
Ozawa
Toshie
T
Gamou
Wataru
W
Habano
Kaoru
K
Inoue
Midori
M
Yoshida
Akiyoshi
A
Nishikawa
Kiyomitsu
K
Nemoto
Masakuni
M
Degawa
D000818:Animals; D018797:Cell Cycle Proteins / Q000235:genetics*; D002994:Clofibrate / Q000633:toxicity; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis; D004249:DNA Damage / Q000235:genetics; D015536:Down-Regulation; D004790:Enzyme Induction; D015870:Gene Expression / Q000187:drug effects*; D020869:Gene Expression Profiling; D006529:Hepatomegaly / Q000139:chemically induced* / Q000235:genetics / Q000473:pathology; D007527:Isoenzymes; D008099:Liver / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D008114:Liver Neoplasms, Experimental / Q000139:chemically induced* / Q000235:genetics / Q000473:pathology; D008297:Male; D009687:Nuclear Proteins / Q000235:genetics*; D020411:Oligonucleotide Array Sequence Analysis; D010634:Phenobarbital / Q000633:toxicity; D051381:Rats; D011916:Rats, Inbred F344; D060888:Real-Time Polymerase Chain Reaction; D013997:Time Factors; D015262:Xenobiotics / Q000633:toxicity; D000097642:GADD45 Proteins
D018797:Cell Cycle Proteins; D002994:Clofibrate; D003577:Cytochrome P-450 Enzyme System; D007527:Isoenzymes; D009687:Nuclear Proteins; D010634:Phenobarbital; D015262:Xenobiotics; C499073:Gadd45a protein, rat; D000097642:GADD45 Proteins