Altered expression of GADD45 genes during the development of chemical-mediated liver hypertrophy and liver tumor promotion in rats

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Author(s)

Abstract

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 <i>GADD45g </i>(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 <i>GADD45g </i>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 <i>CCNB1</i> and <i>CCNA2</i> and cyclin-dependent kinase inhibitor <i>CDKN3 </i>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 <i>GADD45g</i> mRNA observed in this study, may be associated with nongenotoxic chemical-induced tumor promotion of hepatocarcinogenesis rather than liver hypertrophy. 

Journal

  • The Journal of Toxicological Sciences

    The Journal of Toxicological Sciences 36(5), 613-623, 2011-10-01

    The Japanese Society of Toxicology

References:  37

Codes

  • NII Article ID (NAID)
    10029481415
  • NII NACSIS-CAT ID (NCID)
    AN00002808
  • Text Lang
    ENG
  • Article Type
    ART
  • ISSN
    03881350
  • NDL Article ID
    11270388
  • NDL Source Classification
    ZS51(科学技術--薬学)
  • NDL Call No.
    Z19-1022
  • Data Source
    CJP  NDL  J-STAGE 
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