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1998 Fiscal Year Final Research Report Summary

Paradoxical effects of phenobarbital on hepatocarcinogenesis and hepatocytic apoptosis.

Research Project

Project/Area Number 09670213
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field Experimental pathology
Research InstitutionAsahikawa Medical College

Principal Investigator

LEE Gang-Hong  Associate Professor, Department of Pathology, Asahikawa Medical College, 医学部, 助教授 (10261405)

Project Period (FY) 1997 – 1998
KeywordsPhenobarbital / Chemical hepatocarcinogenesis / Inhibition / Hepatocyte / Apoptosis / Mouse / Bcl-2 / Paradox
Research Abstract

Phenobarbital (PB) is the first discovered tumor promoter for rodent livers in terms of the two-stage or initiation-promotion concept of carcinogenesis. In rats and mice initiated with genotoxic carcinogens, phenobarbital has been shown to increase the number of hepatocellular tumors by approximately 5-fold despite its non-genotoxicity.
Importantly, however, it has been also known that, in mice, PB occasionally exhibits strong inhibitory effects on hepatocarcinogenesis initiated with a potent carcinogen, diethylnitrosamine (DEN). For example, while PB enhances development of liver tumors in B6C3F1 mice initiated with DEN as adults, it strongly inhibits hepatocarcinogenesis in the same mice initiated with DEN in their infancy. Such paradoxical outcomes of PB treatment in mice would raise a serious issue when extrapolating the experimental risk data of laboratory animals to human cases.
In this study, I provided evidence that the paradoxical actions of PB on hepatocarcinogenesis can be resolved considering qualitative diversity of initiated lesions and their differential responses to phenobarbital promotion. Thus, I propose that the classical two-stage concept should be reconsidered in terms of qualitative heterogeneity of initiation.
I also found that PB induces apoptosis in mouse hepatocytes in culture cooperating with c-myc overexpression. This is an unexpected phenomenon, because PB has been regarded as an inhibitor on hepatocytic apoptosis. The PB-induced apoptosis was accompanied by a 10-fold increase in Bax, an apoptotic protein.
Consequently, biological effects of PB are quite complicated and clearly need further analysis on their molecular mechanisms.

  • Research Products

    (6 results)

All Other

All Publications (6 results)

  • [Publications] Osanai, M.: "Phenobarbital causes apoptosis in conditionally immortalized mouse hepatocytes depending on deregulated c-myc expression : characeterization of an unexpected effect." Cancer Research. 57. 2896-2903 (1997)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Lee, G.-H.: "Correlation between Bcl-2 expression and histopathology in diethylnitrosamine-induced mouse hepatocellular tumors." American Journal of Pathology. 151. 957-962 (1997)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Lee, G.-H.: "Mechanism of the paradoxical, inhibitory effect of phenobarbital on hepatocarcinogenesis initiated in infant B6C3F_1 mice with diethylnitrosamine." Cancer Research. 58. 1665-1669 (1998)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Osanai, M., Ogawa, K., and Lee, G.-H.: "Phenobarbital causes apoptosis in conditionally immortalized mouse hepatocytes depending on deregulated c-myc expression : characterization of an unexpected effect." Cancer Res.57. 2896-2903 (1997)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Lee, G.-H.: "Correlation between Bcl-2 expression and histopathology in diethylnitrosamine-induced mouse hepatocellular tumors." Am.J.Pathol.151. 957-962 (1997)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Lee, G.-H., Ooasa, T., and Osanai, M.: "Mechanism of the paradoxical, inhibitory effect of phenobarbital on hepatocarcinogenesis initiated infant B6C3F_1 mice with diethylnitrosamine." Cancer Res.58. 1665-1669 (1998)

    • Description
      「研究成果報告書概要(欧文)」より

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Published: 1999-12-08  

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