Digestive Diseases and Sciences

, Volume 58, Issue 7, pp 1923–1933

Chronic Ingestion of Ethanol Induces Hepatocellular Carcinoma in Mice Without Additional Hepatic Insult

  • Mutsumi Tsuchishima
  • Joseph George
  • Hisakazu Shiroeda
  • Tomiyasu Arisawa
  • Tsutomu Takegami
  • Mikihiro Tsutsumi
Original Article

DOI: 10.1007/s10620-013-2574-4

Cite this article as:
Tsuchishima, M., George, J., Shiroeda, H. et al. Dig Dis Sci (2013) 58: 1923. doi:10.1007/s10620-013-2574-4

Abstract

Background

Chronic intake of alcohol increases the risk of gastrointestinal and hepatic carcinogenesis. The present study was focused to investigate the incidence and mechanism of pathogenesis of hepatocellular carcinoma (HCC) during chronic ingestion of alcohol without any additional hepatic injury.

Methods

Ethanol was administered to Institute for Cancer Research male mice through drinking water for 70 weeks at concentrations of 5 % (first week), 10 % (next 8 weeks), and 15 % thereafter. The animals were killed at 60 and 70 weeks, the livers were examined for hepatic tumors, and evaluated for foci of cellular alteration (FCA). Immunohistochemical staining was performed in the liver sections for cytochrome P4502E1 (CYP2E1), 4-hydroxy-nonenal (4-HNE), and proto-oncogene, c-Myc.

Results

At the 60th week, 40 % of the mice in the ethanol group had visible white nodules (5–10 mm) in the liver, but not in the control mice. At the 70th week, several larger nodules (5–22 mm) were present in the livers of 50 % mice in the ethanol group. In the control group, one mouse developed a single nodule. All nodules were histologically trabecular HCC composed of eosinophilic and vacuolated cells. In the livers of both control and ethanol group, several foci with cellular alteration were present, which were significantly higher in ethanol group. Staining for CYP2E1, 4-HNE and c-Myc depicted marked upregulation of all these molecules in the FCA.

Conclusions

Our data demonstrated that upregulation of CYP2E1 and subsequent production of reactive oxygen species along with the persistent expression of c-Myc play a significant role in the pathogenesis of HCC during chronic ingestion of ethanol.

Keywords

Hepatocellular carcinoma HCC Ethanol Carcinogenesis Cellular alteration 

Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  • Mutsumi Tsuchishima
    • 1
  • Joseph George
    • 1
  • Hisakazu Shiroeda
    • 1
  • Tomiyasu Arisawa
    • 1
  • Tsutomu Takegami
    • 2
  • Mikihiro Tsutsumi
    • 1
  1. 1.Department of GastroenterologyKanazawa Medical UniversityUchinada, IshikawaJapan
  2. 2.Medical Research InstituteKanazawa Medical UniversityUchinada, IshikawaJapan