Chronic ingestion of ethanol induces hepatocellular carcinoma in mice without additional hepatic insult.
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.
Department of Gastroenterology, Kanazawa Medical University, Uchinada, Ishikawa 920-0293, Japan.
Mutsumi
M
Tsuchishima
Joseph
J
George
Hisakazu
H
Shiroeda
Tomiyasu
T
Arisawa
Tsutomu
T
Takegami
Mikihiro
M
Tsutsumi
D000818:Animals; D014408:Biomarkers, Tumor / Q000378:metabolism; D006528:Carcinoma, Hepatocellular / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology; D002492:Central Nervous System Depressants / Q000633:toxicity*; D000431:Ethanol / Q000633:toxicity*; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008113:Liver Neoplasms / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D036401:Toxicity Tests, Chronic
D014408:Biomarkers, Tumor; D002492:Central Nervous System Depressants; D000431:Ethanol