Chronic and excessive alcohol consumption has been related to an increased risk of several
cancers, including that of the liver; however, studies in animal models have yet to conclusively determine whether
ethanol acts as a
tumor promoter in hepatic
tumorigenesis. We examined whether prolonged alcohol consumption could act as a hepatic
tumor promoter after initiation by
diethylnitrosamine (DEN) in a rat model. Male Sprague-Dawley rats were injected with 20 mg DEN/kg
body weight 1 wk before introduction of either an
ethanol liquid diet or an isoenergic control liquid diet. Hepatic pathological lesions, hepatocyte proliferation, apoptosis, PPARα and PPARγ, and plasma
insulin-like growth factor 1 (IGF-1) levels were assessed after 6 and 10 mo. Mean body and liver weights, plasma
IGF-1 concentration, hepatic expressions of proliferating cellular
nuclear antigen and Ki-67, and
cyclin D1 in
ethanol-fed rats were all significantly lower after 10 mo of treatment compared with control rats. In addition, levels of hepatic PPARγ
protein, not PPARα, were significantly higher in the
ethanol-fed rats after prolonged treatment. Although
ethanol feeding also resulted in significantly fewer altered hepatic foci,
hepatocellular adenoma was detected in
ethanol-fed rats
at 10 mo, but not in control rats given the same dose of DEN. Together, these results indicate that chronic, excessive
ethanol consumption impairs normal hepatocyte proliferation, which is associated with reduced
IGF-1 levels, but promotes hepatic
carcinogenesis.