title: Long-term ethanol consumption promotes hepatic tumorigenesis but impairs normal hepatocyte proliferation in rats.
abstract: 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.
authors.affiliation: Nutrition and Cancer Biology Laboratory, Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University, Boston, MA 02111, USA.
authors.forename: Pollyanna R G
authors.initials: PR
authors.lastname: Chavez
authors.forename: Fuzhi
authors.initials: F
authors.lastname: Lian
authors.forename: Jayong
authors.initials: J
authors.lastname: Chung
authors.forename: Chun
authors.initials: C
authors.lastname: Liu
authors.forename: Sergio A R
authors.initials: SA
authors.lastname: Paiva
authors.forename: Helmut K
authors.initials: HK
authors.lastname: Seitz
authors.forename: Xiang-Dong
authors.initials: XD
authors.lastname: Wang
mesh_terms: D000437:Alcoholism / Q000150:complications* / Q000473:pathology*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002273:Carcinogens / Q000633:toxicity; D049109:Cell Proliferation; D004052:Diethylnitrosamine / Q000633:toxicity; D000431:Ethanol / Q000633:toxicity; D022781:Hepatocytes / Q000187:drug effects / Q000473:pathology*; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D019394:Ki-67 Antigen / Q000378:metabolism; D008114:Liver Neoplasms, Experimental / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D008297:Male; D047493:PPAR alpha / Q000378:metabolism; D047495:PPAR gamma / Q000378:metabolism; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D002273:Carcinogens; D019394:Ki-67 Antigen; D047493:PPAR alpha; D047495:PPAR gamma; D018809:Proliferating Cell Nuclear Antigen; D004052:Diethylnitrosamine; D000431:Ethanol; D007334:Insulin-Like Growth Factor I