BACKGROUND: Alcohol is a significant risk factor for the development of hepatocellular carcinoma (HCC). To date, no rodent model has demonstrated the formation of hepatic neoplasia in the setting of chronic alcohol consumption alone. METHODS: We investigated whether rats selectively bred for high alcohol preference (P rats), allowed free access to water, or water and 10% (v/v) alcohol, for 6, 12, or 18 months, develop hepatic neoplasia. RESULTS: At necropsy, liver tumor incidence and multiplicity were significantly increased in 18-month alcohol-consuming versus water-consuming P rats. These data were confirmed histologically by glutathione-S-transferase pi-class (GSTp) staining. Phosphorylated mitogen-activated protein kinase/extracellular signal-regulated kinase 1/2 (MAPK/ERK) staining was also increased in the sinusoidal lining cells within livers of alcohol-consuming versus water only P rats. In addition, cytochrome p450IIE1 (CYP2E1) mRNA, protein expression/activity, and intrahepatic oxidative stress were significantly increased in alcohol-consuming P rat livers versus water only. In contrast, acetaldehyde dehydrogenase expression decreased in alcohol-consuming versus water only P rats. No significant difference in alcohol dehydrogenase expression was detected. CONCLUSIONS: These data demonstrate that chronic alcohol consumption is associated with hepatic neoplasia, MAPK/ERK activation, increased CYP2E1 activity, and intrahepatic oxidative stress in P rats. As these rats are well characterized as a model of alcoholism, these findings identify a novel rodent model of alcohol or "alcoholism"-induced liver neoplasia.
BACKGROUND:Alcohol is a significant risk factor for the development of hepatocellular carcinoma (HCC). To date, no rodent model has demonstrated the formation of hepatic neoplasia in the setting of chronic alcohol consumption alone. METHODS: We investigated whether rats selectively bred for high alcohol preference (P rats), allowed free access to water, or water and 10% (v/v) alcohol, for 6, 12, or 18 months, develop hepatic neoplasia. RESULTS: At necropsy, liver tumor incidence and multiplicity were significantly increased in 18-month alcohol-consuming versus water-consuming P rats. These data were confirmed histologically by glutathione-S-transferase pi-class (GSTp) staining. Phosphorylated mitogen-activated protein kinase/extracellular signal-regulated kinase 1/2 (MAPK/ERK) staining was also increased in the sinusoidal lining cells within livers of alcohol-consuming versus water only P rats. In addition, cytochrome p450IIE1 (CYP2E1) mRNA, protein expression/activity, and intrahepatic oxidative stress were significantly increased in alcohol-consuming P rat livers versus water only. In contrast, acetaldehyde dehydrogenase expression decreased in alcohol-consuming versus water only P rats. No significant difference in alcohol dehydrogenase expression was detected. CONCLUSIONS: These data demonstrate that chronic alcohol consumption is associated with hepatic neoplasia, MAPK/ERK activation, increased CYP2E1 activity, and intrahepatic oxidative stress in P rats. As these rats are well characterized as a model of alcoholism, these findings identify a novel rodent model of alcohol or "alcoholism"-induced liver neoplasia.
Authors: L G Carr; T Foroud; P Bice; T Gobbett; J Ivashina; H Edenberg; L Lumeng; T K Li Journal: Alcohol Clin Exp Res Date: 1998-06 Impact factor: 3.455
Authors: Kelly E Mercer; Leah Hennings; Neha Sharma; Keith Lai; Mario A Cleves; Rebecca A Wynne; Thomas M Badger; Martin J J Ronis Journal: Cancer Prev Res (Phila) Date: 2014-04-28
Authors: Isaac S Chan; Cynthia D Guy; Mariana V Machado; Abigail Wank; Vishnu Kadiyala; Gregory Michelotti; Steve Choi; Marzena Swiderska-Syn; Gamze Karaca; Thiago A Pereira; Michele T Yip-Schneider; C Max Schmidt; Anna Mae Diehl Journal: Alcohol Clin Exp Res Date: 2013-10-24 Impact factor: 3.455
Authors: Kelly E Mercer; Casey Pulliam; Leah Hennings; Keith Lai; Mario Cleves; Ellen Jones; Richard R Drake; Martin Ronis Journal: Cancer Prev Res (Phila) Date: 2016-03-22
Authors: Kyle J Thompson; Shayan S Nazari; W Carl Jacobs; Nicholas J Grahame; Iain H McKillop Journal: Alcohol Alcohol Date: 2017-11-01 Impact factor: 2.826
Authors: Jonathon D Klein; Jeremy B Sherrill; Gabriella M Morello; Phillip J San Miguel; Zhenming Ding; Suthat Liangpunsakul; Tiebing Liang; William M Muir; Lawrence Lumeng; Amy C Lossie Journal: PLoS One Date: 2014-12-26 Impact factor: 3.240