title: Alcohol induces liver neoplasia in a novel alcohol-preferring rat model.
abstract: 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.affiliation: Department of Surgery, Indiana University School of Medicine, Indianapolis, 46202, USA.
authors.forename: Michele T
authors.initials: MT
authors.lastname: Yip-Schneider
authors.forename: Courtney J
authors.initials: CJ
authors.lastname: Doyle
authors.forename: Iain H
authors.initials: IH
authors.lastname: McKillop
authors.forename: Sabrina C
authors.initials: SC
authors.lastname: Wentz
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Brandon-Warner
authors.forename: Jesus M
authors.initials: JM
authors.lastname: Matos
authors.forename: Kumaresan
authors.initials: K
authors.lastname: Sandrasegaran
authors.forename: Romil
authors.initials: R
authors.lastname: Saxena
authors.forename: Matthew E
authors.initials: ME
authors.lastname: Hennig
authors.forename: Huangbing
authors.initials: H
authors.lastname: Wu
authors.forename: Joshua A
authors.initials: JA
authors.lastname: Waters
authors.forename: Patrick J
authors.initials: PJ
authors.lastname: Klein
authors.forename: Janice C
authors.initials: JC
authors.lastname: Froehlich
authors.forename: C Max
authors.initials: CM
authors.lastname: Schmidt
mesh_terms: D000428:Alcohol Drinking / Q000473:pathology*; D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000139:chemically induced* / Q000473:pathology; D019392:Cytochrome P-450 CYP2E1 / Q000378:metabolism; D000431:Ethanol / Q000008:administration & dosage / Q000633:toxicity*; D008113:Liver Neoplasms / Q000139:chemically induced* / Q000473:pathology; D008297:Male; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D023421:Models, Animal; D018384:Oxidative Stress / Q000187:drug effects; D051381:Rats
chemical_list: D000431:Ethanol; D019392:Cytochrome P-450 CYP2E1; D020928:Mitogen-Activated Protein Kinases