Alcohol Induces Liver Neoplasia in a Novel Alcohol-Preferring Rat Model

Michele Yip-Schneider, Courtney J. Doyle, Iain H. Mckillop, Sabrina C. Wentz, Elizabeth Brandon-Warner, Jesus M. Matos, Kumar Sandrasegaran, Romil Saxena, Matthew E. Hennig, Huangbing Wu, Joshua A. Waters, Patrick J. Klein, Janice Froehlich, C. Schmidt

Research output: Contribution to journalArticle

13 Citations (Scopus)

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 18months, 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.

Original languageEnglish
Pages (from-to)2216-2225
Number of pages10
JournalAlcoholism: Clinical and Experimental Research
Volume35
Issue number12
DOIs
StatePublished - Dec 2011

Fingerprint

Liver
Rats
Alcohols
Water
Neoplasms
Cytochrome P-450 CYP2E1
Mitogen-Activated Protein Kinase 3
Mitogen-Activated Protein Kinase 1
Mitogen-Activated Protein Kinases
Oxidative stress
Alcohol Drinking
Alcoholism
Rodentia
Oxidative Stress
Glutathione S-Transferase pi
Staining and Labeling
Alcohol Dehydrogenase
Cytochromes
Hepatocellular Carcinoma
Linings

Keywords

  • Alcohol
  • Animal Model
  • Hepatocellular Carcinoma
  • MAPK/ERK
  • Oxidative Stress

ASJC Scopus subject areas

  • Medicine (miscellaneous)
  • Psychiatry and Mental health
  • Toxicology

Cite this

Alcohol Induces Liver Neoplasia in a Novel Alcohol-Preferring Rat Model. / Yip-Schneider, Michele; Doyle, Courtney J.; Mckillop, Iain H.; Wentz, Sabrina C.; Brandon-Warner, Elizabeth; Matos, Jesus M.; Sandrasegaran, Kumar; Saxena, Romil; Hennig, Matthew E.; Wu, Huangbing; Waters, Joshua A.; Klein, Patrick J.; Froehlich, Janice; Schmidt, C.

In: Alcoholism: Clinical and Experimental Research, Vol. 35, No. 12, 12.2011, p. 2216-2225.

Research output: Contribution to journalArticle

Yip-Schneider, Michele ; Doyle, Courtney J. ; Mckillop, Iain H. ; Wentz, Sabrina C. ; Brandon-Warner, Elizabeth ; Matos, Jesus M. ; Sandrasegaran, Kumar ; Saxena, Romil ; Hennig, Matthew E. ; Wu, Huangbing ; Waters, Joshua A. ; Klein, Patrick J. ; Froehlich, Janice ; Schmidt, C. / Alcohol Induces Liver Neoplasia in a Novel Alcohol-Preferring Rat Model. In: Alcoholism: Clinical and Experimental Research. 2011 ; Vol. 35, No. 12. pp. 2216-2225.
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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 18months, 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.",
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AU - Doyle, Courtney J.

AU - Mckillop, Iain H.

AU - Wentz, Sabrina C.

AU - Brandon-Warner, Elizabeth

AU - Matos, Jesus M.

AU - Sandrasegaran, Kumar

AU - Saxena, Romil

AU - Hennig, Matthew E.

AU - Wu, Huangbing

AU - Waters, Joshua A.

AU - Klein, Patrick J.

AU - Froehlich, Janice

AU - Schmidt, C.

PY - 2011/12

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N2 - 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 18months, 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.

AB - 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 18months, 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.

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KW - Hepatocellular Carcinoma

KW - MAPK/ERK

KW - Oxidative Stress

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