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

Abstract

Background Alcohol is a significant risk factor for development of hepatocellular carcinoma (HCC). To date, no rodent model has demonstrated 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. Since these rats are well-characterized as a model of alcoholism, these findings identify a novel rodent model of alcohol or “alcoholism”-induced liver neoplasia.

Alcohol Consumption, Wnt/β-Catenin Signaling, and Hepatocarcinogenesis

“…In the EtOH+DEN-treated mice, we also observed a 4-fold increase in hepatocyte proliferation in the non-tumor hepatic tissue as measured by PCNA immunohistochemistry when compared to the PF+DEN, and chow+DEN-treated mice, p<0.05 (Figure 1a). These results are consistent with Yip-Schneider et al who reported an increase in tumor multiplicity in male alcohol preferring rats receiving EtOH in their drinking water compared to pair-matched rats on water alone [9]. Brandon-Warner et al, also observed increased tumor burden in male DEN-treated mice receiving EtOH in the drinking water, and reported an association between tumor burden and hepatic PCNA and cyclinD1 expression in the EtOH-drinking DEN-treated mice, suggesting an EtOH-related promotional effect [5].…”

“…EtOH metabolism by CYP2E1 and by alcohol dehydrogenase produce the reactive metabolite acetaldehyde, and reduces DNA methylation as a result of disruption of one-carbon metabolism, which may also contribute to tumor initiation [3]. In addition to these initiating mechanisms, chronic EtOH feeding also increases hepatocyte proliferation in animal models of alcoholic liver disease and HCC [4–9]. Several signaling pathways have been implicated in this process, one of which is decreased retinoic acid receptor (RAR) signaling resulting from vitamin A depletion in alcoholic livers [6].…”

Alcohol Consumption Promotes Diethylnitrosamine-Induced Hepatocarcinogenesis in Male Mice through Activation of the Wnt/β-Catenin Signaling Pathway

“…Increased tumor multiplicity was associated with increased cytosolic and nuclear β-catenin expression and proliferation in hepatic non-tumorigenic tissues. These results are consistent with the findings of Yip-Schneider et al (15) who reported an increase in tumor multiplicity in male alcohol-preferring rats receiving EtOH in their drinking water compared to pair-matched rats on water alone. Brandon-Warner et al has also reported increased tumor burden corresponding to a hepatic proliferative response in male DEN-treated mice receiving EtOH in the drinking water, suggestive of an EtOH-related promotional effect (10).…”

“…Apart from the initiation mechanisms, alcohol consumption has proliferative and tumor promoting effects (9–15). Several signaling pathways have been implicated in this process.…”

Soy Protein Isolate Protects Against Ethanol-Mediated Tumor Progression in Diethylnitrosamine-Treated Male Mice

“…Tumor initiation results from ethanol (EtOH) metabolism by alcohol dehydrogenase and cytochrome P450 (CYP) 2E1 thus, producing acetaldehyde and reactive oxygen species which interfere with DNA synthesis and repair mechanisms, leading to mutagenicity and tumorigenesis (4, 11). In addition to initiating effects, EtOH also has proliferative and tumor promoting effects in the liver (7, 8, 12). Our laboratory has demonstrated that EtOH stimulates hepatocyte proliferation in rodents in association with liver injury and hepatic vitamin A depletion (13-15).…”