Chronic ethanol intake promotes double gluthatione S‐transferase/transforming growth factor‐α‐positive hepatocellular lesions in male Wistar rats

The chronic ethanol intake influence on the gluthatione S‐transferase (GST‐P) and transforming growth factor α (TGF‐α) expression in remodeling/persistent preneoplastic lesions (PNLs) was evaluated in the resistant hepatocyte model. Male Wistar rats were allocated into five groups: G1, non‐treated, fed water and chow ad libitum ; G2, non‐treated and pair‐fed chow (restricted to match that of G3 group) and a maltodextrin (MD) solution in tap water (matched ethanol‐derived calories); G3, fed 5% ethanol in drinking water and chow ad libitum ; G4, diethylnitrosamine (DEN, 200 mg/kg, body weight) plus 200 parts per million of 2‐acetylaminofluorene (2‐AAF) for 3 weeks and pair‐fed chow (restricted to match that of G5 group) and an MD solution in tap water (matched ethanol‐derived calories); G5, DEN/2‐AAF treatment, fed ethanol 5% and chow ad libitum . All animals were subjected to 70% partial hepatectomy at week 3 and sacrificed at weeks 12 or 22, respectively. Liver samples were collected for histological analysis or immunohistochemical expression of GST‐P, TGF‐α and proliferating cell nuclear antigen or zymography for matrix metalloproteinases‐2 and ‐9. At the end of ethanol treatment, there was a significant increase in the percentage of liver area occupied by persistent GST‐P‐positive PNLs, the number of TGF‐α‐positive PNLs and the development of liver tumors in ethanol‐fed and DEN/2‐AAF‐treated groups (G5 versus G4, P  < 0.001). In addition, ethanol feeding led to a significant increase in cell proliferation mainly in remodeling and persistent PNLs with immunoreactivity for TGF‐α at week 22 ( P  < 0.001). Gelatinase activities were not altered by ethanol treatment. The results demonstrated that ethanol enhances the selective growth of PNL with double expression of TGF‐α and GST‐P markers. ( Cancer Sci 2008; 99: 221–228)