To assess the relative contributions of undernutrition and ethanol (EtOH) exposure to alcohol-induced hepatotoxicity, female Sprague-Dawley rats were intragastrically infused liquid diets containing 187 or 154 kcal.kg(-3/4).day(-1) with or without 11 g.kg(-1).day(-1) EtOH. EtOH clearance was impaired in the 154 kcal.kg(-3/4).day(-1) EtOH group (P < or = 0.05). A combination of undernutrition and EtOH also increased the induction of hepatic cytochrome P-450 (CYP)2E1 and CYP4A1 mRNA, apoprotein, and activities (P < or = 0.05). This was accompanied by increased oxidative stress (P < or = 0.05). The severity of liver steatosis, macrophage infiltration, and focal necrosis was comparable in both EtOH groups. Alanine aminotransferase levels were elevated (P < or = 0.05) but did not significantly differ between the two EtOH groups. TUNEL analysis also demonstrated a comparable increase in apoptosis in the two EtOH groups (P < or = 0.05). The development of alcohol-induced liver pathology was accompanied by little change in fatty acid (FA) synthesis or degradation at 187 kcal.kg(-3/4).day(-1) but at 154 kcal.kg(-3/4).day(-1) was accompanied by decreased expression of FA synthesis genes and increased expression of peroxisome proliferator-activated receptor-alpha (PPAR-alpha)-regulated FA degradation pathways (P < or = 0.05). In addition, 154 kcal.kg(-3/4).day(-1) EtOH group livers exhibited greater hepatocyte proliferation (P < or = 0.05). We conclude that undernutrition does not exacerbate alcoholic steatohepatitis despite additional oxidative stress produced by an increased induction of CYP2E1 and CYP4A1. However, enhanced ethanol-induced cellular proliferation, perhaps as a result of enhanced PPAR-alpha signaling, may contribute to an increased risk of hepatocellular carcinoma in undernourished alcoholics.