Diphenyleneiodonium sulfate, an NADPH oxidase inhibitor, prevents early alcohol-induced liver injury in the rat

The oxidant source in alcohol-induced liver disease remains unclear. NADPH oxidase (mainly in liver Kupffer cells and infiltrating neutrophils) could be a potential free radical source. We aimed to determine if NADPH oxidase inhibitor diphenyleneiodonium sulfate (DPI) affects nuclear factor-kappaB ( NF-kappaB) activation, liver tumor necrosis factor-alpha (TNF-alpha) mRNA e xpression, and early alcohol-induced liver injury in rats. Male Wistar rats were fed high-fat liquid diets with or without ethanol (10-16 g.kg(-1).day (-1)) continuously for up to 4 wk, using the Tsukamoto-French intragastric enteral feeding protocol. DPI or saline vehicle was administered by subcuta neous injection for 4 wk. Mean urine ethanol concentrations were similar be tween the ethanol-and ethanol plus DPI-treated groups. Enteral ethanol feed ing caused severe fat accumulation, mild inflammation, and necrosis in the liver (pathology score, 4.3 +/- 0.3). In contrast, DPI significantly blunte d these changes (pathology score, 0.8 +/- 0.4). Enteral ethanol administrat ion for 4 wk also significantly increased free radical adduct formation, NF -kappaB activity, and TNF-alpha expression in the liver. DPI almost complet ely blunted these parameters. These results indicate that DPI prevents earl y alcohol-induced liver injury, most likely by inhibiting free radical form ation via NADPH oxidase, thereby preventing NF-kappaB activation and TNF-al pha mRNA expression in the liver.