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Am J Physiol Gastrointest Liver Physiol 280: G1005-G1012, 2001;
0193-1857/01 $5.00
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Vol. 280, Issue 5, G1005-G1012, May 2001

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

Hiroshi Kono1, Ivan Rusyn1,2, Takehiko Uesugi1, Shunhei Yamashina1, Henry D. Connor3, Anna Dikalova3, Ronald P. Mason2,3, and Ronald G. Thurman1,2

1 Laboratory of Hepatobiology and Toxicology, Department of Pharmacology and 2 Curriculum in Toxicology, University of North Carolina, Chapel Hill 27599-7365; and 3 Laboratory of Pharmacology and Chemistry, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709

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-kappa B (NF-kappa B) activation, liver tumor necrosis factor-alpha (TNF-alpha ) mRNA expression, 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 subcutaneous injection for 4 wk. Mean urine ethanol concentrations were similar between the ethanol- and ethanol plus DPI-treated groups. Enteral ethanol feeding caused severe fat accumulation, mild inflammation, and necrosis in the liver (pathology score, 4.3 ± 0.3). In contrast, DPI significantly blunted these changes (pathology score, 0.8 ± 0.4). Enteral ethanol administration for 4 wk also significantly increased free radical adduct formation, NF-kappa B activity, and TNF-alpha expression in the liver. DPI almost completely blunted these parameters. These results indicate that DPI prevents early alcohol-induced liver injury, most likely by inhibiting free radical formation via NADPH oxidase, thereby preventing NF-kappa B activation and TNF-alpha mRNA expression in the liver.

nuclear factor-kappa B; tumor necrosis factor-alpha ; enteral feeding


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