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 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-kappaB 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-kappaB activation and TNF-alpha mRNA expression in the liver.
Kono
H
H
Laboratory of Hepatobiology and Toxicology, Department of Pharmacology, University of North Carolina, Mary Ellen Jones Bldg., Chapel Hill, NC 27599-7365, USA.
Rusyn
I
I
Uesugi
T
T
Yamashina
S
S
Connor
H D
HD
Dikalova
A
A
Mason
R P
RP
Thurman
R G
RG
D000818:Animals; D004041:Dietary Fats; D004750:Enteral Nutrition; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D000431:Ethanol / Q000633:toxicity / Q000652:urine; D005786:Gene Expression Regulation / Q000187:drug effects; D006519:Hepatitis, Alcoholic / Q000473:pathology / Q000503:physiopathology* / Q000517:prevention & control*; D007249:Inflammation / Q000473:pathology; D008099:Liver / Q000187:drug effects* / Q000473:pathology / Q000503:physiopathology; D008297:Male; D008954:Models, Biological; D019255:NADPH Oxidases / Q000037:antagonists & inhibitors*; D016328:NF-kappa B / Q000378:metabolism; D009336:Necrosis; D009861:Onium Compounds / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D014158:Transcription, Genetic / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics
D004041:Dietary Fats; D004791:Enzyme Inhibitors; D016328:NF-kappa B; D009861:Onium Compounds; D014409:Tumor Necrosis Factor-alpha; D000431:Ethanol; C007517:diphenyleneiodonium; D019255:NADPH Oxidases