Allopurinol prevents early alcohol-induced liver injury in rats.
Free radical formation caused by chronic ethanol administration could activate transcription factors such as nuclear factor-kappaB (NF-kappaB), which regulates production of inflammatory cytokines. Xanthine oxidase is one potential source of reactive oxygen species. Therefore, the purpose of this study is to determine whether allopurinol, a xanthine oxidase inhibitor and scavenger of free radicals, would affect free radical formation, NF-kappaB activation, and early alcohol-induced liver injury in rats. Male Wistar rats were fed a high-fat diet with or without ethanol (10-16 g/kg/day) continuously for up to 4 weeks with the Tsukamoto-French enteral protocol. Either allopurinol or saline vehicle was administered daily. Allopurinol had no effect on body weight or the cyclic pattern of ethanol in urine. Mean urine ethanol concentrations were 271 +/- 38 and 252 +/- 33 mg/dl in ethanol- and ethanol + allopurinol-treated rats, respectively. In the control group, serum aspartate aminotransferase and alanine aminotransferase levels were approximately 40 I.U./l and 25 U/l, respectively. Administration of enteral ethanol for 4 weeks increased serum transaminases approximately 5-fold. Allopurinol blunted these increases significantly by approximately 50%. Ethanol treatment also caused severe fatty infiltration, mild inflammation, and necrosis. These pathological changes also were blunted significantly by allopurinol. Furthermore, enteral ethanol caused free radical adduct formation, values that were reduced by approximately 40% by allopurinol. NF-kappaB binding was minimal in the control group but was increased significantly nearly 2.5-fold by ethanol. This increase was blunted to similar values as control by allopurinol. These results indicate that allopurinol prevents early alcohol-induced liver injury, most likely by preventing oxidant-dependent activation of NF-kappaB.
Kono
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Laboratory of Hepatobiology and Toxicology, Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
Rusyn
I
I
Bradford
B U
BU
Connor
H D
HD
Mason
R P
RP
Thurman
R G
RG
D000410:Alanine Transaminase / Q000097:blood; D000493:Allopurinol / Q000494:pharmacology*; D000818:Animals; D001219:Aspartate Aminotransferases / Q000097:blood; D001646:Bile / Q000737:chemistry / Q000378:metabolism; D001835:Body Weight / Q000187:drug effects; D002492:Central Nervous System Depressants / Q000097:blood / Q000652:urine; D004032:Diet; D004586:Electrophoresis; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D000431:Ethanol / Q000097:blood / Q000652:urine; D016166:Free Radical Scavengers / Q000494:pharmacology; D008099:Liver / Q000473:pathology; D008108:Liver Diseases, Alcoholic / Q000473:pathology / Q000517:prevention & control*; D008297:Male; D016328:NF-kappa B / Q000096:biosynthesis; D009687:Nuclear Proteins / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D014969:Xanthine Oxidase / Q000037:antagonists & inhibitors
D002492:Central Nervous System Depressants; D004791:Enzyme Inhibitors; D016166:Free Radical Scavengers; D016328:NF-kappa B; D009687:Nuclear Proteins; D000431:Ethanol; D000493:Allopurinol; D014969:Xanthine Oxidase; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase