Allopurinol prevents early alcohol-induced liver injury in rats.
Allopurinol prevents early alcohol-induced liver injury in rats.
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发表时间：
2000-04
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通讯作者：
Hiroshi Kono;Ivan Rusyn;B. Bradford;H. Connor;Ronald P. Mason;R. G. Thurman
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作者：
Hiroshi Kono;Ivan Rusyn;B. Bradford;H. Connor;Ronald P. Mason;R. G. Thurman
长期使用乙醇引起的自由基形成可能会激活转录因子，例如核因子-kappaB (NF-kappaB)，它调节炎症细胞因子的产生。黄嘌呤氧化酶是活性氧的一种潜在来源。因此，本研究的目的是确定别嘌呤醇（一种黄嘌呤氧化酶抑制剂和自由基清除剂）是否会影响自由基形成、NF-κB 激活和大鼠早期酒精性肝损伤。按照 Tsukamoto-French 肠内方案，对雄性 Wistar 大鼠连续喂食含或不含乙醇的高脂肪饮食（10-16 g/kg/天）长达 4 周。每天施用别嘌呤醇或盐水载体。别嘌呤醇对体重或尿液中乙醇的循环模式没有影响。乙醇和乙醇+别嘌呤醇治疗的大鼠的平均尿液乙醇浓度分别为271 +/- 38和252 +/- 33 mg/dl。在对照组中，血清天冬氨酸转氨酶和丙氨酸转氨酶水平分别约为 40 I.U./l 和 25 U/l。肠内乙醇给药 4 周使血清转氨酶增加约 5 倍。别嘌呤醇使这些增加显着减弱约 50%。乙醇治疗还引起严重的脂肪浸润、轻度炎症和坏死。别嘌呤醇也显着减弱了这些病理变化。此外，肠内乙醇引起自由基加合物形成，别嘌呤醇使自由基加合物的值降低约 40%。 NF-kappaB 结合在对照组中最小，但通过乙醇显着增加近 2.5 倍。这种增加被别嘌呤醇减弱至与对照相似的值。这些结果表明别嘌呤醇可预防早期酒精引起的肝损伤，很可能是通过阻止氧化剂依赖性的 NF-κB 激活来实现的。
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.