Protective effects of allopurinol against acute liver damage and cirrhosis induced by carbon tetrachloride: Modulation of NF-κB, cytokine production and oxidative stress
Protective effects of allopurinol against acute liver damage and cirrhosis induced by carbon tetrachloride: Modulation of NF-κB, cytokine production and oxidative stress
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DOI：
10.1016/j.bbagen.2011.09.018
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发表时间：
2012-02-01
影响因子：
3
通讯作者：
Muriel, Pablo
中科院分区：
文献类型：
--
作者：
Aldaba-Muruato, Liseth R.;Moreno, Mario G.;Muriel, Pablo
背景资料：方法：采用四氯化碳（CCl 4）诱导大鼠急性肝损伤模型，在染毒前1h和染毒后1h分别灌胃别嘌呤醇（50 mg/kg），连续3 d，每天2次。通过CCl 4给药（0.4 g/kg，腹腔注射，每周三次，共8周）建立肝硬化;在CCl 4长期治疗期间，给予别嘌呤醇（100 mg/kg，灌胃，每日一次）。丙氨酸转氨酶（ALT）、γ-谷氨酰转肽酶（γ-GTP）、黄嘌呤氧化酶（XO）、脂质过氧化、还原型和氧化型谷胱甘肽（GSH）。GSSG）、羟脯氨酸和组织病理学分析。核因子-κ B（NF-κ B），促炎和抗炎细胞因子，转化生长因子-β（TGF-β）和金属蛋白酶-13（MMP-13）进行了分析，通过Western blotts.Results：急性损伤增加ALT和γ-GTP的活动，另外增强NF-κ B核转位和细胞因子的生产，如肿瘤坏死因子-α，白细胞介素-1 β，白细胞介素-6。别嘌呤醇部分防止这些影响，而增加白细胞介素-10。急性和慢性CCl 4治疗改变了XO活性，脂质过氧化和GSH/GSSG比值的水平，而这些与别嘌呤醇管理保持在正常范围内。结论：别嘌呤醇具有抗氧化、抗炎和抗纤维化的特性，可能是通过其减少NF-κ B B核转位和TGF-β表达，以及诱导MMP-13的表达。别嘌呤醇可能是治疗肝脏疾病的有效药物。(C)2011 Elsevier B. V.保留所有权利。
Background: The aim of this work was to evaluate the hepatoprotective ability of allopurinol to prevent the liver injury induced by carbon tetrachloride (CCl4).Methods: Acute liver damage was induced with CCl4 (4 g/kg, by gavage); allopurinol (50 mg/kg, by gavage) was given 1 h before and 1 h after CCl4 intoxication and two daily doses for the previous three days. Cirrhosis was established by CCl4 administration (0.4 g/kg, i.p. three times a week, eight weeks); allopurinol was administered (100 mg/kg, by gavage, daily) during the long-term of CCl4 treatment. Alanine aminotransferase (ALT), gamma-glutamyl transpeptidase (gamma-GTP), xanthine oxidase (XO), lipid peroxidation, reduced and oxidized glutathione (GSH. GSSG, respectively), hydroxyproline and histopathologycal analysis were performed. Nuclear factor-kappa B (NF-kappa B), pro-inflammatory and anti-inflammatory cytokines, transforming growth factor-beta (TGF-beta) and metalloproteinase-13 (MMP-13) were analyzed by Western blots.Results: Acute injury increased ALT and gamma-GTP activities, additionally enhanced NF-kappa B nuclear translocation and cytokines production such as tumor necrosis factor-alpha, interleukine-1 beta, and interleukine-6. Allopurinol partially prevented these effects, while increased interleukine-10. Acute and chronic CCl4 treatments altered the levels of XO activity, lipid peroxidation, and GSH/GSSG ratio, while these remained within normal range with allopurinol administration. Necrosis, fibrosis and TGF-beta production induced in chronic injury were partially prevented by allopurinol, interestingly, this drug induced MMP-13 activity.Conclusions: Allopurinol possesses antioxidant, anti-inflammatory and antifibrotic properties, probably by its capacity to reduce NF-kappa B nuclear translocation and TGF-beta expression, as well as to induce MMP-13.General significance: Allopurinol might be effective treatment of liver diseases. (C) 2011 Elsevier B.V. All rights reserved.