Aldaba-Muruato Liseth R, Moreno Mario G, Shibayama Mineko, Tsutsumi Víctor, Muriel Pablo
Departamento de Farmacología, Cinvestav-IPN, Apdo. Postal 14-740, México 07000, DF México.
Biochim Biophys Acta. 2012 Feb;1820(2):65-75. doi: 10.1016/j.bbagen.2011.09.018. Epub 2011 Oct 7.
The aim of this work was to evaluate the hepatoprotective ability of allopurinol to prevent the liver injury induced by carbon tetrachloride (CCl(4)).
Acute liver damage was induced with CCl(4) (4g/kg, by gavage); allopurinol (50mg/kg, by gavage) was given 1h before and 1h after CCl(4) intoxication and two daily doses for the previous three days. Cirrhosis was established by CCl(4) administration (0.4g/kg, i. p. three times a week, eight weeks); allopurinol was administered (100mg/kg, by gavage, daily) during the long-term of CCl(4) treatment. Alanine aminotransferase (ALT), γ-glutamyl transpeptidase (γ-GTP), xanthine oxidase (XO), lipid peroxidation, reduced and oxidized glutathione (GSH, GSSG, respectively), hydroxyproline and histopathologycal analysis were performed. Nuclear factor-κB (NF-κB), pro-inflammatory and anti-inflammatory cytokines, transforming growth factor-β (TGF-β) and metalloproteinase-13 (MMP-13) were analyzed by Western blots.
Acute injury increased ALT and γ-GTP activities, additionally enhanced NF-κB nuclear translocation and cytokines production such as tumor necrosis factor-α, interleukine-1β, and interleukine-6. Allopurinol partially prevented these effects, while increased interleukine-10. Acute and chronic CCl(4) 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-β production induced in chronic injury were partially prevented by allopurinol, interestingly, this drug induced MMP-13 activity.
Allopurinol possesses antioxidant, anti-inflammatory and antifibrotic properties, probably by its capacity to reduce NF-κB nuclear translocation and TGF-β expression, as well as to induce MMP-13. General significance Allopurinol might be effective treatment of liver diseases.
本研究旨在评估别嘌醇预防四氯化碳（CCl₄）所致肝损伤的肝保护能力。
通过灌胃给予CCl₄（4g/kg）诱导急性肝损伤；在CCl₄中毒前1小时和中毒后1小时给予别嘌醇（50mg/kg，灌胃），并在之前三天每天给药两次。通过每周三次腹腔注射CCl₄（0.4g/kg），持续八周建立肝硬化模型；在长期CCl₄治疗期间给予别嘌醇（100mg/kg，每日灌胃）。检测丙氨酸氨基转移酶（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（分别为GSH、GSSG）、羟脯氨酸，并进行组织病理学分析。通过蛋白质免疫印迹法分析核因子-κB（NF-κB）、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）。
急性损伤增加了ALT和γ-GTP活性，此外还增强了NF-κB核转位以及肿瘤坏死因子-α、白细胞介素-1β和白细胞介素-6等细胞因子的产生。别嘌醇部分预防了这些作用，同时增加了白细胞介素-10。急性和慢性CCl₄处理改变了XO活性、脂质过氧化和GSH/GSSG比值水平，而在给予别嘌醇时这些指标保持在正常范围内。别嘌醇部分预防了慢性损伤中诱导的坏死、纤维化和TGF-β产生，有趣的是，该药物诱导了MMP-13活性。
别嘌醇具有抗氧化、抗炎和抗纤维化特性，可能是通过其降低NF-κB核转位和TGF-β表达以及诱导MMP-13的能力实现的。一般意义：别嘌醇可能是治疗肝病的有效药物。
