Karcioglu Saliha Sena, Palabiyik Saziye Sezin, Bayir Yasin, Karakus Emre, Mercantepe Tolga, Halici Zekai, Albayrak Abdulmecit
Department of Pharmacology, Faculty of Medicine, Ataturk University, Erzurum, Turkey.
Department of Pharmaceutical Toxicology, Faculty of Pharmacy, Ataturk University, Erzurum, Turkey.
J Cell Biochem. 2016 Mar;117(3):638-46. doi: 10.1002/jcb.25313. Epub 2015 Sep 1.
Paracetamol is one of the most popular and widely used analgesic and antipyretic agents, but an overdose can cause hepatotoxicity and lead to acute liver failure. Aliskiren directly inhibits renin which downregulates the renin-angiotensin-aldosterone system (RAAS). Recent findings suggest that RAAS system takes part in the pathogenesis of liver fibrosis. We aimed to reveal the relationship between hepatotoxicity and the RAAS by examining paracetamol induced hepatotoxicity. Rats were separated into five groups as follows: control, 100 mg/kg aliskiren (p.o.), 2 g/kg paracetamol (per os (p.o.)), 2 g/kg paracetamol + 50mg/kg aliskiren (p.o.), and 2 g/kg paracetamol + 100 mg/kg aliskiren(p.o.). Samples were analyzed at the biochemical, molecular, and histopathological levels. Paracetamol toxicity increased alanine aminotransferases (ALT), aspartate aminotransferases (AST), renin, and angiotensin II levels in the serum samples. In addition, the SOD activity and glutathione (GSH) levels decreased while Lipid Peroxidation (MDA) levels increased in the livers of the rats treated with paracetamol. Paracetamol toxicity caused a significant increase in TNF-α and TGF-β. Both aliskiren doses showed an improvement in ALT, AST, oxidative parameters, angiotensin II, and inflammatory cytokines. Only renin levels increased in aliskiren treatment groups due to its pharmacological effect. A histopathological examination of the liver showed that aliskiren administration ameliorated the paracetamol-induced liver damage. In immunohistochemical staining, the expression of TNF-α in the cytoplasm of the hepatocytes was increased in the paracetamol group but not in other treatment groups when compared to the control group. In light of these observations, we suggest that the therapeutic administration of aliskiren prevented oxidative stress and cytokine changes and also protected liver tissues during paracetamol toxicity by inhibiting the RAAS.
对乙酰氨基酚是最常用且应用广泛的解热镇痛药之一，但过量服用会导致肝毒性并引发急性肝衰竭。阿利吉仑可直接抑制肾素，从而下调肾素-血管紧张素-醛固酮系统（RAAS）。最近的研究结果表明，RAAS系统参与肝纤维化的发病机制。我们旨在通过检测对乙酰氨基酚诱导的肝毒性来揭示肝毒性与RAAS之间的关系。将大鼠分为以下五组：对照组、100mg/kg阿利吉仑（口服）、2g/kg对乙酰氨基酚（口服）、2g/kg对乙酰氨基酚 + 50mg/kg阿利吉仑（口服）以及2g/kg对乙酰氨基酚 + 100mg/kg阿利吉仑（口服）。在生化、分子和组织病理学水平上对样本进行分析。对乙酰氨基酚毒性使血清样本中的丙氨酸转氨酶（ALT）、天冬氨酸转氨酶（AST）、肾素和血管紧张素II水平升高。此外，用对乙酰氨基酚处理的大鼠肝脏中，超氧化物歧化酶（SOD）活性和谷胱甘肽（GSH）水平降低，而脂质过氧化（MDA）水平升高。对乙酰氨基酚毒性导致肿瘤坏死因子-α（TNF-α）和转化生长因子-β（TGF-β）显著增加。两种剂量的阿利吉仑均使ALT、AST、氧化参数、血管紧张素II和炎性细胞因子有所改善。由于其药理作用，阿利吉仑治疗组中只有肾素水平升高。肝脏组织病理学检查表明，给予阿利吉仑可改善对乙酰氨基酚诱导的肝损伤。在免疫组织化学染色中，与对照组相比，对乙酰氨基酚组肝细胞胞质中TNF-α的表达增加，而其他治疗组未增加。根据这些观察结果，我们认为阿利吉仑的治疗性给药可预防氧化应激和细胞因子变化，并且在对乙酰氨基酚毒性期间通过抑制RAAS保护肝脏组织。
