Elshazly Shimaa M, El-Moselhy Mohamed A, Barakat Waleed
Eur J Pharmacol. 2014 Mar 5;726:116-23. doi: 10.1016/j.ejphar.2014.01.042.
Acetaminophen (APAP) is one of the most widely used analgesic antipyretic drugs and is a major cause of acute liver failure at overdose. The aim of this study is to investigate the possible protective effect of α-lipoic acid (α-LA, 20 or 100 mg/kg administered simultaneously or after 1.5 h) against APAP-induced hepatotoxicity in rats. Administration of APAP (1.5 g/kg i.p.) resulted in elevation of serum ALT and hepatic malondialdehyde (MDA) content, as well as decrease in hepatic glutathione (GSH) content. In addition, elevation in hepatic hemeoxygenase-1 (HO-1) and NADPH oxidase expression was observed accompanied with a significant reduction in glutathione synthase and cystathionine-beta-synthase (CβS) expression. Furthermore, nuclear factor kappa-B (NF-κB) activity was enhanced in APAP-treated rats. Administration of the standard APAP antidote; N-acetylcysteine (NAC, 1200 mg/kg) or α-LA (20 mg/kg), simultaneously or 1.5 h after APAP, ameliorated APAP-induced alterations in liver function, oxidant and inflammatory markers. Importantly, simultaneous administration of NAC or α-LA (20 mg/kg) was more protective than their later administration. However, the beneficial effect of α-LA was lost at higher dose level (100 mg/kg). Taken together, the beneficial effects of α-lipoic acid (20 mg/kg) were comparable to those of NAC which provides a new possible treatment for APAP-induced hepatotoxicity in patients who cannot tolerate NAC. However, careful dose selection is warranted since the beneficial effects of α-LA were lost at higher doses.
对乙酰氨基酚（APAP）是使用最广泛的解热镇痛药之一，也是过量服用导致急性肝衰竭的主要原因。本研究旨在探讨α-硫辛酸（α-LA，20或100mg/kg，同时或在1.5小时后给药）对大鼠APAP诱导的肝毒性可能的保护作用。给予APAP（1.5g/kg腹腔注射）导致血清谷丙转氨酶（ALT）和肝脏丙二醛（MDA）含量升高，以及肝脏谷胱甘肽（GSH）含量降低。此外，观察到肝脏血红素加氧酶-1（HO-1）和NADPH氧化酶表达升高，同时谷胱甘肽合成酶和胱硫醚-β-合酶（CβS）表达显著降低。此外，APAP处理的大鼠中核因子κB（NF-κB）活性增强。给予标准的APAP解毒剂；N-乙酰半胱氨酸（NAC，1200mg/kg）或α-LA（20mg/kg），在APAP给药的同时或1.5小时后给药，可改善APAP诱导的肝功能、氧化剂和炎症标志物的改变。重要的是，同时给予NAC或α-LA（20mg/kg）比稍后给药更具保护作用。然而，α-LA在较高剂量水平（100mg/kg）时失去了有益作用。综上所述，α-硫辛酸（20mg/kg）的有益作用与NAC相当，这为不能耐受NAC的APAP诱导肝毒性患者提供了一种新的可能治疗方法。然而，由于α-LA在较高剂量时失去了有益作用，因此需要谨慎选择剂量。
