Insights in the mechanism underlying the protective effect of α-lipoic acid against acetaminophen-hepatotoxicity

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 alpha-lipoic acid (alpha-LA, 20 or 100 mg/kg administered simultaneously or alter 1.5 h) against APAP-induced hepatotoxicity in rats. Administration of APAP (15 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 (C beta S) expression. Furthermore, nuclear factor kappa-B (NF-kappa B) activity was enhanced in APAP-treated rats. Administration of the standard APAP antidote; N-acetylcysteine (NAC, 1200 mg/kg) or alpha-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 alpha-LA (20 mg/kg) was more protective than their later administration. However, the beneficial effect of alpha-LA was lost at higher dose level (100 mg/kg). Taken together, the beneficial effects of alpha-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 alpha-LA were lost at higher doses. (C) 2014 Elsevier B.V. All rights reserved.