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 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.
Shimaa M
SM
Elshazly
Mohamed A
MA
El-Moselhy
Waleed
W
Barakat
D000082:Acetaminophen / Q000009:adverse effects*; D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D001219:Aspartate Aminotransferases / Q000097:blood; D056486:Chemical and Drug Induced Liver Injury / Q000097:blood / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D019610:Cytoprotection / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D005978:Glutathione / Q000378:metabolism; D008099:Liver / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D008297:Male; D008315:Malondialdehyde / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D008063:Thioctic Acid / Q000494:pharmacology*
D016328:NF-kappa B; D000082:Acetaminophen; D008315:Malondialdehyde; D008063:Thioctic Acid; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase; D005978:Glutathione