Prolonged treatment with N-acetylcystine delays liver recovery from acetaminophen hepatotoxicity

• Published in: Critical care (London, England) England), 2009-01, Vol.13 (2), p.R55-R55, Article R55
• Main Authors: Yang, Runkuan, Miki, Keita, He, Xin, Killeen, Meaghan E, Fink, Mitchell P
• Format: Article
• Language: English
• Subjects: Acetaminophen; Acetaminophen - poisoning; Acetylcysteine; Alanine Transaminase - blood; Analgesics, Non-Narcotic - poisoning; Animals; Antidotes - administration & dosage; Antidotes - pharmacology; Antidotes - therapeutic use; Aspartate Aminotransferases - blood; Care and treatment; Chemical and Drug Induced Liver Injury - drug therapy; Chemical and Drug Induced Liver Injury - enzymology; Complications and side effects; Cystine - administration & dosage; Cystine - analogs & derivatives; Cystine - pharmacology; Cystine - therapeutic use; Diagnosis; Disease Models, Animal; Dosage and administration; Drug Overdose - drug therapy; Glutathione - blood; Health aspects; Liver diseases; Male; Mice; Mice, Inbred C57BL; Risk factors; Time Factors; Treatment Outcome
• ISSN: 1364-8535; 1466-609X; 1364-8535
• DOI: 10.1186/cc7782

Acetaminophen (APAP) toxicity is the most common cause of acute liver failure in the US and Europe. Massive hepatocyte necrosis is the predominant feature of APAP-induced acute liver injury (ALI). Liver regeneration is a vital process for survival after a toxic insult, it occurs at a relative late time point after the injurious phase. Currently, N-acetylcysteine (NAC), a glutathione precursor, is the antidote for acetaminophen overdose. However, NAC is effective only for patients who present within hours of an acute overdose, and is less effective for late-presenting patients. It is possible that in delayed patients, previously reduced endogenous glutathione (GSH) level has restored and prolonged treatment with NAC might be toxic and impair liver regeneration. Therefore, we hypothesize that prolonged treatment with NAC impairs liver regeneration in ALI induced by APAP. ALI was induced in C57BL/6 male mice by a single dose of APAP (350 mg/kg) by intraperitoneal injection. After two hours of APAP challenge, the mice were given 100 mg/kg NAC dissolved in 0.6 mL saline, or saline treatment every 12 hours for a total of 72 hours. Seventy-two hours after APAP challenge, compared with saline treatment, NAC treatment significantly increased serum transaminases (alanine transaminase/aspartate aminotransferase), induced evident hepatocyte vacuolation in the periportal area and delayed liver regeneration seen in histopathology. This detrimental effect was associated with reduced hepatic nuclear factor (NF)-kappaB DNA binding and decreased expression of cell cycle protein cyclin D1, two important factors in liver regeneration. Prolonged treatment with NAC impairs liver regeneration in ALI induced by APAP.