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


METHODS
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.


RESULTS
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.


CONCLUSIONS
Prolonged treatment with NAC impairs liver regeneration in ALI induced by APAP.
Department of Critical Care Medicine, University of Pittsburgh Medical School, 3550 Terrace Street, Pittsburgh, PA 15261, USA. Yangr@ccm.upmc.edu
Runkuan
R
Yang
Keita
K
Miki
Xin
X
He
Meaghan E
ME
Killeen
Mitchell P
MP
Fink
D000082:Acetaminophen / Q000506:poisoning*; D000410:Alanine Transaminase / Q000097:blood; D018712:Analgesics, Non-Narcotic / Q000506:poisoning*; D000818:Animals; D000931:Antidotes / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D001219:Aspartate Aminotransferases / Q000097:blood; D056486:Chemical and Drug Induced Liver Injury / Q000188:drug therapy* / Q000201:enzymology; D003553:Cystine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D004195:Disease Models, Animal; D062787:Drug Overdose / Q000188:drug therapy*; D005978:Glutathione / Q000097:blood; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D013997:Time Factors; D016896:Treatment Outcome
D018712:Analgesics, Non-Narcotic; D000931:Antidotes; D000082:Acetaminophen; D003553:Cystine; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase; D005978:Glutathione; C030905:N-monoacetylcystine