![]() In addition, there is evidence showing that reduced endogenous GSH concentration gradually gets back to a normal level at the late time point, after which continuous treatment with NAC may no longer replenish endogenous GSH. There are two possibilities: delayed treatment with NAC is not effective when massive hepatonecrosis has occurred at a late hour, liver regeneration becomes evident and plays a crucial role in liver recovery however, delayed NAC treatment does not maintain the proliferation of primary hepatocytes. However, this antidotal therapy is effective only for patients who present within hours of an acute overdose, and is less effective for late-presenting patients. Ĭurrently, N-acetylcysteine (NAC), a GSH precursor, is the antidote for APAP overdose. After the loss of a large number of parenchymal cells, the metabolic work of surviving hepatocytes is increased and more ATP is needed for maintaining homeostasis and regeneration. In addition, nutrients and metabolic status can also influence regeneration, because APAP induces massive hepatocyte necrosis. ![]() Currently, nuclear factor (NF)-κB is thought to play a major role in the initiation of liver regeneration after cell or tissue loss (such as by hepatotectomy). Many factors can influence liver regeneration. Once hepatocytes express cyclin D1, they have passed the G 1 restriction point and are committed to DNA replication. The induction of cyclin D1 is the most reliable marker for cell cycle (G 1 phase) progression in hepatocytes. As hepatocytes are mostly in a quiescent state (G 0), the regeneration process requires entry into the highly regulated cell cycle. Regeneration ensures the replacement of necrotic cells and the full recovery of organ function. ![]() Liver regeneration is a vital process for survival after a toxic insult. Massive necrosis of the hepatocyte is a characteristic feature of APAP-induced acute lung injury (ALI). This increases the membrane permeability transition and causes the collapse of the mitochondrial membrane potential, which results in a diminished mitochondrial capacity to synthesize ATP, and ATP depletion leads to cell death. The toxic response to APAP is triggered by a highly reactive metabolite, N-acetyl-p-benzoquinone imine (NAPQI), which reacts with and depletes glutathione (GSH), after which it forms covalent adducts and initiates mitochondrial oxidative stress. Prolonged treatment with NAC impairs liver regeneration in ALI induced by APAP.Īcetaminophen (APAP) toxicity is the most common cause of acute liver failure in the US and Europe however, the underlying mechanisms of APAP-induced hepatotoxicity are still not completely understood. This detrimental effect was associated with reduced hepatic nuclear factor (NF)-κB DNA binding and decreased expression of cell cycle protein cyclin D1, two important factors in liver regeneration. 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. 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. MethodsĪLI was induced in C57BL/6 male mice by a single dose of APAP (350 mg/kg) by intraperitoneal injection. Therefore, we hypothesize that prolonged treatment with NAC impairs liver regeneration in ALI induced by APAP. 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. However, NAC is effective only for patients who present within hours of an acute overdose, and is less effective for late-presenting patients. Currently, N-acetylcysteine (NAC), a glutathione precursor, is the antidote for acetaminophen overdose. Liver regeneration is a vital process for survival after a toxic insult, it occurs at a relative late time point after the injurious phase. Massive hepatocyte necrosis is the predominant feature of APAP-induced acute liver injury (ALI). Acetaminophen (APAP) toxicity is the most common cause of acute liver failure in the US and Europe. ![]()
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