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Acetaminophen (APAP) overdose is the most common cause of acute liver failure in the United States and decades of intense study of its pathogenesis resulted in development of the antidote Nacetylcysteine, which facilitates scavenging of the reactive metabolite and is the only treatment in clinical use. However, the narrow therapeutic window of this intervention necessitates a better understanding of the intricacies of APAP-induced liver injury for development of additional therapeutic approaches which can benefit late presenting patients. More recent investigations into APAP hepatotoxicity have established the critical role of mitochondrial dysfunction in mediating liver injury as well as clarified mechanisms of APAP-induced hepatocyte cell death. Thus it is now established that mitochondrial oxidative and nitrosative stress is a key mechanistic feature involved in downstream signaling after APAP overdose. The identification of specific mediators of necrotic cell death further establishes the regulated nature of APAP-induced hepatocyte cell death. In addition, the discovery of the role of mitochondrial dynamics and autophagy in APAPinduced liver injury provide additional insight into the elaborate cell signaling mechanisms involved in pathogenesis of this important clinical problem. In spite of these new insights into mechanisms of liver injury, significant controversy still exists on the role of innate immunity in APAP-induced hepatotoxicity.

Citation

Anup Ramachandran, Hartmut Jaeschke. Acetaminophen Toxicity Novel Insights into Mechanisms and Future Perspectives. Gene expression. 2017 Oct 20


PMID: 29054140

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