Elsevier

Redox Biology

Volume 10, December 2016, Pages 148-156
Redox Biology

Oxidative stress during acetaminophen hepatotoxicity: Sources, pathophysiological role and therapeutic potential

https://doi.org/10.1016/j.redox.2016.10.001Get rights and content
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Highlights

  • Oxidative stress plays a critical role in acetaminophen hepatotoxicity.

  • Mitochondria are the main source of ROS and RNS that are responsible for the toxicity.

  • Cytochrome P450 and inflammatory cells are probably not relevant sources of ROS for the toxicity.

  • Mitochondrial oxidative stress is a promising therapeutic target against APAP overdose.

Abstract

Acetaminophen (APAP) hepatotoxicity is characterized by an extensive oxidative stress. However, its source, pathophysiological role and possible therapeutic potential if targeted, have been controversially described. Earlier studies argued for cytochrome P450-generated reactive oxygen species (ROS) during APAP metabolism, which resulted in massive lipid peroxidation and subsequent liver injury. However, subsequent studies convincingly challenged this assumption and the current paradigm suggests that mitochondria are the main source of ROS, which impair mitochondrial function and are responsible for cell signaling resulting in cell death. Although immune cells can be a source of ROS in other models, no reliable evidence exists to support a role for immune cell-derived ROS in APAP hepatotoxicity. Recent studies suggest that mitochondrial targeted antioxidants can be viable therapeutic agents against hepatotoxicity induced by APAP overdose, and re-purposing existing drugs to target oxidative stress and other concurrent signaling events can be a promising strategy to increase its potential application in patients with APAP overdose.

Keywords

Acetaminophen hepatotoxicity, mitochondria, oxidant stress
Antioxidants
Lipid peroxidation
Innate immunity
Peroxynitrite

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