Abstract
Acetaminophen is one of the most common over-the-counter pain medications used worldwide and is considered safe at therapeutic dose. However, intentional and unintentional overdose accounts for up to 70% of acute liver failure cases in the western world. Extensive research has demonstrated that the induction of oxidative stress and mitochondrial dysfunction are central to the development of acetaminophen-induced liver injury. Despite the insight gained on the mechanism of acetaminophen toxicity, there still is only one clinically approved pharmacological treatment option, N-acetylcysteine. N-acetylcysteine increases the cell's antioxidant defense and protects liver cells from further acetaminophen-induced oxidative damage. Because it primarily protects healthy liver cells rather than rescuing the already injured cells alternative treatment strategies that target the latter cell population are warranted. In this study, we investigated mitochondria as therapeutic target for the development of novel treatment strategies for acetaminophen-induced liver injury. Characterization of the mitochondrial toxicity due to acute acetaminophen overdose in vitro in human cells using detailed respirometric analysis revealed that complex I-linked (NADH-dependent) but not complex II-linked (succinate-dependent) mitochondrial respiration is inhibited by acetaminophen. Treatment with a novel cell-permeable succinate prodrug rescues acetaminophen-induced impaired mitochondrial respiration. This suggests cell-permeable succinate prodrugs as a potential alternative treatment strategy to counteract acetaminophen-induced liver injury.
Highlights
Acetaminophen is one of the most common over-the-counter medications used worldwide [1, 2]
We demonstrated that APAP induces an immediate inhibition of mitochondrial respiration in human-derived cells through interference with complex I (CI) or upstream metabolism while respiration associated with complex II (CII) and downstream complexes remains unaffected
The toxicity profile of APAP on mitochondrial respiration was not exclusive to hepatic cells and was confirmed in fresh human platelets, presenting them as suitable surrogate tissue to study the role of mitochondrial dysfunction in acute APAP-induced toxicity
Summary
Acetaminophen (paracetamol, N-acetyl-p-aminophenol; APAP) is one of the most common over-the-counter medications used worldwide [1, 2]. NAC replenishes glutathione levels, increases the cell’s antioxidant defense and protects from further oxidative damage induced by APAP. It is more of preventive rather than rescuing nature, with lesser benefit for the already damaged cells [5, 7, 11]. Alternative treatment strategies that target the already damage liver cells are warranted In this this study, we investigated mitochondria as potential therapeutic target for treatment of APAP-induced liver injury in vitro. We evaluated the efficacy of a cell-permeable succinate prodrug (NV241), a mitochondrially targeted alternative energy substrate, to rescue the impaired mitochondrial respiration following acute overdose of APAP
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