Abstract
The current study aims at repurposing the anti-arthritic drug diacerein (DCN) for the treatment of acetaminophen hepatotoxicity and investigating the potential underlying mechanisms. Mice were randomly divided into six groups receiving either no treatment (control group), 20 mg/kg DCN i.p, 400 mg/kg acetaminophen i.p, DCN 4 h before acetaminophen, DCN 2 h after acetaminophen, or 400 mg/kg N-acetylcysteine (NAC) i.p, 2 h after acetaminophen. Biomarkers of liver dysfunction, oxidative stress, and apoptosis were assessed. Hepatic necroinflammatory changes were evaluated along with hepatic expression of NF-κB and caspase-1. The levels of NLRP3, IL-1β, IL-4, MCP-1, and TNF-α in the liver, as well as CYP2E1 mRNA expression, were measured. Diacerein significantly reduced biomarkers of liver dysfunction, oxidative stress, hepatocyte necrosis, and infiltration of neutrophils and macrophages whether administered 4 h before or 2 h after acetaminophen. Further, the effects were comparable to those of NAC. Diacerein also counteracted acetaminophen-induced hepatocellular apoptosis by increasing Bcl-2 and decreasing Bax and caspase-3 expression levels. Moreover, DCN normalized hepatic TNF-α and significantly decreased NF-κB p65 expression. Accordingly, DCN can prevent or reverse acetaminophen hepatotoxicity in mice, suggesting potential utility as a repurposed drug for clinical treatment.
Highlights
Drug-induced hepatotoxicity is a potentially life-threatening adverse drug reaction responsible for the majority of acute liver failure cases and a leading reason for liver transplantation (Khoury et al 2015).Acetaminophen (Paracetamol, N-acetyl-p-aminophenol) is among the most frequently used analgesic and antipyretic drugs
The current study demonstrates that DCN can prevent or mitigate hepatotoxicity in mice by reducing oxidative stress, inflammation, necrosis, and apoptosis induced by acetaminophen overdose
Administration of acetaminophen significantly (p < 0.01) elevated serum ALT activity by 10.36-fold, AST activity by 7.89-fold, and lactate dehydrogenase (LDH) activity by 3.10-fold compared to compared to the control group (Fig. 1A–C, respectively)
Summary
Acetaminophen (Paracetamol, N-acetyl-p-aminophenol) is among the most frequently used analgesic and antipyretic drugs. It is safe at recommended doses, overdose may result in hepatotoxicity and acute liver failure (Yan et al 2018; Simões et al 2019). Acetaminophen hepatotoxicity involves multiple stages and pathogenic mechanisms, including the generation of toxic metabolite, oxidative stress, mitochondrial dysfunction, and sterile inflammation, leading to hepatocyte death (Yan et al 2018; Mary and Ezhilarasan 2020). The remaining NAPQI can covalently bind to liver proteins, generating cytotoxic arylated proteins. In combination, these processes initiate oxidative stress that leads to hepatocyte death, mainly via necrosis (Lee et al 1996; Athersuch et al 2018)
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