Novel strategies for the treatment of acetaminophen hepatotoxicity

Abstract

Introduction: Acetaminophen (APAP) hepatotoxicity is the leading cause of acute liver failure in the western world. Despite extensive investigations into the mechanisms of cell death, only a single antidote, N-acetylcysteine, is in clinical use. However, there have recently been more efforts made to translate mechanistic insight into identification of therapeutic targets and potential new drugs for this indication.

Areas covered: After a short review of the key events in the pathophysiology of APAP-induced liver injury and recovery, the pros and cons of targeting individual steps in the pathophysiology as therapeutic targets are discussed. While the re-purposed drug fomepizole (4-methylpyrazole) and the new entity calmangafodipir are most advanced based on the understanding of their mechanism of action, several herbal medicine extracts and their individual components are also considered.

Expert opinion: Fomepizole (4-methylpyrazole) is safe and has shown efficacy in preclinical models, human hepatocytes and in volunteers against APAP overdose. The safety of calmangafodipir in APAP overdose patients was shown but it lacks solid preclinical efficacy studies. Both drugs require a controlled phase III trial to achieve regulatory approval. All studies of herbal medicine extracts and components suffer from poor experimental design, which questions their clinical utility at this point.

Keywords: 4-methylpyrazole; Acetaminophen-induced liver injury; calmangafodipir; fomepizole; herbal medicine; traditional Chinese Medicine.

Figure 1:

Therapeutics can target various steps in the APAP pathophysiology: APAP hepatotoxicity is initiated by formation of the reactive metabolite NAPQI by cytochrome P450 mediated activation in microsomes. Elevated NAPQI depletes hepatic glutathione stores and forms mitochondrial protein adducts resulting in enhanced superoxide release into the cytosol. This activates the MAP kinase JNK, which translocates to mitochondria and amplifies the mitochondrial oxidative and nitrosative stress. This ultimately activates the mitochondrial permeability transition (MPT) resulting in release of endonuclease G (EndoG) and apoptosis inducing factor (AIF) into the cytosol and their translocation to the nucleus. The resulting nuclear DNA fragmentation induces hepatocyte necrosis and release of damage associated molecular patterns (DAMPS). This initiates a reparative innate immune response by activating resident Kupffer cells, which release cytokines and chemokines to attract circulating neutrophils into the necrotic foci to remove dead cells and activate regeneration. Additional mechanisms of recovery include activation of the Nrf2 pathway resulting in its disengagement from its cytosolic partner Keap 1 followed by nuclear translocation and induction of genes such as those involved in replenishing hepatic GSH content. Stressed cells could also activate mitochondrial biogenesis to compensate for lost mitochondrial function and attempt to recover from the liver injury. Interventions can target various steps of this pathway, with 4-methylpyrazole inhibiting both cytochrome P450 mediated NAPQI formation as well as downstream JNK activation. Calmangafodipir is thought to function as a SOD mimetic to prevent mitochondrial oxidant stress, while activators of the A2B receptors enhance the innate immune response to accelerate recovery. Enhancement of mitochondrial biogenesis by treatments such as SRT1720 also facilitate this process of recovery after APAP-induced acute liver injury. This figure includes templates from Servier Medical Art, which is licensed under a Creative Commons Attribution 3.0 generic license; https://smart.servier.com.