Clinically relevant therapeutic approaches against acetaminophen hepatotoxicity and acute liver failure

Abstract

Liver injury and acute liver failure caused by an acetaminophen (APAP) overdose is a significant clinical problem in western countries. With the introduction of the mouse model of APAP hepatotoxicity in the 1970 s, fundamental mechanisms of cell death were discovered. This included the recognition that part of the APAP dose is metabolized by cytochrome P450 generating a reactive metabolite that is detoxified by glutathione. After the partial depletion of glutathione, the reactive metabolite will covalently bind to sulfhydryl groups of proteins, which is the initiating event of the toxicity. This insight led to the introduction of N-acetyl-L-cysteine, a glutathione precursor, as antidote against APAP overdose in the clinic. Despite substantial progress in our understanding of the pathomechanisms over the last decades viable new antidotes only emerged recently. This review will discuss the background, mechanisms of action, and the clinical prospects of the existing FDA-approved antidote N-acetylcysteine, of several new drug candidates under clinical development [4-methylpyrazole (fomepizole), calmangafodipir] and examples of additional therapeutic targets (Nrf2 activators) and regeneration promoting agents (thrombopoietin mimetics, adenosine A2B receptor agonists, Wharton's Jelly mesenchymal stem cells). Although there are clear limitations of certain therapeutic approaches, there is reason to be optimistic. The substantial progress in the understanding of the pathophysiology of APAP hepatotoxicity led to the consideration of several drugs for development as clinical antidotes against APAP overdose in recent years. Based on the currently available information, it is likely that this will result in additional drugs that could be used as adjunct treatment for N-acetylcysteine.

Keywords: A2B adenosine receptor; Acetaminophen-induced liver injury; Calmangafodipir; Fomepizole; Nrf2; Thrombopoietin mimetic.

Figure 1:. Clinically relevant therapeutic targets in acetaminophen hepatotoxicity.

Acetaminophen (APAP) toxicity is initiated by cytochrome P450 2E1 (Cyp2E1)-mediated formation of the reactive metabolite, NAPQI, which depletes cellular glutathione and subsequently forms protein adducts in mitochondria. This induces a mild oxidant stress, which activates the MAP kinase JNK in the cytosol, which translocates to mitochondria and amplifies the mitochondrial oxidative/nitrosative stress. These insults ultimately cause induction of the mitochondrial permeability transition and translocation of mitochondrial proteins to the nucleus where they produce subsequent DNA fragmentation. The resulting hepatocyte necrosis occurs in centrilobular cells surrounding the central vein and induces an innate immune response, which facilitates liver recovery and hepatocyte regeneration to repopulate areas of necrosis. Therapeutics such as N-acetylcysteine (NAC) allow the rapid resynthesis of hepatic glutathione stores and, thus, protect against cell death by scavenging NAPQI and peroxynitrite. 4-Methylpyrazole (4MP, fomepizole) has dual mechanisms of action, inhibiting Cyp2E1 activity as well as JNK activation to block the signaling cascade leading to cell necrosis. Nrf2 activators would induce the Nrf2-mediated antioxidant response to facilitate GSH resynthesis. Calmangafodipir would theoretically scavenge mitochondrial free radicals and, thus, prevent downstream signaling towards cell necrosis. Late-acting therapeutics such as the A2BAR agonist or Whartons Jelly Mesenchymal Stem Cells (WJMSC) enhance the reparative innate immune response and also facilitate hepatocyte regeneration for rapid recovery of homeostasis, which is probably also facilitated by interventions such as a thrombopoietin mimetic (TPOm).