Recent Advances in Acetaminophen Hepatotoxicity

A special issue of Livers (ISSN 2673-4389).

Deadline for manuscript submissions: 31 October 2024 | Viewed by 19332

Special Issue Editor


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Guest Editor
Department of Pharmacology, Toxicology & Therapeutics, University of Kansas Medical Center, Kansas City, KS 66160, USA
Interests: drug-induced liver injury; acetaminophen; acute liver failure; hepatic ischemia-reperfusion injury; obstructive cholestasis
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Special Issue Information

Dear Colleagues,

Acetaminophen (paracetamol, APAP) is one the most consumed analgesic and anti-pyretic drugs in the world. Generally considered safe at therapeutic doses, intentional or unintentional overdosing can cause severe liver injury and even acute liver failure. In western countries, APAP is responsible for thousands of hospitalizations annually and is the major cause of acute liver failure. Since the establishment of the clinically relevant mouse model in 1973, numerous studies investigating the mechanism of APAP-induced liver injury were published. Based on early mechanistic insight, the current standard of care, N-acetylcysteine (NAC), was developed. Although NAC is still the only clinically approved antidote available, additional mechanistic insight led to the discovery of promising new drugs, such as fomepizole which, based on the solid understanding of its mechanism of action and proven safety profile, is under clinical development. Further drugs or compounds with various modes of action are also under consideration as future antidotes. In addition to the mechanisms of injury, the inflammatory response leading to regeneration and recovery is another focus of research. However, no viable drug candidates promoting regeneration have been identified. This Special Issue is aimed at providing selected contributions on advances in the mechanistic understanding of APAP-induced liver injury and the regeneration and identification of new therapeutic targets and interventions.

Potential topics include but are not limited to:

  • Mitochondria and APAP hepatotoxicity;
  • Oxidant stress and peroxynitrite in APAP hepatotoxicity; 
  • Adaptive Responses (Autophagy, Mitophagy) in APAP hepatotoxicity;
  • ER stress in APAP hepatotoxicity;
  • Sterile inflammation in APAP hepatotoxicity;
  • Macrophages and neutrophils in APAP hepatotoxicity and regeneration;
  • Translational studies in APAP hepatotoxicity and regeneration;
  • N-acetylcysteine and APAP hepatotoxicity;
  • Fomepizole and APAP hepatotoxicity;
  • Novel therapeutic approaches to APAP hepatotoxicity and regeneration.

Prof. Dr. Hartmut W. Jaeschke
Guest Editor

Manuscript Submission Information

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Keywords

  • mitochondria
  • oxidant stress and peroxynitrite
  • adaptive responses (autophagy, mitophagy)
  • ER stress
  • sterile inflammation
  • macrophages and neutrophils
  • regeneration
  • N-acetylcysteine
  • fomepizole

Published Papers (7 papers)

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Editorial

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3 pages, 198 KiB  
Editorial
Acetaminophen Hepatotoxicity: Not as Simple as One Might Think! Introductory Comments on the Special Issue—Recent Advances in Acetaminophen Hepatotoxicity
by Hartmut Jaeschke
Livers 2022, 2(3), 105-107; https://doi.org/10.3390/livers2030008 - 1 Jul 2022
Cited by 2 | Viewed by 2548
Abstract
Acetaminophen (N-acetyl-para-aminophenol (APAP)) is one of the most-studied drugs worldwide [...] Full article
(This article belongs to the Special Issue Recent Advances in Acetaminophen Hepatotoxicity)

Review

Jump to: Editorial

10 pages, 1018 KiB  
Review
High-Dose Acetaminophen as a Treatment for Cancer
by Jeffrey Wu, Bradley Maller, Rujul Kaul, Andrea Galabow, Allyn Bryan and Alexander Neuwelt
Livers 2024, 4(1), 84-93; https://doi.org/10.3390/livers4010007 - 31 Jan 2024
Viewed by 1158
Abstract
The use of high-dose acetaminophen (AAP) with n-acetylcysteine (NAC) rescue was studied as an anti-cancer treatment in phase I trials with promising signals of anti-tumor efficacy. Correlative analysis suggested that AAP has a free-radical-independent mechanism of anti-tumor activity—in contrast to the well-established mechanism [...] Read more.
The use of high-dose acetaminophen (AAP) with n-acetylcysteine (NAC) rescue was studied as an anti-cancer treatment in phase I trials with promising signals of anti-tumor efficacy. Correlative analysis suggested that AAP has a free-radical-independent mechanism of anti-tumor activity—in contrast to the well-established mechanism of AAP hepatotoxicity. Subsequent “reverse translational” studies in the pre-clinical setting have identified novel mechanisms of action of high-dose AAP, including modulation of JAK-STAT signaling in both the tumor cell and the tumor immune microenvironment. Importantly, these effects are free-radical-independent and not reversed by concurrent administration of the established AAP rescue agents fomepizole and NAC. By administering high-dose AAP concurrently with fomepizole and NAC, 100-fold higher AAP levels than those of standard dosing can be achieved in mice without detected toxicity and with substantial anti-tumor efficacy against commonly used mouse models of lung and breast cancer that are resistant to standard first-line anti-cancer therapies. With these recent advances, additional clinical trials of high-dose AAP with concurrent NAC and fomepizole-based rescue are warranted. Full article
(This article belongs to the Special Issue Recent Advances in Acetaminophen Hepatotoxicity)
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28 pages, 2000 KiB  
Review
The Evolution of Circulating Biomarkers for Use in Acetaminophen/Paracetamol-Induced Liver Injury in Humans: A Scoping Review
by Mitchell R. McGill and Steven C. Curry
Livers 2023, 3(4), 569-596; https://doi.org/10.3390/livers3040039 - 27 Oct 2023
Viewed by 1661
Abstract
Acetaminophen (APAP) is a widely used drug, but overdose can cause severe acute liver injury. The first reports of APAP hepatotoxicity in humans were published in 1966, shortly after the development of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) as the first biomarkers [...] Read more.
Acetaminophen (APAP) is a widely used drug, but overdose can cause severe acute liver injury. The first reports of APAP hepatotoxicity in humans were published in 1966, shortly after the development of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) as the first biomarkers of liver injury as opposed to liver function. Thus, the field of liver injury biomarkers has evolved alongside the growth in APAP hepatotoxicity incidence. Numerous biomarkers have been proposed for use in the management of APAP overdose patients in the intervening years. Here, we comprehensively review the development of these markers from the 1960s to the present day and briefly discuss possible future directions. Full article
(This article belongs to the Special Issue Recent Advances in Acetaminophen Hepatotoxicity)
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10 pages, 1023 KiB  
Review
Regeneration and Recovery after Acetaminophen Hepatotoxicity
by Bharat Bhushan and Udayan Apte
Livers 2023, 3(2), 300-309; https://doi.org/10.3390/livers3020021 - 9 Jun 2023
Cited by 1 | Viewed by 2327
Abstract
Liver regeneration is a compensatory response to tissue injury and loss. It is known that liver regeneration plays a crucial role in recovery following acetaminophen (APAP)-induced hepatotoxicity, which is the major cause of acute liver failure (ALF) in the US. Regeneration increases proportional [...] Read more.
Liver regeneration is a compensatory response to tissue injury and loss. It is known that liver regeneration plays a crucial role in recovery following acetaminophen (APAP)-induced hepatotoxicity, which is the major cause of acute liver failure (ALF) in the US. Regeneration increases proportional to the extent of liver injury upon APAP overdose, ultimately leading to regression of injury and spontaneous recovery in most cases. However, severe APAP overdose results in impaired liver regeneration and unchecked progression of liver injury, leading to failed recovery and mortality. Inter-communication between various cell types in the liver is important for effective regenerative response following APAP hepatotoxicity. Various non-parenchymal cells such macrophages, stellate cells, and endothelial cells produce mediators crucial for proliferation of hepatocytes. Liver regeneration is orchestrated by synchronized actions of several proliferative signaling pathways involving numerous kinases, nuclear receptors, transcription factors, transcriptional co-activators, which are activated by cytokines, growth factors, and endobiotics. Overt activation of anti-proliferative signaling pathways causes cell-cycle arrest and impaired liver regeneration after severe APAP overdose. Stimulating liver regeneration by activating proliferating signaling and suppressing anti-proliferative signaling in liver can prove to be important in developing novel therapeutics for APAP-induced ALF. Full article
(This article belongs to the Special Issue Recent Advances in Acetaminophen Hepatotoxicity)
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13 pages, 1535 KiB  
Review
Mitochondria in Acetaminophen-Induced Liver Injury and Recovery: A Concise Review
by Anup Ramachandran and Hartmut Jaeschke
Livers 2023, 3(2), 219-231; https://doi.org/10.3390/livers3020014 - 10 Apr 2023
Cited by 4 | Viewed by 2136
Abstract
Mitochondria are critical organelles responsible for the maintenance of cellular energy homeostasis. Thus, their dysfunction can have severe consequences in cells responsible for energy-intensive metabolic function, such as hepatocytes. Extensive research over the last decades have identified compromised mitochondrial function as a central [...] Read more.
Mitochondria are critical organelles responsible for the maintenance of cellular energy homeostasis. Thus, their dysfunction can have severe consequences in cells responsible for energy-intensive metabolic function, such as hepatocytes. Extensive research over the last decades have identified compromised mitochondrial function as a central feature in the pathophysiology of liver injury induced by an acetaminophen (APAP) overdose, the most common cause of acute liver failure in the United States. While hepatocyte mitochondrial oxidative and nitrosative stress coupled with induction of the mitochondrial permeability transition are well recognized after an APAP overdose, recent studies have revealed additional details about the organelle’s role in APAP pathophysiology. This concise review highlights these new advances, which establish the central role of the mitochondria in APAP pathophysiology, and places them in the context of earlier information in the literature. Adaptive alterations in mitochondrial morphology as well as the role of cellular iron in mitochondrial dysfunction and the organelle’s importance in liver recovery after APAP-induced injury will be discussed. Full article
(This article belongs to the Special Issue Recent Advances in Acetaminophen Hepatotoxicity)
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21 pages, 1388 KiB  
Review
Acetaminophen-Induced Hepatotoxicity in Obesity and Nonalcoholic Fatty Liver Disease: A Critical Review
by Karima Begriche, Clémence Penhoat, Pénélope Bernabeu-Gentey, Julie Massart and Bernard Fromenty
Livers 2023, 3(1), 33-53; https://doi.org/10.3390/livers3010003 - 12 Jan 2023
Cited by 5 | Viewed by 5632
Abstract
The epidemic of obesity, type 2 diabetes and nonalcoholic liver disease (NAFLD) favors drug consumption, which augments the risk of adverse events including liver injury. For more than 30 years, a series of experimental and clinical investigations reported or suggested that the common [...] Read more.
The epidemic of obesity, type 2 diabetes and nonalcoholic liver disease (NAFLD) favors drug consumption, which augments the risk of adverse events including liver injury. For more than 30 years, a series of experimental and clinical investigations reported or suggested that the common pain reliever acetaminophen (APAP) could be more hepatotoxic in obesity and related metabolic diseases, at least after an overdose. Nonetheless, several investigations did not reproduce these data. This discrepancy might come from the extent of obesity and steatosis, accumulation of specific lipid species, mitochondrial dysfunction and diabetes-related parameters such as ketonemia and hyperglycemia. Among these factors, some of them seem pivotal for the induction of cytochrome P450 2E1 (CYP2E1), which favors the conversion of APAP to the toxic metabolite N-acetyl-p-benzoquinone imine (NAPQI). In contrast, other factors might explain why obesity and NAFLD are not always associated with more frequent or more severe APAP-induced acute hepatotoxicity, such as increased volume of distribution in the body, higher hepatic glucuronidation and reduced CYP3A4 activity. Accordingly, the occurrence and outcome of APAP-induced liver injury in an obese individual with NAFLD would depend on a delicate balance between metabolic factors that augment the generation of NAPQI and others that can mitigate hepatotoxicity. Full article
(This article belongs to the Special Issue Recent Advances in Acetaminophen Hepatotoxicity)
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11 pages, 1674 KiB  
Review
Role of Pyroptosis in Acetaminophen-Induced Hepatotoxicity
by Hartmut Jaeschke, David S. Umbaugh and Anup Ramachandran
Livers 2022, 2(4), 425-435; https://doi.org/10.3390/livers2040032 - 13 Dec 2022
Cited by 3 | Viewed by 2094
Abstract
Acetaminophen (APAP) is a widely used pain reliever that can cause liver injury or liver failure in response to an overdose. Understanding the mechanisms of APAP-induced cell death is critical for identifying new therapeutic targets. In this respect it was hypothesized that hepatocytes [...] Read more.
Acetaminophen (APAP) is a widely used pain reliever that can cause liver injury or liver failure in response to an overdose. Understanding the mechanisms of APAP-induced cell death is critical for identifying new therapeutic targets. In this respect it was hypothesized that hepatocytes die by oncotic necrosis, apoptosis, necroptosis, ferroptosis and more recently pyroptosis. The latter cell death is characterized by caspase-dependent gasdermin cleavage into a C-terminal and an N-terminal fragment, which forms pores in the plasma membrane. The gasdermin pores can release potassium, interleukin-1β (IL-1β), IL-18, and other small molecules in a sublytic phase, which can be the main function of the pores in certain cell types such as inflammatory cells. Alternatively, the process can progress to full lysis of the cell (pyroptosis) with extensive cell contents release. This review discusses the experimental evidence for the involvement of pyroptosis in APAP hepatotoxicity as well as the arguments against pyroptosis as a relevant mechanism of APAP-induced cell death in hepatocytes. Based on the critical evaluation of the currently available literature and understanding of the pathophysiology, it can be concluded that pyroptotic cell death is unlikely to be a relevant contributor to APAP-induced liver injury. Full article
(This article belongs to the Special Issue Recent Advances in Acetaminophen Hepatotoxicity)
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