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  1. Article ; Online: Acetaminophen Hepatotoxicity: Paradigm for Understanding Mechanisms of Drug-Induced Liver Injury.

    Jaeschke, Hartmut / Ramachandran, Anup

    Annual review of pathology

    2024  Volume 19, Page(s) 453–478

    Abstract: Acetaminophen (APAP) overdose is the clinically most relevant drug hepatotoxicity in western countries, and, because of translational relevance of animal models, APAP is mechanistically the most studied drug. This review covers intracellular signaling ... ...

    Abstract Acetaminophen (APAP) overdose is the clinically most relevant drug hepatotoxicity in western countries, and, because of translational relevance of animal models, APAP is mechanistically the most studied drug. This review covers intracellular signaling events starting with drug metabolism and the central role of mitochondrial dysfunction involving oxidant stress and peroxynitrite. Mitochondria-derived endonucleases trigger nuclear DNA fragmentation, the point of no return for cell death. In addition, adaptive mechanisms that limit cell death are discussed including autophagy, mitochondrial morphology changes, and biogenesis. Extensive evidence supports oncotic necrosis as the mode of cell death; however, a partial overlap with signaling events of apoptosis, ferroptosis, and pyroptosis is the basis for controversial discussions. Furthermore, an update on sterile inflammation in injury and repair with activation of Kupffer cells, monocyte-derived macrophages, and neutrophils is provided. Understanding these mechanisms of cell death led to discovery of
    MeSH term(s) Humans ; Animals ; Acetaminophen/adverse effects ; Chemical and Drug Induced Liver Injury/etiology ; Apoptosis ; Acetylcysteine/pharmacology ; Acetylcysteine/therapeutic use ; Autophagy
    Chemical Substances Acetaminophen (362O9ITL9D) ; Acetylcysteine (WYQ7N0BPYC)
    Language English
    Publishing date 2024-01-24
    Publishing country United States
    Document type Journal Article ; Review
    ZDB-ID 2227429-7
    ISSN 1553-4014 ; 1553-4006
    ISSN (online) 1553-4014
    ISSN 1553-4006
    DOI 10.1146/annurev-pathmechdis-051122-094016
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: Comments on: Unveiling the therapeutic promise of natural products in alleviating drug-induced liver injury: Present advancements and future prospects.

    Jaeschke, Hartmut / Ramachandran, Anup

    Phytotherapy research : PTR

    2024  Volume 38, Issue 4, Page(s) 1781–1782

    MeSH term(s) Humans ; Biological Products/therapeutic use ; Chemical and Drug Induced Liver Injury/drug therapy
    Chemical Substances Biological Products
    Language English
    Publishing date 2024-02-05
    Publishing country England
    Document type Letter
    ZDB-ID 639136-9
    ISSN 1099-1573 ; 0951-418X
    ISSN (online) 1099-1573
    ISSN 0951-418X
    DOI 10.1002/ptr.8145
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  3. Article ; Online: Central mechanisms of acetaminophen hepatotoxicity: mitochondrial dysfunction by protein adducts and oxidant stress.

    Jaeschke, Hartmut / Ramachandran, Anup

    Drug metabolism and disposition: the biological fate of chemicals

    2023  

    Abstract: Acetaminophen (APAP) is an analgesic and antipyretic drug used worldwide, which is safe at therapeutic doses. However, an overdose can induce liver injury and even liver failure. Mechanistic studies in mice beginning with the seminal papers published by ... ...

    Abstract Acetaminophen (APAP) is an analgesic and antipyretic drug used worldwide, which is safe at therapeutic doses. However, an overdose can induce liver injury and even liver failure. Mechanistic studies in mice beginning with the seminal papers published by B.B. Brodie's group in the 1970s have resulted in important insight into the pathophysiology. Although the metabolic activation of APAP with generation of a reactive metabolite, glutathione depletion and protein adduct formation are critical initiating events, more recently the mitochondria came into focus as important target and decision point of cell death. This review provides a comprehensive overview of the induction of mitochondrial superoxide and peroxynitrite formation and its propagation through a mitogen activated protein kinase cascade, the mitochondrial permeability transition pore opening caused by iron-catalyzed protein nitration and the mitochondria-dependent nuclear DNA fragmentation. In addition, the role of adaptive mechanisms that can modulate the pathophysiology including autophagy, mitophagy, Nrf2 activation and mitochondrial biogenesis, are discussed. Importantly, it is outlined how the mechanisms elucidated in mice translate to human hepatocytes and APAP overdose patients, and how this mechanistic insight explains the mechanism of action of the clinically approved antidote
    Language English
    Publishing date 2023-08-11
    Publishing country United States
    Document type Journal Article
    ZDB-ID 186795-7
    ISSN 1521-009X ; 0090-9556
    ISSN (online) 1521-009X
    ISSN 0090-9556
    DOI 10.1124/dmd.123.001279
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  4. Article ; Online: Mitochondria in Acetaminophen-Induced Liver Injury and Recovery: A Concise Review.

    Ramachandran, Anup / Jaeschke, Hartmut

    Livers

    2023  Volume 3, Issue 2, Page(s) 219–231

    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 ... ...

    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 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.
    Language English
    Publishing date 2023-04-10
    Publishing country Switzerland
    Document type Journal Article
    ISSN 2673-4389
    ISSN (online) 2673-4389
    DOI 10.3390/livers3020014
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  5. Article ; Online: Putative Effects of an Orally Administered Anti-TLR4 Antibody on Gut Microbiota and Acetaminophen Hepatotoxicity in Mice.

    Jaeschke, Hartmut / Ramachandran, Anup

    Microbiology spectrum

    2022  Volume 11, Issue 1, Page(s) e0186322

    MeSH term(s) Animals ; Mice ; Acetaminophen/toxicity ; Chemical and Drug Induced Liver Injury ; Drug-Related Side Effects and Adverse Reactions ; Gastrointestinal Microbiome ; Liver/pathology ; Toll-Like Receptor 4/immunology ; Antibodies/pharmacology
    Chemical Substances Acetaminophen (362O9ITL9D) ; Toll-Like Receptor 4 ; Antibodies
    Language English
    Publishing date 2022-12-13
    Publishing country United States
    Document type Letter ; Research Support, N.I.H., Extramural ; Comment
    ZDB-ID 2807133-5
    ISSN 2165-0497 ; 2165-0497
    ISSN (online) 2165-0497
    ISSN 2165-0497
    DOI 10.1128/spectrum.01863-22
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  6. Article ; Online: Does acetaminophen hepatotoxicity involve apoptosis, inflammatory liver injury, and lipid peroxidation?

    Jaeschke, Hartmut / Ramachandran, Anup

    Journal of biochemical and molecular toxicology

    2021  Volume 35, Issue 2, Page(s) e22718

    Language English
    Publishing date 2021-01-23
    Publishing country United States
    Document type Letter ; Comment
    ZDB-ID 1410020-4
    ISSN 1099-0461 ; 1095-6670
    ISSN (online) 1099-0461
    ISSN 1095-6670
    DOI 10.1002/jbt.22718
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  7. Article ; Online: Oxidant Stress and Acetaminophen Hepatotoxicity: Mechanism-Based Drug Development.

    Ramachandran, Anup / Jaeschke, Hartmut

    Antioxidants & redox signaling

    2021  Volume 35, Issue 9, Page(s) 718–733

    Abstract: Significance: ...

    Abstract Significance:
    MeSH term(s) Acetaminophen/adverse effects ; Animals ; Chemical and Drug Induced Liver Injury/etiology ; Chemical and Drug Induced Liver Injury/metabolism ; Drug Development ; Humans ; Liver/metabolism ; Mice ; Mice, Inbred C57BL ; Oxidants/metabolism ; Oxidative Stress
    Chemical Substances Oxidants ; Acetaminophen (362O9ITL9D)
    Language English
    Publishing date 2021-07-07
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 1483836-9
    ISSN 1557-7716 ; 1523-0864
    ISSN (online) 1557-7716
    ISSN 1523-0864
    DOI 10.1089/ars.2021.0102
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  8. Article ; Online: Targeting the sterile inflammatory response during acetaminophen hepatotoxicity with natural products.

    Jaeschke, Hartmut / Ramachandran, Anup

    Toxicology letters

    2021  Volume 355, Page(s) 170–171

    MeSH term(s) Acetaminophen ; Analgesics, Non-Narcotic ; Biological Products ; Chemical and Drug Induced Liver Injury ; Humans
    Chemical Substances Analgesics, Non-Narcotic ; Biological Products ; Acetaminophen (362O9ITL9D)
    Language English
    Publishing date 2021-11-18
    Publishing country Netherlands
    Document type Letter ; Comment
    ZDB-ID 433788-8
    ISSN 1879-3169 ; 0378-4274
    ISSN (online) 1879-3169
    ISSN 0378-4274
    DOI 10.1016/j.toxlet.2021.11.006
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  9. Article ; Online: Clinically relevant therapeutic approaches against acetaminophen hepatotoxicity and acute liver failure.

    Ramachandran, Anup / Akakpo, Jephte Y / Curry, Steven C / Rumack, Barry H / Jaeschke, Hartmut

    Biochemical pharmacology

    2024  , Page(s) 116056

    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 ... ...

    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.
    Language English
    Publishing date 2024-02-10
    Publishing country England
    Document type Journal Article ; Review
    ZDB-ID 208787-x
    ISSN 1873-2968 ; 0006-2952
    ISSN (online) 1873-2968
    ISSN 0006-2952
    DOI 10.1016/j.bcp.2024.116056
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  10. Article ; Online: Spatial analysis of renal acetaminophen metabolism and its modulation by 4-methylpyrazole with DESI mass spectrometry imaging.

    Akakpo, Jephte Yao / Olivos, Hernando / Shrestha, Bindesh / Midey, Anthony / Jaeschke, Hartmut / Ramachandran, Anup

    Toxicological sciences : an official journal of the Society of Toxicology

    2024  Volume 198, Issue 2, Page(s) 328–346

    Abstract: Acute kidney injury (AKI) is a common complication in acetaminophen (APAP) overdose patients and can negatively impact prognosis. Unfortunately, N-acetylcysteine, which is the standard of care for the treatment of APAP hepatotoxicity does not prevent ... ...

    Abstract Acute kidney injury (AKI) is a common complication in acetaminophen (APAP) overdose patients and can negatively impact prognosis. Unfortunately, N-acetylcysteine, which is the standard of care for the treatment of APAP hepatotoxicity does not prevent APAP-induced AKI. We have previously demonstrated the renal metabolism of APAP and identified fomepizole (4-methylpyrazole, 4MP) as a therapeutic option to prevent APAP-induced nephrotoxicity. However, the kidney has several functionally distinct regions, and the dose-dependent effects of APAP on renal response and regional specificity of APAP metabolism are unknown. These aspects were examined in this study using C57BL/6J mice treated with 300-1200 mg/kg APAP and mass spectrometry imaging (MSI) to provide spatial cues relevant to APAP metabolism and the effects of 4MP. We find that renal APAP metabolism and generation of the nonoxidative (APAP-GLUC and APAP-SULF) and oxidative metabolites (APAP-GSH, APAP-CYS, and APAP-NAC) were dose-dependently increased in the kidney. This was recapitulated on MSI which revealed that APAP overdose causes an accumulation of APAP and APAP GLUC in the inner medulla and APAP-CYS in the outer medulla of the kidney. APAP-GSH, APAP-NAC, and APAP-SULF were localized mainly to the outer medulla and the cortex where CYP2E1 expression was evident. Interestingly, APAP also induced a redistribution of reduced GSH, with an increase in oxidized GSH within the kidney cortex. 4MP ameliorated these region-specific variations in the formation of APAP metabolites in renal tissue sections. In conclusion, APAP metabolism has a distinct regional distribution within the kidney, the understanding of which provides insight into downstream mechanisms of APAP-induced nephrotoxicity.
    MeSH term(s) Humans ; Mice ; Animals ; Acetaminophen/toxicity ; Acetaminophen/metabolism ; Fomepizole/therapeutic use ; Glutathione/metabolism ; Mice, Inbred C57BL ; Kidney/metabolism ; Mass Spectrometry ; Spatial Analysis ; Acute Kidney Injury/chemically induced ; Chemical and Drug Induced Liver Injury/drug therapy
    Chemical Substances Acetaminophen (362O9ITL9D) ; Fomepizole (83LCM6L2BY) ; Glutathione (GAN16C9B8O)
    Language English
    Publishing date 2024-01-16
    Publishing country United States
    Document type Journal Article
    ZDB-ID 1420885-4
    ISSN 1096-0929 ; 1096-6080
    ISSN (online) 1096-0929
    ISSN 1096-6080
    DOI 10.1093/toxsci/kfae011
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