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Hartmut Jaeschke, Anup Ramachandran
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 N-acetylcysteine and recently fomepizole as effective antidotes against APAP toxicity.
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Jaeschke, H., & Ramachandran, A. (2024). Acetaminophen Hepatotoxicity: Paradigm for Understanding Mechanisms of Drug-Induced Liver Injury. Annual Review of Pathology Mechanisms of Disease, 19(1), 453–478. https://doi.org/10.1146/annurev-pathmechdis-051122-094016
Jaeschke, Hartmut, and Anup Ramachandran. "Acetaminophen Hepatotoxicity: Paradigm for Understanding Mechanisms of Drug-Induced Liver Injury." Annual Review of Pathology Mechanisms of Disease, vol. 19, no. 1, 2024, pp. 453–478, https://doi.org/10.1146/annurev-pathmechdis-051122-094016.
Jaeschke, Hartmut, and Anup Ramachandran. "Acetaminophen Hepatotoxicity: Paradigm for Understanding Mechanisms of Drug-Induced Liver Injury." Annual Review of Pathology Mechanisms of Disease 19, no. 1 (2024): 453–478. https://doi.org/10.1146/annurev-pathmechdis-051122-094016.
Jaeschke H., Ramachandran A. Acetaminophen Hepatotoxicity: Paradigm for Understanding Mechanisms of Drug-Induced Liver Injury // Annual Review of Pathology Mechanisms of Disease. — 2024. — Vol. 19, № 1. — P. 453–478. — URL: https://doi.org/10.1146/annurev-pathmechdis-051122-094016
@article{jaeschke2024acetaminophen,
title = {{Acetaminophen Hepatotoxicity: Paradigm for Understanding Mechanisms of Drug-Induced Liver Injury}},
author = {Hartmut Jaeschke and Anup Ramachandran},
journal = {Annual Review of Pathology Mechanisms of Disease},
year = {2024},
volume = {19},
number = {1},
pages = {453--478},
doi = {10.1146/annurev-pathmechdis-051122-094016},
url = {https://doi.org/10.1146/annurev-pathmechdis-051122-094016}
}TY - JOUR AU - Jaeschke, Hartmut AU - Ramachandran, Anup TI - Acetaminophen Hepatotoxicity: Paradigm for Understanding Mechanisms of Drug-Induced Liver Injury JO - Annual Review of Pathology Mechanisms of Disease VL - 19 IS - 1 SP - 453 EP - 478 PY - 2024 DA - 2024/01/24 DO - 10.1146/annurev-pathmechdis-051122-094016 UR - https://doi.org/10.1146/annurev-pathmechdis-051122-094016 ER -
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