Evidence map›Paper›PMID 35024303›Full record

ReviewActa pharmaceutica Sinica. B2021

Recommendations for the use of the acetaminophen hepatotoxicity model for mechanistic studies and how to avoid common pitfalls.

Hartmut Jaeschke, Olamide B Adelusi, Jephte Y Akakpo, Nga T Nguyen, Giselle Sanchez-Guerrero, David S Umbaugh, Wen-Xing Ding, Anup Ramachandran

Abstract readReview
In one paragraph

Review in Acta pharmaceutica Sinica. B, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 77 papers.

0numbers the graph read from it
0cells of the map it votes in
77citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

77 citing papers in PubMed.

  1. A Multi-Omic Mosaic Model of Acetaminophen Induced Alanine Aminotransferase Elevation.Journal of medical toxicology : official journal of the American College of Medical Toxicology · 2023
    Trial
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  16. Review
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  18. Are New Approach Methodologies (NAMs) the Holy Grail of toxicology?Toxicological sciences : an official journal of the Society of Toxicology · 2025
    Review
  19. Article
  20. Article

17 more citing papers are in PubMed but not listed here.

4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

8 authors.

Hartmut JaeschkeDepartment of Pharmacology, Toxicology & Therapeutics, University of Kansas Medical Center, Kansas City, KS 66160, USA.
Olamide B AdelusiDepartment of Pharmacology, Toxicology & Therapeutics, University of Kansas Medical Center, Kansas City, KS 66160, USA.
Jephte Y AkakpoDepartment of Pharmacology, Toxicology & Therapeutics, University of Kansas Medical Center, Kansas City, KS 66160, USA.
Nga T NguyenDepartment of Pharmacology, Toxicology & Therapeutics, University of Kansas Medical Center, Kansas City, KS 66160, USA.
Giselle Sanchez-GuerreroDepartment of Pharmacology, Toxicology & Therapeutics, University of Kansas Medical Center, Kansas City, KS 66160, USA.
David S UmbaughDepartment of Pharmacology, Toxicology & Therapeutics, University of Kansas Medical Center, Kansas City, KS 66160, USA.
Wen-Xing DingDepartment of Pharmacology, Toxicology & Therapeutics, University of Kansas Medical Center, Kansas City, KS 66160, USA.
Anup RamachandranDepartment of Pharmacology, Toxicology & Therapeutics, University of Kansas Medical Center, Kansas City, KS 66160, USA.

Funding

Nuclear Receptors in Liver Health and DiseaseP20GM103549 · NIGMS · UNIVERSITY OF KANSAS MEDICAL CENTER · PI JAESCHKE, HARTMUT W. · 2012 to 2015
$8.1M
Pilot Grants ProgramP30GM118247 · NIGMS · UNIVERSITY OF KANSAS MEDICAL CENTER · PI WEINMAN, STEVEN A · 2016 to 2020
$5.5M
Autophagy and Drug-Induced Liver InjuryR01DK102142 · NIDDK · UNIVERSITY OF KANSAS MEDICAL CENTER · PI DING, WEN-XING, JAESCHKE, HARTMUT W. · 2014 to 2022
$2.7M
Mitochondrial Dysfunction and Drug HepatotoxicityR01DK070195 · NIDDK · UNIVERSITY OF KANSAS MEDICAL CENTER · PI JAESCHKE, HARTMUT W. · 2005 to 2010
$1.8M
The Immune Response After Drug Induced HepatotoxicityR01DK125465 · NIDDK · UNIVERSITY OF KANSAS MEDICAL CENTER · PI RAMACHANDRAN, ANUP · 2021 to 2025
$1.7M
Mitochondrial free radical production, biogenesis and their effect on liver regeneration after Acetaminophen (APAP) overdose.F31DK120194 · NIDDK · UNIVERSITY OF KANSAS MEDICAL CENTER · PI AKAKPO, JEPHTE Y. · 2018 to 2020
$98k
NIDDK NIH HHS F31 DK120194NIDDK NIH HHS R01 DK070195NIDDK NIH HHS R01 DK102142NIDDK NIH HHS R01 DK125465NIGMS NIH HHS P20 GM103549NIGMS NIH HHS P30 GM118247
6 · The paper itself

Abstract

Acetaminophen (APAP) is a widely used analgesic and antipyretic drug, which is safe at therapeutic doses but can cause severe liver injury and even liver failure after overdoses. The mouse model of APAP hepatotoxicity recapitulates closely the human pathophysiology. As a result, this clinically relevant model is frequently used to study mechanisms of drug-induced liver injury and even more so to test potential therapeutic interventions. However, the complexity of the model requires a thorough understanding of the pathophysiology to obtain valid results and mechanistic information that is translatable to the clinic. However, many studies using this model are flawed, which jeopardizes the scientific and clinical relevance. The purpose of this review is to provide a framework of the model where mechanistically sound and clinically relevant data can be obtained. The discussion provides insight into the injury mechanisms and how to study it including the critical roles of drug metabolism, mitochondrial dysfunction, necrotic cell death, autophagy and the sterile inflammatory response. In addition, the most frequently made mistakes when using this model are discussed. Thus, considering these recommendations when studying APAP hepatotoxicity will facilitate the discovery of more clinically relevant interventions.

Indexed as

Acetaminophen hepatotoxicityAIF, apoptosis-inducing factorAMPK, AMP-activated protein kinaseAPAP, acetaminophenApoptosisARE, antioxidant response elementATG, autophagy-related genesAutophagyBSO, buthionine sulfoximineCAD, caspase-activated DNaseCYP, cytochrome P450 enzymesDAMPs, damage-associated molecular patternsDMSO, dimethylsulfoxideDrug metabolismEndoG, endonuclease GFerroptosisFSP1, ferroptosis suppressing protein 1Gclc, glutamate–cysteine ligase catalytic subunitGclm, glutamate–cysteine ligase modifier subunitGPX4, glutathione peroxidase 4GSH, glutathioneGSSG, glutathione disulfideHMGB1, high mobility group box protein 1HNE, 4-hydroxynonenalInnate immunityJNK, c-jun N-terminal kinaseKEAP1, Kelch-like ECH-associated protein 1LAMP, lysosomal-associated membrane proteinLC3, light chain 3LOOH, lipid hydroperoxidesLPO, lipid peroxidationMAP kinase, mitogen activated protein kinaseMCP-1, monocyte chemoattractant protein-1MDA, malondialdehydeMitochondriaMnSOD, manganese superoxide dismutaseMPT, mitochondrial permeability transitionmTORC1, mammalian target of rapamycin complex 1NAC, N-acetylcysteineNAPQI, N-acetyl-p-benzoquinone imineNF-κB, nuclear factor κBNQO1, NAD(P)H:quinone oxidoreductase 1NRF2NRF2, nuclear factor erythroid 2-related factor 2PUFAs, polyunsaturated fatty acidsROS, reactive oxygen speciesSMAC/DIABLO, second mitochondria-derived activator of caspase/direct inhibitor of apoptosis-binding protein with low pITLR, toll like receptorTUNEL, terminal deoxynucleotidyl transferase dUTP nick end labelingUGT, UDP-glucuronosyltransferases

Identifiers

PMID35024303
PMCPMC8727921

What OpenQuestion holds

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Read underepoch 390

Registered trials

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.