Mitochondrial protein adduct and superoxide generation are prerequisites for early activation of c-jun N-terminal kinase within the cytosol after an acetaminophen overdose in mice

Nguyen, Nga; Du, Kuo; Akakpo, Jephte Y.; Umbaugh, David S.; Jaeschke, Hartmut; Ramachandran, Anup

doi:10.1016/j.toxlet.2020.12.005

Cited by 42 publications

(29 citation statements)

References 46 publications

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“…Mitochondrial protein targets are of specific interest, as they have been correlated to the initiation of APAP’s hepatotoxicity ( Tirmenstein and Nelson, 1989 ; Ramachandran and Jaeschke, 2019 ). They have been proposed as a source of APAP-induced mitochondrial dysfunction ( Hu et al, 2016 ), and are believed to be linked to the inhibition of electron transport chain ( Lee et al, 2015 ), reactive oxygen species formation ( Jiang et al, 2015 ) and mitogen-activated protein kinase and c-Jun N terminal kinase activation ( Nguyen et al, 2021 ).…”

Section: Discussionmentioning

confidence: 99%

Protein Targets of Acetaminophen Covalent Binding in Rat and Mouse Liver Studied by LC-MS/MS

et al. 2021

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Acetaminophen (APAP) is a mild analgesic and antipyretic used commonly worldwide. Although considered a safe and effective over-the-counter medication, it is also the leading cause of drug-induced acute liver failure. Its hepatotoxicity has been linked to the covalent binding of its reactive metabolite, N-acetyl p-benzoquinone imine (NAPQI), to proteins. The aim of this study was to identify APAP-protein targets in both rat and mouse liver, and to compare the results from both species, using bottom-up proteomics with data-dependent high resolution mass spectrometry and targeted multiple reaction monitoring (MRM) experiments. Livers from rats and mice, treated with APAP, were homogenized and digested by trypsin. Digests were then fractionated by mixed-mode solid-phase extraction prior to liquid chromatography-tandem mass spectrometry (LC-MS/MS). Targeted LC-MRM assays were optimized based on high-resolution MS/MS data from information-dependent acquisition (IDA) using control liver homogenates treated with a custom alkylating reagent yielding an isomeric modification to APAP on cysteine residues, to build a modified peptide database. A list of putative in vivo targets of APAP were screened from data-dependent high-resolution MS/MS analyses of liver digests, previous in vitro studies, as well as selected proteins from the target protein database (TPDB), an online resource compiling previous reports of APAP targets. Multiple protein targets in each species were found, while confirming modification sites. Several proteins were modified in both species, including ATP-citrate synthase, betaine-homocysteine S-methyltransferase 1, cytochrome P450 2C6/29, mitochondrial glutamine amidotransferase-like protein/ES1 protein homolog, glutamine synthetase, microsomal glutathione S-transferase 1, mitochondrial-processing peptidase, methanethiol oxidase, protein/nucleic acid deglycase DJ-1, triosephosphate isomerase and thioredoxin. The targeted method afforded better reproducibility for analysing these low-abundant modified peptides in highly complex samples compared to traditional data-dependent experiments.

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Section: Discussionmentioning

confidence: 99%

Protein Targets of Acetaminophen Covalent Binding in Rat and Mouse Liver Studied by LC-MS/MS

et al. 2021

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“…First recognized by Mitchell and co-workers 40 , 41 , it is now well established that this metabolic activation of APAP leads to extensive GSH depletion and then covalent binding of the reactive metabolite to proteins, which initiates the toxicity 19 . However, it is not the total protein binding in the cell that is critical for hepatotoxicity but the adduct formation on mitochondria 42 , 43 , which triggers the early mitochondrial superoxide release 44 leading to all the subsequent signaling events characteristic of APAP-induced programmed necrosis 45 , 46 . This means that the entire mechanism of APAP-induced cell death depends on this CYP-mediated NAPQI formation and its reaction with GSH or protein sulfhydryl groups ( Fig.…”

Section: General Recommendations For Investigating Therapeutic Efficacy and Mechanisms Of Actionmentioning

confidence: 99%

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

Jaeschke

Adelusi

Akakpo

et al. 2021

Acta Pharmaceutica Sinica B

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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.

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“…[ 44 ] For positive control, strong green fluorescence was detected when cells treated with carbonyl cyanide‐ p ‐trifluoromethoxyphenylhydrazone (FCCP), a membrane potential uncoupler that can decrease mitochondrial potential. [ 45 ] Collectively, the high chemical stability and minimal cell cytotoxicity have laid a good foundation for further biological research and applications.…”

Section: Resultsmentioning

confidence: 99%

Tailorable Membrane‐Penetrating Nanoplatform for Highly Efficient Organelle‐Specific Localization

Zhang

Wang

Feng

et al. 2021

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Given the breadth of currently arising opportunities and concerns associated with nanoparticles for biomedical imaging, various types of nanoparticles have been widely exploited, especially for cellular/subcellular level probing. However, most currently reported nanoparticles either have inefficient delivery into cells or lack specificity for intracellular destinations. The absence of well‐defined nanoplatforms remains a critical challenge hindering practical nano‐based bio‐imaging. Herein, the authors elaborate on a tailorable membrane‐penetrating nanoplatform as a carrier with encapsulated actives and decorated surfaces to tackle the above‐mentioned issues. The tunable contents in such a versatile nanoplatform offer huge flexibility to reach the expected properties and functions. Aggregation‐induced emission luminogen (AIEgen) is applied to achieve sought‐after photophysical properties, specific targeting moieties are installed to give high affinity towards different desired organelles, and critical grafting of cell‐penetrating cyclic disulfides (CPCDs) to promote cellular uptake efficiency without sacrificing the specificity. Hereafter, to validate its practicability, the tailored nano products are successfully applied to track the dynamic correlation between mitochondria and lysosomes during autophagy. The authors believe that the strategy and described materials can facilitate the development of functional nanomaterials for various life science applications.

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Mitochondrial protein adduct and superoxide generation are prerequisites for early activation of c-jun N-terminal kinase within the cytosol after an acetaminophen overdose in mice

Cited by 42 publications

References 46 publications

Protein Targets of Acetaminophen Covalent Binding in Rat and Mouse Liver Studied by LC-MS/MS

Protein Targets of Acetaminophen Covalent Binding in Rat and Mouse Liver Studied by LC-MS/MS

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

Tailorable Membrane‐Penetrating Nanoplatform for Highly Efficient Organelle‐Specific Localization

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