Acetaminophen hepatotoxicity: A mitochondrial perspective

Ramachandran, Anup; Jaeschke, Hartmut

doi:10.1016/bs.apha.2019.01.007

Cited by 47 publications

(36 citation statements)

References 111 publications

(117 reference statements)

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“…The same modification site (Cys106) of PARK7 was recently found following APAP treatment of liver microtissues using data-independent MS/MS acquisition ( Bruderer et al, 2015 ). 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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“…Several medications commonly used during pregnancy have been linked to an increased risk of developing ASD including acetaminophen [ 52 ] and selective serotonin reuptake inhibitors [ 53 ]. Acetaminophen has known toxicity by increasing reactive metabolites leading to suppression of mitochondrial function [ 54 ]. Fluoxetine, a commonly used selective serotonin reuptake inhibitor, has been shown to inhibit multiple mitochondrial enzymes in several laboratory studies [ 55 ] and may result in long-term changes in energy metabolism with neonatal exposure [ 56 ].…”

Section: Prenatal Risk Factors For Asd Modulate Mitochondrial Funcmentioning

confidence: 99%

Mitochondria May Mediate Prenatal Environmental Influences in Autism Spectrum Disorder

Frye

Cakir

Rose

et al. 2021

JPM

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We propose that the mitochondrion, an essential cellular organelle, mediates the long-term prenatal environmental effects of disease in autism spectrum disorder (ASD). Many prenatal environmental factors which increase the risk of developing ASD influence mitochondria physiology, including toxicant exposures, immune activation, and nutritional factors. Unique types of mitochondrial dysfunction have been associated with ASD and recent studies have linked prenatal environmental exposures to long-term changes in mitochondrial physiology in children with ASD. A better understanding of the role of the mitochondria in the etiology of ASD can lead to targeted therapeutics and strategies to potentially prevent the development of ASD.

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“…Induction of mitochondrial biogenesis is mediated by upregulation of the transcription factor PGC1α [12,13], which is considered to be the master regulator for mitochondrial biogenesis. Mitochondrial biogenesis is an important factor in liver recovery and regeneration after acute injury [8,68] and it has been demonstrated that facilitation of mitochondrial biogenesis in surviving cells surrounding the necrotic area helps liver regeneration after APAP-induced liver injury [81]. Mitochondrial biogenesis is also an important mediator of chronic liver injury [82], for example, in instances of hepatitis B infection [83], and upregulation of mitochondrial biogenesis also protected against inflammatory liver injury [84].…”

Section: Mitochondrial Biogenesis In Liver Injurymentioning

confidence: 99%

“…Interestingly, many of the drugs that have been implicated in iDILI can impair mitochondrial function or induce mitochondrial permeabilization, including nucleoside analog reverse transcriptase inhibitors (NRTIs) [7]. Likewise, extensive investigation of APAP-induced hepatotoxicity has established the critical role of mitochondrial dysfunction in pathophysiology [8], and this has also been demonstrated to be relevant in APAP-overdose patients [9,10]. Hence, understanding all aspects of mitochondrial biology influencing cellular responses in DILI is critical to gaining mechanistic insight into the pathophysiology of DILI.…”

Section: Introductionmentioning

confidence: 99%

Mitochondrial Dynamics in Drug-Induced Liver Injury

Ramachandran¹,

Umbaugh²,

Jaeschke³

2021

Livers

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Mitochondria have been studied for decades from the standpoint of metabolism and ATP generation. However, in recent years mitochondrial dynamics and its influence on bioenergetics and cellular homeostasis is also being appreciated. Mitochondria undergo regular cycles of fusion and fission regulated by various cues including cellular energy requirements and pathophysiological stimuli, and the network of critical proteins and membrane lipids involved in mitochondrial dynamics is being revealed. Hepatocytes are highly metabolic cells which have abundant mitochondria suggesting a biologically relevant role for mitochondrial dynamics in hepatocyte injury and recovery. Here we review information on molecular mediators of mitochondrial dynamics and their alteration in drug-induced liver injury. Based on current information, it is evident that changes in mitochondrial fusion and fission are hallmarks of liver pathophysiology ranging from acetaminophen-induced or cholestatic liver injury to chronic liver diseases. These alterations in mitochondrial dynamics influence multiple related mitochondrial responses such as mitophagy and mitochondrial biogenesis, which are important adaptive responses facilitating liver recovery in several contexts, including drug-induced liver injury. The current focus on characterization of molecular mechanisms of mitochondrial dynamics is of immense relevance to liver pathophysiology and have the potential to provide significant insight into mechanisms of liver recovery and regeneration after injury.

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Acetaminophen hepatotoxicity: A mitochondrial perspective

Cited by 47 publications

References 111 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

Mitochondria May Mediate Prenatal Environmental Influences in Autism Spectrum Disorder

Mitochondrial Dynamics in Drug-Induced Liver Injury

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