Please use this identifier to cite or link to this item: https://doi.org/10.1074/mcp.RA118.000875
Title: Reactive Metabolite-induced Protein Glutathionylation: A Potentially Novel Mechanism Underlying Acetaminophen Hepatotoxicity
Authors: Chan, James Chun Yip 
Soh, Alex Cheow Khoon
Kioh, Dorinda Yan Qin 
Li, Jianguo 
Verma, Chandra 
Koh, Siew Kwan
Beuerman, Roger Wilmer 
Zhou, Lei 
Chan, Eric Chun Yong 
Keywords: Science & Technology
Life Sciences & Biomedicine
Biochemical Research Methods
Biochemistry & Molecular Biology
Post-translational modifications
Metabolomics
Chemical biology
Protein Modification
Protein adducts
Acetaminophen
Drug-induced toxicity
Hepatotoxicity
Protein glutathionylation
PARA-BENZOQUINONE IMINE
S-GLUTATHIONYLATION
IN-VIVO
MITOCHONDRIAL RESPIRATION
COVALENT BINDING
OXIDATIVE STRESS
REDOX REGULATION
PLASMA-MEMBRANE
OXIDANT STRESS
LIVER
Issue Date: 1-Oct-2018
Publisher: American Society for Biochemistry and Molecular Biology Inc.
Citation: Chan, James Chun Yip, Soh, Alex Cheow Khoon, Kioh, Dorinda Yan Qin, Li, Jianguo, Verma, Chandra, Koh, Siew Kwan, Beuerman, Roger Wilmer, Zhou, Lei, Chan, Eric Chun Yong (2018-10-01). Reactive Metabolite-induced Protein Glutathionylation: A Potentially Novel Mechanism Underlying Acetaminophen Hepatotoxicity. MOLECULAR & CELLULAR PROTEOMICS 17 (10) : 2034-2050. ScholarBank@NUS Repository. https://doi.org/10.1074/mcp.RA118.000875
Abstract: © 2018 Chan et al. Although covalent protein binding is established as the pivotal event underpinning acetaminophen (APAP) toxicity, its mechanistic details remain unclear. In this study, we demonstrated that APAP induces widespread protein glutathionylation in a time-, dose- and bioactivation-dependent manner in HepaRG cells. Proteo-metabonomic mapping provided evidence that APAP-induced glutathionylation resulted in functional deficits in energy metabolism, elevations in oxidative stress and cytosolic calcium, as well as mitochondrial dysfunction that correlate strongly with the well-established toxicity features of APAP. We also provide novel evidence that APAP-induced glutathionylation of carnitine O-palmitoyltransferase 1 (CPT1) and voltage-dependent anion-selective channel protein 1 are respectively involved in inhibition of fatty acid β-oxidation and opening of the mitochondrial permeability transition pore. Importantly, we show that the inhibitory effect of CPT1 glutathionylation can be mitigated by PPARα induction, which provides a mechanistic explanation for the prophylactic effect of fibrates, which are PPARα ligands, against APAP toxicity. Finally, we propose that APAP-induced protein glutathionylation likely occurs secondary to covalent binding, which is a previously unknown mechanism of glutathionylation, suggesting that this post-translational modification could be functionally implicated in drug-induced toxicity.
Source Title: MOLECULAR & CELLULAR PROTEOMICS
URI: https://scholarbank.nus.edu.sg/handle/10635/171313
ISSN: 15359476
15359484
DOI: 10.1074/mcp.RA118.000875
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