Please use this identifier to cite or link to this item: https://doi.org/10.1074/mcp.RA118.000875
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dc.titleReactive Metabolite-induced Protein Glutathionylation: A Potentially Novel Mechanism Underlying Acetaminophen Hepatotoxicity
dc.contributor.authorChan, James Chun Yip
dc.contributor.authorSoh, Alex Cheow Khoon
dc.contributor.authorKioh, Dorinda Yan Qin
dc.contributor.authorLi, Jianguo
dc.contributor.authorVerma, Chandra
dc.contributor.authorKoh, Siew Kwan
dc.contributor.authorBeuerman, Roger Wilmer
dc.contributor.authorZhou, Lei
dc.contributor.authorChan, Eric Chun Yong
dc.date.accessioned2020-07-16T03:44:37Z
dc.date.available2020-07-16T03:44:37Z
dc.date.issued2018-10-01
dc.identifier.citationChan, 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
dc.identifier.issn15359476
dc.identifier.issn15359484
dc.identifier.urihttps://scholarbank.nus.edu.sg/handle/10635/171313
dc.description.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.
dc.language.isoen
dc.publisherAmerican Society for Biochemistry and Molecular Biology Inc.
dc.sourceElements
dc.subjectScience & Technology
dc.subjectLife Sciences & Biomedicine
dc.subjectBiochemical Research Methods
dc.subjectBiochemistry & Molecular Biology
dc.subjectPost-translational modifications
dc.subjectMetabolomics
dc.subjectChemical biology
dc.subjectProtein Modification
dc.subjectProtein adducts
dc.subjectAcetaminophen
dc.subjectDrug-induced toxicity
dc.subjectHepatotoxicity
dc.subjectProtein glutathionylation
dc.subjectPARA-BENZOQUINONE IMINE
dc.subjectS-GLUTATHIONYLATION
dc.subjectIN-VIVO
dc.subjectMITOCHONDRIAL RESPIRATION
dc.subjectCOVALENT BINDING
dc.subjectOXIDATIVE STRESS
dc.subjectREDOX REGULATION
dc.subjectPLASMA-MEMBRANE
dc.subjectOXIDANT STRESS
dc.subjectLIVER
dc.typeArticle
dc.date.updated2020-07-15T08:56:35Z
dc.contributor.departmentBIOLOGY (NU)
dc.contributor.departmentDEPT OF PHARMACY
dc.contributor.departmentDUKE-NUS MEDICAL SCHOOL
dc.description.doi10.1074/mcp.RA118.000875
dc.description.sourcetitleMOLECULAR & CELLULAR PROTEOMICS
dc.description.volume17
dc.description.issue10
dc.description.page2034-2050
dc.published.statePublished
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