Please use this identifier to cite or link to this item:
https://doi.org/10.1074/mcp.RA118.000875
DC Field | Value | |
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dc.title | Reactive Metabolite-induced Protein Glutathionylation: A Potentially Novel Mechanism Underlying Acetaminophen Hepatotoxicity | |
dc.contributor.author | Chan, James Chun Yip | |
dc.contributor.author | Soh, Alex Cheow Khoon | |
dc.contributor.author | Kioh, Dorinda Yan Qin | |
dc.contributor.author | Li, Jianguo | |
dc.contributor.author | Verma, Chandra | |
dc.contributor.author | Koh, Siew Kwan | |
dc.contributor.author | Beuerman, Roger Wilmer | |
dc.contributor.author | Zhou, Lei | |
dc.contributor.author | Chan, Eric Chun Yong | |
dc.date.accessioned | 2020-07-16T03:44:37Z | |
dc.date.available | 2020-07-16T03:44:37Z | |
dc.date.issued | 2018-10-01 | |
dc.identifier.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 | |
dc.identifier.issn | 15359476 | |
dc.identifier.issn | 15359484 | |
dc.identifier.uri | https://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.iso | en | |
dc.publisher | American Society for Biochemistry and Molecular Biology Inc. | |
dc.source | Elements | |
dc.subject | Science & Technology | |
dc.subject | Life Sciences & Biomedicine | |
dc.subject | Biochemical Research Methods | |
dc.subject | Biochemistry & Molecular Biology | |
dc.subject | Post-translational modifications | |
dc.subject | Metabolomics | |
dc.subject | Chemical biology | |
dc.subject | Protein Modification | |
dc.subject | Protein adducts | |
dc.subject | Acetaminophen | |
dc.subject | Drug-induced toxicity | |
dc.subject | Hepatotoxicity | |
dc.subject | Protein glutathionylation | |
dc.subject | PARA-BENZOQUINONE IMINE | |
dc.subject | S-GLUTATHIONYLATION | |
dc.subject | IN-VIVO | |
dc.subject | MITOCHONDRIAL RESPIRATION | |
dc.subject | COVALENT BINDING | |
dc.subject | OXIDATIVE STRESS | |
dc.subject | REDOX REGULATION | |
dc.subject | PLASMA-MEMBRANE | |
dc.subject | OXIDANT STRESS | |
dc.subject | LIVER | |
dc.type | Article | |
dc.date.updated | 2020-07-15T08:56:35Z | |
dc.contributor.department | BIOLOGY (NU) | |
dc.contributor.department | DEPT OF PHARMACY | |
dc.contributor.department | DUKE-NUS MEDICAL SCHOOL | |
dc.description.doi | 10.1074/mcp.RA118.000875 | |
dc.description.sourcetitle | MOLECULAR & CELLULAR PROTEOMICS | |
dc.description.volume | 17 | |
dc.description.issue | 10 | |
dc.description.page | 2034-2050 | |
dc.published.state | Published | |
Appears in Collections: | Elements Staff Publications |
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MCP_01.pdf | Published version | 3.55 MB | Adobe PDF | OPEN | Published | View/Download |
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