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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: | Post-translational Modifications Metabolomics DRNTU::Science::Biological sciences |
Issue Date: | 2018 | Source: | Chan, J. C. Y., Soh, A. C. K., Kioh, D. Y. Q., Li, J., Verma, C., Koh, . . . Chan, E. C. Y. (2018). Reactive Metabolite-induced Protein Glutathionylation: A Potentially Novel Mechanism Underlying Acetaminophen Hepatotoxicity. Molecular & Cellular Proteomics, 17(10), 2034-2050. doi:10.1074/mcp.RA118.000875 | Series/Report no.: | Molecular & Cellular Proteomics | Abstract: | 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. | URI: | https://hdl.handle.net/10356/89802 http://hdl.handle.net/10220/46390 |
ISSN: | 1535-9476 | DOI: | 10.1074/mcp.RA118.000875 | Schools: | School of Biological Sciences | Rights: | © 2018 American Society for Biochemistry and Molecular Biology. This paper was published in Molecular & Cellular Proteomics and is made available as an electronic reprint (preprint) with permission of American Society for Biochemistry and Molecular Biology. The published version is available at: [http://dx.doi.org/10.1074/mcp.RA118.000875]. One print or electronic copy may be made for personal use only. Systematic or multiple reproduction, distribution to multiple locations via electronic or other means, duplication of any material in this paper for a fee or for commercial purposes, or modification of the content of the paper is prohibited and is subject to penalties under law. | Fulltext Permission: | open | Fulltext Availability: | With Fulltext |
Appears in Collections: | SBS Journal Articles |
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Reactive Metabolite-induced Protein.pdf | 3.55 MB | Adobe PDF | View/Open |
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