PXD009986
PXD009986 is an original dataset announced via ProteomeXchange.
Dataset Summary
| Title | Reactive Metabolite-induced Protein Glutathionylation Mechanistically Accounts for Acetaminophen Hepatotoxicity |
| Description | 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 suggest that APAP-induced protein glutathionylation likely occurs secondary to covalent binding, which is a previously unknown mechanism of glutathionylation, demonstrating that this post-translational modification is functionally implicated in drug-induced toxicity. |
| HostingRepository | jPOST |
| AnnounceDate | 2018-09-20 |
| AnnouncementXML | Submission_2022-09-18_03:15:43.076.xml |
| DigitalObjectIdentifier | |
| ReviewLevel | Peer-reviewed dataset |
| DatasetOrigin | Original dataset |
| RepositorySupport | Unsupported dataset by repository |
| PrimarySubmitter | James Chan |
| SpeciesList | scientific name: Homo sapiens (Human); NCBI TaxID: 9606; |
| ModificationList | L-methionine sulfoxide; unknown modification |
| Instrument | TripleTOF 5600 |
Dataset History
| Revision | Datetime | Status | ChangeLog Entry |
|---|---|---|---|
| 0 | 2018-05-31 20:03:50 | ID requested | |
| 1 | 2018-09-19 18:10:51 | announced | |
| 2 | 2021-02-04 17:08:55 | announced | 2021-02-04: Updated FTP location. |
| ⏵ 3 | 2022-09-18 03:15:43 | announced | 2022-09-18: Updated FTP location. |
Publication List
| Chan JCY, Soh ACK, Kioh DYQ, Li J, Verma C, Koh SK, Beuerman RW, Zhou L, Chan ECY, Reactive Metabolite-induced Protein Glutathionylation: A Potentially Novel Mechanism Underlying Acetaminophen Hepatotoxicity. Mol Cell Proteomics, 17(10):2034-2050(2018) [pubmed] |
Keyword List
| submitter keyword: Glutathionylation, proteomics, hepatotoxicity, drug induced toxicity, post-translational modification, proteo-metabolomics, HepaRG |
Contact List
| Eric Chan Chun Yong | |
|---|---|
| lab head | |
| James Chan | |
| contact affiliation | Skin Research Institute of Singapore |
| dataset submitter | |
Full Dataset Link List
| jPOST dataset URI |
| Dataset FTP location NOTE: Most web browsers have now discontinued native support for FTP access within the browser window. But you can usually install another FTP app (we recommend FileZilla) and configure your browser to launch the external application when you click on this FTP link. Or otherwise, launch an app that supports FTP (like FileZilla) and use this address: ftp://ftp.jpostdb.org/JPST000435/ |
to receive all new ProteomeXchange dataset release announcements!
