دورية أكاديمية
Identification of flucloxacillin-modified hepatocellular proteins: implications in flucloxacillin-induced liver injury.
| العنوان: | Identification of flucloxacillin-modified hepatocellular proteins: implications in flucloxacillin-induced liver injury. |
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| المؤلفون: | Ali SE; Department of Molecular & Clinical Pharmacology, University of Liverpool, Sherrington Buildings, Ashton Street, Liverpool, L69 3GE, UK., Waddington JC; Department of Molecular & Clinical Pharmacology, University of Liverpool, Sherrington Buildings, Ashton Street, Liverpool, L69 3GE, UK., Lister A; Department of Molecular & Clinical Pharmacology, University of Liverpool, Sherrington Buildings, Ashton Street, Liverpool, L69 3GE, UK., Sison-Young R; Department of Molecular & Clinical Pharmacology, University of Liverpool, Sherrington Buildings, Ashton Street, Liverpool, L69 3GE, UK., Jones RP; Department of Hepatobiliary Surgery, Aintree University Hospital, Liverpool University Hospitals, NHS Foundation Trust, Liverpool, UK., Rehman AH; Department of Hepatobiliary Surgery, Aintree University Hospital, Liverpool University Hospitals, NHS Foundation Trust, Liverpool, UK., Goldring CEP; Department of Molecular & Clinical Pharmacology, University of Liverpool, Sherrington Buildings, Ashton Street, Liverpool, L69 3GE, UK., Naisbitt DJ; Department of Molecular & Clinical Pharmacology, University of Liverpool, Sherrington Buildings, Ashton Street, Liverpool, L69 3GE, UK., Meng X; Department of Molecular & Clinical Pharmacology, University of Liverpool, Sherrington Buildings, Ashton Street, Liverpool, L69 3GE, UK. |
| المصدر: | Toxicological sciences : an official journal of the Society of Toxicology [Toxicol Sci] 2023 Mar 20; Vol. 192 (1), pp. 106-116. |
| نوع المنشور: | Journal Article; Research Support, Non-U.S. Gov't |
| اللغة: | English |
| بيانات الدورية: | Publisher: Oxford University Press Country of Publication: United States NLM ID: 9805461 Publication Model: Print Cited Medium: Internet ISSN: 1096-0929 (Electronic) Linking ISSN: 10960929 NLM ISO Abbreviation: Toxicol Sci Subsets: MEDLINE |
| أسماء مطبوعة: | Publication: 1999- : Cary, NC : Oxford University Press Original Publication: Orlando, FL : Academic Press, c1998- |
| مواضيع طبية MeSH: | Carcinoma, Hepatocellular* , Chemical and Drug Induced Liver Injury, Chronic* , Liver Neoplasms* , Chemical and Drug Induced Liver Injury*/etiology, Humans ; Floxacillin/toxicity ; Liver/metabolism ; Albumins |
| مستخلص: | Flucloxacillin is a β-lactam antibiotic associated with a high incidence of drug-induced liver injury. Although expression of HLA-B*57:01 is associated with increased susceptibility, little is known of the pathological mechanisms involved in the induction of the clinical phenotype. Irreversible protein modification is suspected to drive the reaction through the provision of flucloxacillin-modified peptides that are presented to T-cells by the protein encoded by the risk allele. In this study, we have shown that flucloxacillin binds to multiple proteins within human primary hepatocytes, including major hepatocellular proteins (hemoglobin and albumin) and mitochondrial proteins. Inhibition of membrane transporters multidrug resistance-associated protein 2 (MRP2) and P-glycoprotein (P-gp) appeared to reduce the levels of covalent binding. A diverse range of proteins with different functions was found to be targeted by flucloxacillin, including adaptor proteins (14-3-3), proteins with catalytic activities (liver carboxylesterase 1, tRNA-splicing endonuclease subunit Sen2, All-trans-retinol dehydrogenase ADH1B, Glutamate dehydrogenase 1 mitochondrial, Carbamoyl-phosphate synthase [ammonia] mitochondrial), and transporters (hemoglobin, albumin, and UTP-glucose-1-phosphate uridylyltransferase). These flucloxacillin-modified intracellular proteins could provide a potential source of neoantigens for HLA-B*57:01 presentation by hepatocytes. More importantly, covalent binding to critical cellular proteins could be the molecular initiating events that lead to flucloxacillin-induced cholestasis Data are available via ProteomeXchange with identifier PXD038581. (© The Author(s) 2023. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.) |
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| معلومات مُعتمدة: | MR/L006758/1 United Kingdom MRC_ Medical Research Council; MR/R009635/1 United Kingdom MRC_ Medical Research Council; G0700654 United Kingdom MRC_ Medical Research Council |
| فهرسة مساهمة: | Keywords: covalent binding; flucloxacillin DILI; hepatocytes; membrane transporters |
| المشرفين على المادة: | 43B2M34G2V (Floxacillin) 0 (Albumins) |
| تواريخ الأحداث: | Date Created: 20230214 Date Completed: 20230321 Latest Revision: 20240313 |
| رمز التحديث: | 20240313 |
| مُعرف محوري في PubMed: | PMC10371196 |
| DOI: | 10.1093/toxsci/kfad015 |
| PMID: | 36782357 |
| قاعدة البيانات: | MEDLINE |
| تدمد: | 1096-0929 |
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| DOI: | 10.1093/toxsci/kfad015 |