Cell Membrane Transporters Facilitate the Accumulation of Hepatocellular Flucloxacillin Protein Adducts: Implication in Flucloxacillin-Induced Liver Injury

Waddington, James C ORCID: 0000-0003-2641-5055, Ali, Serat-E ORCID: 0000-0002-9806-8796, Penman, Sophie L ORCID: 0000-0001-5326-1675, Whitaker, Paul, Hamlett, Jane, Chadwick, Amy ORCID: 0000-0002-7399-8655, Naisbitt, Dean J, Park, B Kevin ORCID: 0000-0001-8384-824X and Meng, Xiaoli ORCID: 0000-0002-7774-2075 (2020) Cell Membrane Transporters Facilitate the Accumulation of Hepatocellular Flucloxacillin Protein Adducts: Implication in Flucloxacillin-Induced Liver Injury. CHEMICAL RESEARCH IN TOXICOLOGY, 33 (12). pp. 2939-2943.

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Official URL: http://dx.doi.org/10.1021/acs.chemrestox.0c00400

Abstract

Flucloxacillin is a β-lactam antibiotic associated with a high incidence of drug-induced liver reactions. Although expression of HLA-B*57:01 increases susceptibility, little is known about the pathological mechanisms involved in the induction of the clinical phenotype. Irreversible protein modification is suspected to drive the reaction through the presentation of flucloxacillin-modified peptides by the risk allele. In this study, the binding of flucloxacillin to proteins of liver-like cells was characterized. Flucloxacillin was shown to bind to proteins localized in bile canaliculi regions, coinciding with the site of clinical disease. The localization of flucloxacillin was mediated primarily by the membrane transporter multidrug resistance-associated protein 2. Modification of multiple proteins by flucloxacillin in bile canaliculi regions may provide a potential local source of neo-antigens for HLA presentation in the liver.

Item Type:	Article
Uncontrolled Keywords:	Cell Line, Cell Membrane, Humans, Floxacillin, Membrane Transport Proteins, Molecular Structure, Chemical and Drug Induced Liver Injury
Depositing User:	Symplectic Admin
Date Deposited:	12 Nov 2020 10:41
Last Modified:	18 Jan 2023 23:22
DOI:	10.1021/acs.chemrestox.0c00400
Related URLs:	Author Publisher
URI:	https://livrepository.liverpool.ac.uk/id/eprint/3106699