Mass Spectrometric and Functional Aspects of Drug-Protein Conjugation

Tailor, Arun ORCID: 0000-0002-9698-3480, Waddington, James C ORCID: 0000-0003-2641-5055, Meng, Xiaoli ORCID: 0000-0002-7774-2075 and Park, B Kevin ORCID: 0000-0001-8384-824X (2016) Mass Spectrometric and Functional Aspects of Drug-Protein Conjugation. CHEMICAL RESEARCH IN TOXICOLOGY, 29 (12). pp. 1912-1935.

Access the full-text of this item by clicking on the Open Access link.

Text acs%2Echemrestox%2E6b00147.pdf - Author Accepted Manuscript Download (1MB)

Abstract

The covalent binding of drugs (metabolites) to proteins to form drug-protein adducts can have an adverse effect on the body. These adducts are thought to be responsible for idiosyncratic drug reactions including severe drug hypersensitivity reactions. Major advances in proteomics technology have allowed for the identification and quantification of target proteins for certain drugs. Human serum albumin (HSA) and Hb have been identified as accessible targets and potential biomarkers for drug-protein adducts formation, for numerous drugs (metabolites) including β-lactam antibiotics, reactive drug metabolites such as quinone imines (acetaminophen) and acyl glucuronides (diclofenac), and covalent inhibitors (neratinib). For example, MS/MS analysis of plasma samples from patients taking flucloxacillin revealed that flucloxacillin and its 5-hydroxymethyl metabolite formed covalent adducts with lysine residues on albumin via opening of the β-lactam ring. Other proteins such as P450 and keratin are also potential targets for covalent binding. However, for most drugs, the properties of these target proteins including their location, their quantity, the timing of conjugate generation, and their biological function are not well understood. In this review, currently available proteomic technologies including MS/MS analysis to identify antigens, precise location of modifications, and the immunological consequence of hapten-protein complex are illustrated. Moving forward, identification of the nature of the antigenic determinants that trigger immune responses to drug-protein adducts will increase our ability to predict idiosyncratic toxicity for a given compound.

Item Type:	Article
Uncontrolled Keywords:	Humans, Proteins, Pharmaceutical Preparations, Mass Spectrometry
Depositing User:	Symplectic Admin
Date Deposited:	13 Oct 2016 13:49
Last Modified:	19 Jan 2023 07:29
DOI:	10.1021/acs.chemrestox.6b00147
Open Access URL:	http://pubs.acs.org/doi/pdfplus/10.1021/acs.chemre...
Related URLs:	Author Publisher
URI:	https://livrepository.liverpool.ac.uk/id/eprint/3003755