Separation and detection methods for covalent drug-protein adducts.

Zhou, S 2003, 'Separation and detection methods for covalent drug-protein adducts.', Journal of Chromatography. B, Analytical Technologies in the Biomedical and Life Sciences, vol. 797, no. 12, pp. 63-90.

Document type: Journal Article
Collection: Journal Articles

Title Separation and detection methods for covalent drug-protein adducts.
Author(s) Zhou, S
Year 2003
Journal name Journal of Chromatography. B, Analytical Technologies in the Biomedical and Life Sciences
Volume number 797
Issue number 12
Start page 63
End page 90
Total pages 28
Publisher Elsevier BV
Abstract Covalent binding of reactive metabolites of drugs to proteins has been a predominant hypothesis for the mechanism of toxicity caused by numerous drugs. The development of efficient and sensitive analytical methods for the separation, identification, quantification of drug–protein adducts have important clinical and toxicological implications. In the last few decades, continuous progress in analytical methodology has been achieved with substantial increase in the number of new, more specific and more sensitive methods for drug–protein adducts. The methods used for drug–protein adduct studies include those for separation and for subsequent detection and identification. Various chromatographic (e.g., affinity chromatography, ion-exchange chromatography, and high-performance liquid chromatography) and electrophoretic techniques [e.g., sodium dodecyl sulfate–polyacrylamide gel electrophoresis (SDS–PAGE), two-dimensional SDS–PAGE, and capillary electrophoresis], used alone or in combination, offer an opportunity to purify proteins adducted by reactive drug metabolites. Conventionally, mass spectrometric (MS), nuclear magnetic resonance, and immunological and radioisotope methods are used to detect and identify protein targets for reactive drug metabolites. However, these methods are labor-intensive, and have provided very limited sequence information on the target proteins adducted, and thus the identities of the protein targets are usually unknown. Moreover, the antibody-based methods are limited by the availability, quality, and specificity of antibodies to protein adducts, which greatly hindered the identification of specific protein targets of drugs and their clinical applications. Recently, the use of powerful MS technologies (e.g., matrix-assisted laser desorption/ionization time-of-flight) together with analytical proteomics have enabled one to separate, identify unknown protein adducts, and establish the sequence context of specific adducts by offering the opportunity to search for adducts in proteomes containing a large number of proteins with protein adducts and unmodified proteins. The present review highlights the separation and detection technologies for drug–protein adducts, with an emphasis on methodology, advantages and limitations to these techniques. Furthermore, a brief discussion of the application of these techniques to individual drugs and their target proteins will be outlined.
Subject Basic Pharmacology
Keyword(s) drug-protein adducts
aldehyde dehydrogenase
binding protein
carbamoyl phosphate synthase
cytochrome P450 1A2
cytochrome P450 2C
cytochrome P450 2D6
cytochrome P450 3A4
formate tetrahydrofolate ligase
glutamate ammonia ligase
glutamate dehydrogenase
glutathione peroxidase
initiation factor
lamin A
microsome enzyme
protein disulfide isomerase
proton transporting adenosine triphosphate synthase
tienilic acid
DOI - identifier 10.1016/S1570-0232(03)00399-4
Copyright notice © 2003 Elsevier B.V. All rights reserved.
ISSN 1570-0232
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