title: Abacavir forms novel cross-linking abacavir protein adducts in patients.
abstract: Abacavir (ABC), a nucleoside-analogue reverse transcriptase inhibitor, is associated with severe hypersensitivity reactions that are thought to involve the activation of CD8+ T cells in a HLA-B*57:01-restricted manner. Recent studies have claimed that noncovalent interactions of ABC with HLA-B*57:01 are responsible for the immunological reactions associated with ABC. However, the formation of hemoglobin-ABC aldehyde (ABCA) adducts in patients exposed to ABC suggests that protein conjugation might represent a pathway for antigen formation. To further characterize protein conjugation reactions, we used mass spectrometric methods to define ABCA modifications in patients receiving ABC therapy. ABCA formed a novel intramolecular cross-linking adduct on human serum albumin (HSA) in patients and in vitro via Michael addition, followed by nucleophilic adduction of the aldehyde with a neighboring protein nucleophile. Adducts were detected on Lys159, Lys190, His146, and Cys34 residues in the subdomain IB of HSA. Only a cysteine adduct and a putative cross-linking adduct were detected on glutathione S-transferase Pi (GSTP). These findings reveal that ABC forms novel types of antigens in all patients taking the drug. It is therefore vital that the immunological consequences of such pathways of haptenation are explored in the in vitro models that have been used by various groups to define new mechanisms of drug hypersensitivity exemplified by ABC.
authors.affiliation: MRC Centre for Drug Safety Science, Department of Molecular and Clinical Pharmacology, University of Liverpool , Sherrington Building, Ashton Street, Liverpool L69 3GE, United Kingdom.
authors.forename: Xiaoli
authors.initials: X
authors.lastname: Meng
authors.forename: Alexandre S
authors.initials: AS
authors.lastname: Lawrenson
authors.forename: Neil G
authors.initials: NG
authors.lastname: Berry
authors.forename: James L
authors.initials: JL
authors.lastname: Maggs
authors.forename: Neil S
authors.initials: NS
authors.lastname: French
authors.forename: David J
authors.initials: DJ
authors.lastname: Back
authors.forename: Saye H
authors.initials: SH
authors.lastname: Khoo
authors.forename: Dean J
authors.initials: DJ
authors.lastname: Naisbitt
authors.forename: B Kevin
authors.initials: BK
authors.lastname: Park
mesh_terms: D000595:Amino Acid Sequence; D001798:Blood Proteins / Q000737:chemistry / Q000378:metabolism*; D015224:Dideoxynucleosides / Q000378:metabolism* / Q000627:therapeutic use; D015658:HIV Infections / Q000097:blood / Q000188:drug therapy*; D006801:Humans; D008969:Molecular Sequence Data; D018894:Reverse Transcriptase Inhibitors / Q000378:metabolism* / Q000627:therapeutic use; D053719:Tandem Mass Spectrometry; D000099227:Abacavir
chemical_list: D001798:Blood Proteins; D015224:Dideoxynucleosides; D018894:Reverse Transcriptase Inhibitors; D000099227:Abacavir