Studies on the reactivity of acyl glucuronides-VI. Modulation of reversible and covalent interaction of diflunisal acyl glucuronide and its isomers with human plasma protein in vitro

Williams A.M. and Dickinson R.G. (1994) Studies on the reactivity of acyl glucuronides-VI. Modulation of reversible and covalent interaction of diflunisal acyl glucuronide and its isomers with human plasma protein in vitro. Biochemical Pharmacology, 47 3: 457-467. doi:10.1016/0006-2952(94)90176-7


Author Williams A.M.
Dickinson R.G.
Title Studies on the reactivity of acyl glucuronides-VI. Modulation of reversible and covalent interaction of diflunisal acyl glucuronide and its isomers with human plasma protein in vitro
Journal name Biochemical Pharmacology   Check publisher's open access policy
ISSN 0006-2952
Publication date 1994-02-09
Sub-type Article (original research)
DOI 10.1016/0006-2952(94)90176-7
Volume 47
Issue 3
Start page 457
End page 467
Total pages 11
Subject 3004 Pharmacology
Abstract Acyl glucuronide conjugates are chemically reactive metabolites which can undergo hydrolysis, rearrangement (isomerization via acyl migration) and covalent binding reactions with protein. The present study was undertaken to identify factors modulating the reactivity of diflunisal acyl glucuronide (DAG) with human serum albumin (HSA) in vitro, by comprehensively evaluating the interplay of the three pathways above when DAG and a mixture of its 2-, 3- and 4-isomers (iso-DAG) were incubated with protein. Buffer, plasma, fraction V HSA, fatty acid-free HSA, globulin-free HSA and fatty acid- and globulin-free HSA were investigated at pH 7.4 and 37°, each in the absence and presence of warfarin, diazepam and diflunisal (DF) as reversible binding competitors. DAG and iso-DAG were highly reversibly bound (ca. 98-99.5%) in plasma and HSA solutions. The binding was primarily at the benzodiazepine site, since displacement occurred in the presence of diazepam and fatty acids but not warfarin. DAG degradation, via rearrangement, hydrolysis and covalent adduct formation (in that order of quantitative importance), was retarded in plasma and HSA solutions compared to buffer. The protective effect of protein was afforded by the high reversible binding to the (non-catalytic) benzodiazepine site. The warfarin site appeared to be catalytic for DAG hydrolysis, whereas rearrangement appeared to be hydroxide ion-catalysed only. In contrast to DAG, iso-DAG degradation was greatly accelerated in the presence of protein, through both covalent binding and catalysis of hydrolysis. Covalent binding via DAG was increased in the presence of warfarin but decreased in the presence of diazepam, DF and fatty acids. The opposite effects were found for covalent binding via iso-DAG. The data suggest that covalent binding of DF to HSA via DAG and iso-DAG occurs by different mechanisms (presumably transacylation and glycation, respectively) at different sites (benzodiazepine and warfarin, respectively) whereas reversible binding occurs primarily at the same site (benzodiazepine).
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status Unknown

Document type: Journal Article
Sub-type: Article (original research)
Collection: Scopus Import
 
Versions
Version Filter Type
Citation counts: Scopus Citation Count Cited 60 times in Scopus Article | Citations
Google Scholar Search Google Scholar
Created: Tue, 28 Jun 2016, 01:24:47 EST by System User