Xenobiotic Acyl Glucuronides and Acyl CoA Thioesters as Protein- Reactive Metabolites With the Potential to Cause Idiosyncratic Drug Reactions
Some carboxylic acid-containing drugs have been implicated in rare but serious adverse reactions. These compounds can be bioactivated via two distinct pathways: by UDP-glucuronosyltransferase-catalyzed conjugation with glucuronic acid, resulting in the formation of acyl glucuronides, or by acyl-CoA synthetase-catalyzed formation of acyl- CoA thioesters. This review compares the two types of potentially reactive metabolites with respect to their stability, protein-reactivity, target selectivity, and disposition in the liver, and summarizes the evidence which links acyl glucuronide and acyl-CoA thioester formation with downstream toxicologic effects. While with increasing drug concentration the acyl glucuronide pathway may prevail, CoA intermediates may be more reactive. Both metabolites are electrophilic species which can acylate target proteins if they escape inactivation by S-glutathione-thioester formation. A crucial factor is the up-concentration of acyl glucuronides in hepatocytes and the biliary tree, due to vectorial transport by conjugate export pumps, where they may selectively acylate canalicular membrane proteins. Furthermore, positional isomers, which are avidly formed by acyl migration, can glycate proteins in the liver and at more distal sites. In contrast, acyl-CoA esters may be more rapidly hydrolysed or further metabolized in hepatocytes, and their hepatobiliary transport has not been well explored. While there is accumulating evidence that acyl glucuronides can alter cellular function by various mechanisms, including haptenation of peptides, critical protein acylation or glycation, or direct stimulation of neutrophils and macrophages, the role of acyl-CoA intermediates is less clear. More work is needed to provide a causal link between protein-reactive acyl glucuronides and acyl-CoA thioesters and the rare and unpredictable idiosyncratic drug reactions in humans.
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Document Type: Review Article
Publication date: August 1, 2002
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- Current Drug Metabolism aims to cover all the latest and outstanding developments in drug metabolism and disposition. The journal serves as an international forum for the publication of timely reviews in drug metabolism. Current Drug Metabolism is an essential journal for academic, clinical, government and pharmaceutical scientists who wish to be kept informed and up-to-date with the latest and most important developments. The journal covers the following areas:
In vitro systems including CYP-450; enzyme induction and inhibition; drug-drug interactions and enzyme kinetics; pharmacokinetics, toxicokinetics, species scaling and extrapolations; P-glycoprotein and transport carriers; target organ toxicity and interindividual variability; drug metabolism and disposition studies; extrahepatic metabolism; phase I and phase II metabolism; recent developments for the identification of drug metabolites and adducts.
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