Abstract
Several carboxylic acid-containing drugs have been withdrawn from clinical use due to adverse drug reactions including idiosyncratic hepatotoxicity and anaphylaxis. Carboxylic acid drugs are increasingly being shown to be metabolized to chemically-reactive acyl-CoA thioester-linked intermediary metabolites that are proposed to potentially mediate these toxicities. Acyl-CoA thioesters possess an electrophilic carbonyl-carbon and are able to undergo non-enzyme catalyzed transacylation reactions with biological nucleophiles leading to covalent binding to protein and drug-protein adduct formation. Such drug-protein adducts are proposed to mediate idiosyncratic drug toxicity reactions to carboxylic acid drugs, similar to the more studied mechanism of chemically-reactive acyl glucuronides potentially mediating carboxylic acid drug toxicity through the formation of immunogenic covalent protein adducts. Carboxylic acid drug acyl-CoA formation is catalyzed by acyl-CoA synthetase enzymes located with highest activity in liver tissue and in mitochondrial, peroxisomal, microsomal, and cytosolic cellular fractions. As is also true for unstable and reactive acyl glucuronide metabolites, the role of reactive acyl-CoA thioester metabolites in mediating idiosyncratic drug toxicity is difficult to assess. Importantly, in comparison to acyl glucuronide formation, results from mechanistic studies have revealed that acyl-CoA thioester formation can be the predominant pathway leading to covalent protein adduct formation in vitro and in vivo. This review includes an examination of the metabolism of carboxylic acid-containing drugs to reactive acyl-CoA thioesters leading to covalent binding to protein and potential implications with regard to carboxylic acid drug toxicity.
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Grillo, M.P., Li, C. & Benet, L.Z. Acyl-CoA thioesters as chemically-reactive intermediates of carboxylic acid-containing drugs. Med Chem Res 32, 2058–2070 (2023). https://doi.org/10.1007/s00044-023-03144-5
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DOI: https://doi.org/10.1007/s00044-023-03144-5