Association between the Risk of Drug-induced Liver Injury and the Reactive Metabolites Acyl Glucuronides

Acyl glucuronides (AG), reactive metabolites formed via the glucuronidation of carboxylic acid-containing drugs such as non-steroidal anti-inflammatory drugs (NSAIDs), are closely associated with drug-induced liver injury (DILI), particularly idiosyncratic types. AG can covalently bind to proteins, potentially disrupting their function and triggering immune responses. Their toxicity is influenced by chemical instability, stereoselectivity, and interactions with specific uridine 5'-diphospho-glucuronosyltransferase (UGT) isoforms. Transporters such as multidrug resistance-associated protein 2 (MRP2) and breast cancer resistance protein (BCRP) mediate AG disposition, while enzymes like β-glucuronidase and esterases regulate AG degradation. Studies have shown that AG derived from NSAIDs differ in their ability to form protein adducts, with propionic acid derivatives exhibiting higher reactivity. Glutathione (GSH), a key detoxifying molecule, plays a critical role in mitigating AG toxicity. GSH depletion in rats has been shown to increase AG accumulation and protein binding, even for drugs generally considered safe. Quantitative analysis of AG formation, degradation, and protein binding using liver microsomes and LC-MS/MS has revealed that AG degradation rates can distinguish between safe drugs, those requiring a warning, and those withdrawn. Furthermore, AG exhibit stereoselective binding to UGTs, with R-enantiomers often showing higher reactivity. These findings underscore the importance of evaluating AG kinetics and protein interactions in predicting DILI risk. Future research should focus on the qualitative assessment of AG-protein adducts and the development of personalized risk models. Integrating AG behavior into drug safety evaluations may enhance the prediction and prevention of DILI, contributing to safer drug development and regulatory strategies.