Stereoselective Covalent Adduct Formation of Acyl Glucuronide Metabolite of Nonsteroidal Anti-Inflammatory Drugs with UDP-Glucuronosyltransferase |
| |
| Authors: | Atsushi Kawase Rio Yamashita Tsubasa Yoshizato Mashiro Yoshikawa Hiroaki Shimada Masahiro Iwaki |
| |
| Affiliation: | 1.Department of Pharmacy, Faculty of Pharmacy, Kindai University, Osaka 577-8502, Japan; (R.Y.); (T.Y.); (M.Y.); (H.S.); (M.I.);2.Pharmaceutical Research and Technology Institute, Kindai University, Osaka 577-8502, Japan;3.Antiaging Center, Kindai University, Osaka 577-8502, Japan |
| |
| Abstract: | A reactive metabolite of nonsteroidal anti-inflammatory drugs (NSAIDs), acyl-β-D-glucuronide (AG), covalently binds to endogenous proteins. The covalent adduct formation of NSAIDs-AG may lead to the dysfunction of target proteins. Therefore, it is important to clarify the detailed characterization of the formation of covalent protein adducts of NSAID-AG. UDP-glucuronosyltransferase (UGT) catalyzes the conversion of NSAIDs to NSAIDs-AG. The aim of this study was to perform a quantitative analysis of the covalent adduct formation of NSAIDs-AG with UGT. Diclofenac-AG and ketoprofen-AG formed covalent adducts with organelle proteins. Next, the number of covalent adducts formed between NSAIDs-AG and UGT isoforms (UGT1A1, UGT1A9, UGT2B4, and UGT2B9) was determined. The capacity of diclofenac-AG to form covalent adducts with UGT1A9 or UGT2B7 was approximately 10 times higher than that of mefenamic acid-AG. The amounts of covalent adducts of AG of propionic acid derivative NSAIDs with UGT2B were higher than those with UGT1A. Stereoselectivity was observed upon covalent binding to UGT. A significant negative correlation between the half-lives of NSAIDs-AG in phosphate buffers and the amount of covalent adduct with UGT2B7 was observed, suggesting the more labile NSAID-AG forms higher irreversible bindings to UGT. This report provides comprehensive information on the covalent adduct formation of NSAIDs-AGs with UGT. |
| |
| Keywords: | NSAIDs glucuronidation glucuronide stereoselective liver injury covalent adduct endoplasmic reticulum |
|
|
