Nonsteroidal anti-inflammatory drugs (NSAIDs) can cause idiosyncratic liver injury. Mechanisms involved in NSAID-induced liver injury are complex. Previous studies have suggested that acyl glucuronide of NSAIDs (NSAIDs-Glu) plays an important role in the development of liver injury via covalently binds to proteins and the resultant adduct induces immunological toxicity. As only some NSAIDs-Glu are commercially available, the evaluation of covalent protein adduct formation using ready-made NSAIDs-Glu is difficult and inconvenient. Moreover, glucuronidation potency varies with the NSAID, including stereoisomers. Therefore, in this study, we simultaneously examined the glucuronidation and covalent adduct formation using enantiomers of parent NSAIDs (ibuprofen, naproxen, pranoprofen, ketoprofen, and flurbiprofen) in rat liver microsomes. Glucuronides and covalent adducts were quantified by HPLC. The amount of covalent adduct increased with NSAIDs-Glu formation in the rat liver microsomes in a time-dependent manner. A significant positive correlation was observed between the AUC of NSAIDs-Glu and that of covalent adduct, except ketoprofen. Although ketoprofen exhibited the highest glucuronidation rate among the NSAIDs investigated, the amount of covalent adduct was similar to that for pranoprofen, which had the lowest glucuronidation rate. Thus, it may be difficult for ketoprofen glucuronide to covalently bind with proteins in the rat liver microsomes. Our results suggested that the amount of glucuronide formed is a key factor in predicting covalent bond formation with protein in NSAIDs, in addition to degradability and bindability with proteins of NSAIDs-Glu. Further studies are required to confirm the relationship between the tendency of glucuronidation and the formation of covalent adducts of NSAIDs.
Download full-text PDF |
Source |
|---|---|
| http://dx.doi.org/10.1016/j.ejps.2017.11.018 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
JAK3 Inhibitors: Covalent and Noncovalent Interactions of a Cyanamide Group Investigated by Multiscale Free-Energy Simulations.
J Chem Inf Model
January 2025
Medicinal Chemistry and Drug Design Technologies Department, Chiesi Farmaceutici S.p.A., Largo F. Belloli 11/A, 43122 Parma, Italy.
Janus kinase type 3 (JAK3), an emerging target for treating autoimmune diseases, possesses a front pocket cysteine that is targeted by covalent modifiers, best represented by the marketed drug ritlecitinib (). Recently, 2,3-dihydro-1-inden-1-ylcyanamides have been developed as novel JAK3 inhibitors. Among them, the -(6-(7-pyrrolo[2,3-]pyrimidin-4-yl)-2,3-dihydro-1-inden-1-yl)cyanamide inhibitor () and its methylated analogue (), while being potent inhibitors, displayed different mechanisms of action (covalent vs noncovalent) and binding modes (Casimiro-Garcia et al.
View Article and Find Full Text PDFProgress in Tandem Mass Spectrometry Data Analysis for Nucleic Acids.
Mass Spectrom Rev
January 2025
Department of Chemistry, University of Texas at Austin, Austin, Texas, USA.
Mass spectrometry (MS) has become a critical tool in the characterization of covalently modified nucleic acids. Well-developed bottom-up approaches, where nucleic acids are digested with an endonuclease and the resulting oligonucleotides are separated before MS and MS/MS analysis, provide substantial insight into modified nucleotides in biological and synthetic nucleic. Top-down MS presents an alternative approach where the entire nucleic acid molecule is introduced to the mass spectrometer intact and then fragmented by MS/MS.
View Article and Find Full Text PDFUnveiling the enzymatic pathway of UMG-SP2 urethanase: insights into polyurethane degradation at the atomic level.
Chem Sci
December 2024
LAQV@REQUIMTE, Departamento de Química e Bioquímica, Faculdade de Ciências, Universidade do Porto Rua do Campo Alegre s/n 4169-007 Porto Portugal
The recently discovered metagenomic urethanases UMG-SP1, UMG-SP2, and UMG-SP3 have emerged as promising tools to establish a bio-based recycling approach for polyurethane (PU) waste. These enzymes are capable of hydrolyzing urethane bonds in low molecular weight dicarbamates as well as in thermoplastic PU and the amide bond in polyamide employing a Ser-Ser -Lys triad for catalysis, similar to members of the amidase signature protein superfamily. Understanding the catalytic mechanism of these urethanases is crucial for enhancing their enzymatic activity and improving PU bio-recycling processes.
View Article and Find Full Text PDFExploring Stibanyl Ligand for Accessing Arsinidene and Arsaketene Adducts, and Phosphaketene.
Inorg Chem
January 2025
College of Material, Chemistry and Chemical Engineering, Key Laboratory of Organosilicon Chemistry and Material Technology, Ministry of Education, Hangzhou Normal University, Hangzhou 311121, China.
The salt metathesis reaction involving a diamine-based antimony chloride precursor with sodium arsaethynolate in the presence of PMe leads to the formation of stibanyl-functionalized PMe-arsinidene (). Detailed analyses through single-crystal X-ray diffraction and density functional theory of confirm the presence of covalent Sb-As bonds and reveal its polarized nature with a multiple-bond character. In contrast to the formation of complex , substituting PMe with xylyl isocyanide or 1,3-diisopropyl-4,5-dimethyl-imidazolin-2-ylidene () produces an isocyanide-arsinidene adduct () and an -arsaketene complex (), respectively.
View Article and Find Full Text PDFPolyamine Adducts with AP Sites: Interaction with DNA Polymerases and AP Endonucleases.
Chem Res Toxicol
January 2025
SB RAS Institute of Chemical Biology and Fundamental Medicine, 8 Lavrentieva Avenue, Novosibirsk 630090, Russia.
Biological polyamines, such as spermine, spermidine, and putrescine, are abundant intracellular compounds mostly bound to nucleic acids. Due to their nucleophilic nature, polyamines easily react with apurinic/apyrimidinic (AP) sites, DNA lesions that are constantly formed in DNA by spontaneous base loss and as intermediates of base excision repair. A covalent intermediate is formed, promoting DNA strand cleavage at the AP site, and is later hydrolyzed regenerating the polyamine.
View Article and Find Full Text PDFWant AI Summaries of new PubMed Abstracts delivered to your In-box?
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!