One-electron oxidation of diclofenac by human cytochrome P450s as a [potential] bioactivation mechanism for formation of 2’-(glutathion-S-yl)-deschloro-diclofenac Adapted from: One-electron oxidation of diclofenac by human cytochrome P450s as a [potential] bioactivation mechanism for formation of 2’-(glutathion-S-yl)-deschloro-diclofenac
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Studies on cytochrome P-450-mediated bioactivation of diclofenac in rats and in human hepatocytes: identification of glutathione conjugated metabolites.
The nonsteroidal anti-inflammatory drug diclofenac causes a rare but potentially fatal hepatotoxicity that may be associated with the formation of reactive metabolites. In this study, three glutathione (GSH) adducts, namely 5-hydroxy-4-(glutathion-S-yl)diclofenac (M1), 4'-hydroxy-3'-(glutathion-S-yl)diclofenac (M2), and 5-hydroxy-6-(glutathion-S-yl)diclofenac (M3), were identified by liquid chr...
متن کاملIdentification of a novel glutathione adduct of diclofenac, 4'-hydroxy-2'-glutathion-deschloro-diclofenac, upon incubation with human liver microsomes.
Clinical use of the nonsteroidal anti-inflammatory drug diclofenac (DF) is associated with an incidence of idiosyncratic hepatoxicity. The formation of reactive metabolites of DF in vivo has been proposed to be responsible for such toxicity. One type of reactive metabolite, a benzoquinone imine of DF formed through oxidation by cytochromes P450, can be trapped by glutathione in vitro in liver m...
متن کاملDmd061689 309..316
39-Hydroxy-49-methoxydiclofenac (VI) is a human-specific metabolite known to accumulate in the plasma of patients after repeated administration of diclofenac sodium. Diclofenac also produces glutathioneconjugated metabolites, some of which are human-specific. In the present study, we investigated whether these metabolites could be generated in humanized chimeric mice produced from TK-NOG mice. ...
متن کاملDetection of a novel reactive metabolite of diclofenac: evidence for CYP2C9-mediated bioactivation via arene oxides.
A new glutathione adduct (M4) was tentatively identified, likely as 2'-hydroxy-3'-(glutathione-S-yl)-monoclofenac, using liquid chromatography-tandem mass spectrometry analysis of incubations of diclofenac with human liver microsomes. The same conjugate was not detected in incubations with either rat or monkey liver microsomes. Formation of M4 was mediated specifically by CYP2C9 in human liver ...
متن کاملShort Communication A Novel Bioactivation Pathway for 2-[2-(2,6-Dichlorophenyl) aminophenyl]ethanoic Acid (Diclofenac) Initiated by Cytochrome P450-Mediated Oxidative Decarboxylation
Diclofenac (2-[2-(2,6-dichlorophenyl)aminophenyl]ethanoic acid), a nonsteroidal antiinflammatory drug, undergoes bioactivation by cytochrome P450 oxidation to chemically reactive metabolites that are capable of reacting with endogenous nucleophiles such as glutathione (GSH) and proteins and that may play a role in the idiosyncratic hepatotoxicity associated with the drug. Here, we investigated ...
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تاریخ انتشار 2013