| Bioactivation of lumiracoxib by peroxidases and human liver microsomes: identification of multiple quinone imine intermediates and GSH adducts. | |
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MedLine Citation:
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PMID: 19063590 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Lumiracoxib (Prexige; 2-[(2-fluoro-6-chlorophenyl)amino]-5-methyl-benzeneacetic acid) is a cyclooxygenase-2 selective inhibitor for the symptomatic treatment of osteoarthritis. Recently, the drug has been withdrawn in several countries due to serious liver side effects. Li et al. recently have shown that lumiracoxib is bioactivated to a proposed quinone imine that is trapped by N-acetylcysteine (NAC) to form two NAC adducts in human and rat liver microsomal incubations. The current study demonstrated that the lumiracoxib metabolite 4'-hydroxylumiracoxib (M5) can also be bioactivated by peroxidases such as horseradish peroxidase, myeloperoxidase, and prostaglandin H synthases. Efforts were also made to identify GSH adducts formed by P450s in human liver microsomal incubations of lumiracoxib. We herein report the detection and characterization of mono-, di-, tri-, and tetra-GSH adducts in these oxidizing systems. Most of the conjugates were generated as a result of bioactivation of M5 by both peroxidases and P450s. Quinone imine (M15) and two GSH-conjugated quinone imines (M17 and M18) were identified as intermediates in the formation of these conjugates. The latter two were formed through sequential elimination of the fluorine and chlorine groups of GSH-conjugated M15. An additional GSH adduct, which appeared to be formed directly from parent, was only observed in human liver microsomal incubations. A mechanism was proposed for the bioactivation of lumiracoxib and the formation of the observed GSH adducts. These results suggest that bioactivation of lumiracoxib and M5 may result in GSH depletion, covalent binding to proteins, and oxidative stress and may potentially lead to hepatotoxicity. |
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Authors:
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Ping Kang; Deepak Dalvie; Evan Smith; Matt Renner |
Publication Detail:
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Type: Journal Article |
Journal Detail:
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Title: Chemical research in toxicology Volume: 22 ISSN: 1520-5010 ISO Abbreviation: Chem. Res. Toxicol. Publication Date: 2009 Jan |
Date Detail:
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Created Date: 2009-01-19 Completed Date: 2009-03-30 Revised Date: 2009-11-06 |
Medline Journal Info:
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Nlm Unique ID: 8807448 Medline TA: Chem Res Toxicol Country: United States |
Other Details:
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Languages: eng Pagination: 106-17 Citation Subset: IM |
Affiliation:
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Pharmacokinetics Dynamics and Metabolism, Research Analytical, Pfizer Global Research and Development, 10724 Science Center Drive, San Diego, California 92121, USA. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Benzoquinones
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chemistry,
toxicity Cyclooxygenase 2 Inhibitors / chemistry*, pharmacology, toxicity Diclofenac / analogs & derivatives*, chemistry, pharmacology, toxicity Glutathione / chemistry*, metabolism Humans Imines / chemistry, toxicity Microsomes, Liver / metabolism* Peroxidases / metabolism* Spectrophotometry, Ultraviolet |
| Chemical | |
Reg. No./Substance:
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0/Benzoquinones; 0/Cyclooxygenase 2 Inhibitors; 0/Imines; 0/lumiracoxib; 106-51-4/benzoquinone; 15307-86-5/Diclofenac; 70-18-8/Glutathione; EC 1.11.1.-/Peroxidases |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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