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Research ArticleArticle

Interaction of the Electrophilic Ketoprofenyl-Glucuronide and Ketoprofenyl-Coenzyme A Conjugates with Cytosolic Glutathione S-Transferases

Sandra Osbild, Jérome Bour, Benoît Maunit, Cécile Guillaume, Carine Asensio, Jean-François Muller, Patrick Netter, Glbert Kirsch, Denyse Bagrel, Françoise Lapicque and Eric Battaglia
Drug Metabolism and Disposition February 2008, 36 (2) 260-267; DOI: https://doi.org/10.1124/dmd.107.016808
Sandra Osbild
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Jérome Bour
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Benoît Maunit
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Cécile Guillaume
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Carine Asensio
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Jean-François Muller
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Patrick Netter
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Glbert Kirsch
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Denyse Bagrel
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Françoise Lapicque
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Eric Battaglia
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Abstract

Carboxylic acid-containing drugs are metabolized mainly through the formation of glucuronide and coenzyme A esters. These conjugates have been suspected to be responsible for the toxicity of several nonsteroidal anti-inflammatory drugs because of the reactivity of the electrophilic ester bond. In the present study we investigated the reactivity of ketoprofenyl-acylglucuronide (KPF-OG) and ketoprofenyl-acyl-coenzyme A (KPF-SCoA) toward cytosolic rat liver glutathione S-transferases (GST). We observed that KPF-SCoA, but not KPF-OG inhibited the conjugation of 1-chloro-2,4-dinitrobenzene and 4-nitroquinoline N-oxide catalyzed by both purified cytosolic rat liver GST and GST from FAO and H5-6 rat hepatoma cell lines. Photoaffinity labeling with KPF-SCoA suggested that the binding of this metabolite may overlap the binding site of 4-methylumbelliferone sulfate. Furthermore, high-performance liquid chromatography and mass spectrometry analysis showed that both hydrolysis and transacylation reactions were observed in the presence of GST and glutathione. The formation of ketoprofenyl-S-acyl-glutathione could be kinetically characterized (apparent Km = 196.0 ± 70.6 μM). It is concluded that KPF-SCoA is both a GST inhibitor and a substrate of a GST-dependent transacylation reaction. The reactivity and inhibitory potency of thioester CoA derivatives toward GST may have potential implications on the reported in vivo toxicity of some carboxylic acid-containing drugs.

Footnotes

  • This work was supported in part by Région de Lorraine. S.O. is a recipient of a fellowship from Ministère de la Recherche et de l'Enseignement Supérieur (France).

  • Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.

  • doi:10.1124/dmd.107.016808.

  • ABBREVIATIONS: NSAID, nonsteroidal anti-inflammatory drug; KPF, ketoprofen (2-(3-benzoylphenyl) propionic acid); COX, cyclooxygenase; KPF-OG, ketoprofenyl-acylglucuronide; KPF-SCoA, ketoprofenyl-acyl-Coenzyme A; GST, glutathione S-transferase(s); GSH, glutathione reduced form; CDNB, 1-chloro-2,4-dinitrobenzene; NQO, 4-nitroquinoline N-oxide; HPLC, high-performance liquid chromatography; MALDI-TOF, matrix-assisted laser desorption ionization/time of flight; PSD, post source decay; MS, mass spectroscopy; KPF-SG, ketoprofenyl-S-acyl-glutathione; 4-MU sulfate, 4-methylumbelliferone sulfate.

    • Received May 23, 2007.
    • Accepted October 24, 2007.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 36 (2)
Drug Metabolism and Disposition
Vol. 36, Issue 2
1 Feb 2008
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Research ArticleArticle

Interaction of the Electrophilic Ketoprofenyl-Glucuronide and Ketoprofenyl-Coenzyme A Conjugates with Cytosolic Glutathione S-Transferases

Sandra Osbild, Jérome Bour, Benoît Maunit, Cécile Guillaume, Carine Asensio, Jean-François Muller, Patrick Netter, Glbert Kirsch, Denyse Bagrel, Françoise Lapicque and Eric Battaglia
Drug Metabolism and Disposition February 1, 2008, 36 (2) 260-267; DOI: https://doi.org/10.1124/dmd.107.016808

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Research ArticleArticle

Interaction of the Electrophilic Ketoprofenyl-Glucuronide and Ketoprofenyl-Coenzyme A Conjugates with Cytosolic Glutathione S-Transferases

Sandra Osbild, Jérome Bour, Benoît Maunit, Cécile Guillaume, Carine Asensio, Jean-François Muller, Patrick Netter, Glbert Kirsch, Denyse Bagrel, Françoise Lapicque and Eric Battaglia
Drug Metabolism and Disposition February 1, 2008, 36 (2) 260-267; DOI: https://doi.org/10.1124/dmd.107.016808
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