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Drug Metabolism and Disposition Fast Forward
First published on October 25, 2007; DOI: 10.1124/dmd.107.016808

0090-9556/08/3602-260-267$20.00
DMD 36:260-267, 2008

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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

Laboratoire d'Ingénierie Moléculaire et Biochimie Pharmacologique, Institut Jean Barriol FR Centre National de la Recherche Scientifique 2843, Université Paul Verlaine-Metz, Metz, France (S.O., G.K., D.B., E.B.); Laboratoire de Spectrométrie de Masse et de Chimie Laser, Institut Jean Barriol FR Centre National de la Recherche Scientifique 2843, Université Paul Verlaine-Metz, Metz Technopole, France (J.B., B.M., J.F.M.); and Unité Mixte de Recherche 7561, Centre National de la Recherche Scientifique-UHP, Physiopathologie et Pharmacologie Articulaires, Facultéde Médecine-BP 184, Vandoeuvre les Nancy, Nancy, France (C.G., C.A., P.N., F.L.)

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.

Address correspondence to: Dr. Eric Battaglia, LIMBP, Université Paul Verlaine-Metz, rue Général Delestraint, 57070 Metz, France. E-mail: battaglia{at}univ-metz.fr






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