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Vol. 56, Issue 1, 226-234, July 1999

Human and Rat Liver UDP-Glucuronosyltransferases Are Targets of Ketoprofen Acylglucuronide

Nadège Terrier, Etienne Benoit, Claire Senay, Françoise Lapicque, Anna Radominska-Pandya, Jacques Magdalou, and Sylvie Fournel-Gigleux

Unité Mixte de Recherche 7561 Centre National de la Recherche Scientifique-Université Henri Poincaré Nancy 1, Vandoeuvre-lès-Nancy, France (N.T., C.S., F.L., J.M., S.F.-G.); Unité Associée Institut National de la Recherche Agronomique-Direction Générale Enseignement-Recherche, Toxicologie et Métabolisme Comparés des Xénobiotiques, Ecole Nationale Vétérinaire de Lyon, Marcy l'Etoile, France (E.B.); and Department of Biochemistry and Molecular Biology, University of Arkansas for Medical Sciences, Little Rock, Arkansas (A.R.-P.)

Acylglucuronides formed from carboxylic acids by UDP-glucuronosyltransferases (UGTs) are electrophilic metabolites able to covalently bind proteins. In this study, we demonstrate the reactivity of the acylglucuronide from the nonsteroidal anti-inflammatory drug, ketoprofen, toward human and rat liver UGTs. Ketoprofen acylglucuronide irreversibly inhibited the glucuronidation of 1-naphthol and 2-naphthol catalyzed by human liver microsomes or by the recombinant rat liver isoform, UGT2B1, which is the main isoform involved in the glucuronidation of the drug. A decrease of about 35% in the glucuronidation of 2-naphthol was observed when ketoprofen acylglucuronide was produced in situ in cultured V79 cells expressing UGT2B1. Inhibition was always associated with the formation of microsomal protein-ketoprofen adducts. The presence of these covalent adducts within the endoplasmic reticulum of cells expressing UGT2B1 was demonstrated following addition of ketoprofen to culture medium by immunofluorescence microscopy with antiketoprofen antibodies. Immunoblots of liver microsomes incubated with ketoprofen acylglucuronide and probed with antiketoprofen antibodies revealed the presence of several protein adducts; among those was a major immunoreactive protein at 56 kDa, in the range of the apparent molecular mass of UGTs. The adduct formation partially prevented the photoincorporation of the UDP-glucuronic acid (UDP-GlcUA) analog, [beta -32P]5N3UDP-GlcUA, on the UGTs, suggesting that ketoprofen glucuronide covalently reacted with the UDP-GlcUA binding domain. Finally, UGT purification from rat liver microsomes incubated with ketoprofen glucuronide led to the isolation of UGT adducts recognized by both anti-UGT and antiketoprofen antibodies, providing strong evidence that UGTs are targets of this metabolite.

Copyright © 1999 by The American Society for Pharmacology and Experimental Therapeutics


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Copyright © 1999 by the American Society for Pharmacology and Experimental Therapeutics