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Drug Metabolism and Disposition Fast Forward
First published on November 28, 2006; DOI: 10.1124/dmd.106.012880

0090-9556/07/3502-306-314$20.00
DMD 35:306-314, 2007

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Induction of Glutathione Synthesis Explains Pharmacodynamics of High-Dose Busulfan in Mice and Highlights Putative Mechanisms of Drug Interaction

Jérôme Bouligand, Alain Deroussent, Nicolas Simonnard, Paule Opolon, Jackie Morizet, Elisabeth Connault, Estelle Daudigeos, Micheline Re, Angelo Paci, and Gilles Vassal

Unité Propre de Recherche et de l'Enseignement Supérieur, Equipe d'Accueil 3535, Pharmacology and New Treatments of Cancers, IFR54, University Paris XI and Institut Gustave Roussy, Villejuif, France (J.B., N.S., J.M., E.D., M.R., A.P., G.V.); Mass Spectrometry Platform, IFR54, Institut Gustave Roussy, Villejuif, France (A.D., G.V.); and Unité Mixte de Recherche 8121, Vectorology and Gene Transfer, IFR54, Centre National de la Recherche Scientifique and Institut Gustave Roussy, Villejuif, France (P.O., E.C.)

Busulfan is an example of a drug eliminated through glutathione S-transferase (GST)-catalyzed conjugation with reduced glutathione (GSH). We studied the pharmacokinetics and toxicity of busulfan in C57BL6 mice in correlation with liver GST activity and GSH synthesis by accurate determination of precursors, namely, {gamma}-glutamyl-cysteine and cysteine. A significantly lower incidence of acute toxicity was observed in mice receiving busulfan 16.5 mg/kg twice a day compared with animals receiving 33 mg/kg once a day. In both cases, a total dose of 132 mg/kg was administered over 4 days. The difference in toxicity was explained by pharmacokinetics since a strong induction of clearance was observed only in animals treated twice daily. Induction of metabolism was correlated with an increase in liver cysteine content and enhanced glutathione synthesis rate, whereas GST activity was unchanged. To our knowledge, this is the first time that in vivo flux of GSH synthesis has been shown to be closely related to a drug plasma clearance and toxicity. These results allow hypothesizing that GSH liver synthesis may directly influence busulfan clearance in humans with possible implications in the occurrence of hepatic veno-occlusive disease.

Address correspondence to: Professor Gilles Vassal, UPRES EA3535, Pharmacology and New Treatments of Cancers, Institut Gustave Roussy, 39 rue Camille Desmoulins, Villejuif 94800, France. E-mail: gilles.vassal{at}igr.fr




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I. R. Younis, M. Elliott, C. J. Peer, A. J. L. Cooper, J. T. Pinto, G. W. Konat, M. Kraszpulski, W. P. Petros, and P. S. Callery
Dehydroalanine Analog of Glutathione: An Electrophilic Busulfan Metabolite That Binds to Human Glutathione S-Transferase A1-1
J. Pharmacol. Exp. Ther., December 1, 2008; 327(3): 770 - 776.
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