Endotoxin suppresses the oltipraz-mediated induction of major hepatic glutathione transferases and cytochromes P450 in the rat

Authors

  • Karine Mahéo,

    1. INSERM Unité 456, Détoxication et Réparation Tissulaire, Faculté des Sciences Pharmaceutiques et Biologiques, Université de Rennes I, Rennes, France
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  • Fabrice Morel Ph.D.,

    Corresponding author
    1. INSERM Unité 456, Détoxication et Réparation Tissulaire, Faculté des Sciences Pharmaceutiques et Biologiques, Université de Rennes I, Rennes, France
    • INSERM Unité 456, Faculté des Sciences Pharmaceutiques et Biologiques, Université de Rennes I, 2 avenue Léon Bernard 35043 Rennes cedex, France. Fax: 33-2-99-33-6242
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  • Jocelyne Antras-Ferry,

    1. INSERM Unité 456, Détoxication et Réparation Tissulaire, Faculté des Sciences Pharmaceutiques et Biologiques, Université de Rennes I, Rennes, France
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  • Sophie Langouët,

    1. INSERM Unité 456, Détoxication et Réparation Tissulaire, Faculté des Sciences Pharmaceutiques et Biologiques, Université de Rennes I, Rennes, France
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  • Fabienne Desmots,

    1. INSERM Unité 456, Détoxication et Réparation Tissulaire, Faculté des Sciences Pharmaceutiques et Biologiques, Université de Rennes I, Rennes, France
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  • Laurent Corcos,

    1. INSERM Unité 456, Détoxication et Réparation Tissulaire, Faculté des Sciences Pharmaceutiques et Biologiques, Université de Rennes I, Rennes, France
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  • André Guillouzo

    1. INSERM Unité 456, Détoxication et Réparation Tissulaire, Faculté des Sciences Pharmaceutiques et Biologiques, Université de Rennes I, Rennes, France
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  • Karine Mahéo is a recipient of a fellowship from the Ministère de la Recherche et de l'Enseignement Supérieur, and Sophie Langouët is a recipient of a fellowship from the Association pour la Recherche sur le Cancer.

Abstract

The effect of Escherichia coli lipopolysaccharide (LPS), a classic inducer of the acute-phase response, has been analyzed on both constitutive and oltipraz (a chemoprotective agent)-inducible messenger RNAs (mRNAs) and enzyme activities of major cytochromes P450 (CYPs) and glutathione transferases (rGSTs) in rat liver. At the dose administered (1 mg/kg) and the time studied (6 and 24 hours), endotoxin had no effect on the expression of either CYPs and GSTs with the exception of CYP1A2, which was reduced at both mRNA and activity levels. A strong increase of rGSTA1/2, rGSTM1, rGSTP1, CYP1A2, CYP2B1/2, and CYP2E1 was observed after 3 days of treatment with oltipraz (0.075%, wt/wt). Oltipraz induction of these enzymes (with the exception of CYP2E1) was found to be suppressed at both mRNA, protein, and activity levels during the acute-phase response to endotoxin. Moreover, it is shown that oltipraz induction of CYP1A2 and CYP2B1/2 and its suppression by E. coli LPS occurred at a transcriptional level. These data support the idea that the chemoprotective effect of oltipraz is altered in the course of inflammation and that adaptation in chemoprotective strategies should be considered in certain physiopathologic situations.

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