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Rapid CommunicationShort Communication

Interactions of Endosulfan and Methoxychlor Involving CYP3A4 and CYP2B6 in Human HepaRG Cells

Camille C. Savary, Rozenn Jossé, Arnaud Bruyère, Fabrice Guillet, Marie-Anne Robin and André Guillouzo
Drug Metabolism and Disposition August 2014, 42 (8) 1235-1240; DOI: https://doi.org/10.1124/dmd.114.057786
Camille C. Savary
Inserm U991, Faculté des Sciences Pharmaceutiques et Biologiques de Rennes (C.C.S., R.J., M.-A.R., A.G.), Université de Rennes 1, Rennes, France; and Xenoblis, Saint-Gregoire, France (A.B., F.G.)
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Rozenn Jossé
Inserm U991, Faculté des Sciences Pharmaceutiques et Biologiques de Rennes (C.C.S., R.J., M.-A.R., A.G.), Université de Rennes 1, Rennes, France; and Xenoblis, Saint-Gregoire, France (A.B., F.G.)
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Arnaud Bruyère
Inserm U991, Faculté des Sciences Pharmaceutiques et Biologiques de Rennes (C.C.S., R.J., M.-A.R., A.G.), Université de Rennes 1, Rennes, France; and Xenoblis, Saint-Gregoire, France (A.B., F.G.)
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Fabrice Guillet
Inserm U991, Faculté des Sciences Pharmaceutiques et Biologiques de Rennes (C.C.S., R.J., M.-A.R., A.G.), Université de Rennes 1, Rennes, France; and Xenoblis, Saint-Gregoire, France (A.B., F.G.)
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Marie-Anne Robin
Inserm U991, Faculté des Sciences Pharmaceutiques et Biologiques de Rennes (C.C.S., R.J., M.-A.R., A.G.), Université de Rennes 1, Rennes, France; and Xenoblis, Saint-Gregoire, France (A.B., F.G.)
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André Guillouzo
Inserm U991, Faculté des Sciences Pharmaceutiques et Biologiques de Rennes (C.C.S., R.J., M.-A.R., A.G.), Université de Rennes 1, Rennes, France; and Xenoblis, Saint-Gregoire, France (A.B., F.G.)
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Abstract

Humans are usually exposed to several pesticides simultaneously; consequently, combined actions between pesticides themselves or between pesticides and other chemicals need to be addressed in the risk assessment. Many pesticides are efficient activators of pregnane X receptor (PXR) and/or constitutive androstane receptor (CAR), two major nuclear receptors that are also activated by other substrates. In the present work, we searched for interactions between endosulfan and methoxychlor, two organochlorine pesticides whose major routes of metabolism involve CAR- and PXR-regulated CYP3A4 and CYP2B6, and whose mechanisms of action in humans remain poorly understood. For this purpose, HepaRG cells were treated with both pesticides separately or in mixture for 24 hours or 2 weeks at concentrations relevant to human exposure levels. In combination they exerted synergistic cytotoxic effects. Whatever the duration of treatment, both compounds increased CYP3A4 and CYP2B6 mRNA levels while differently affecting their corresponding activities. Endosulfan exerted a direct reversible inhibition of CYP3A4 activity that was confirmed in human liver microsomes. By contrast, methoxychlor induced this activity. The effects of the mixture on CYP3A4 activity were equal to the sum of those of each individual compound, suggesting an additive effect of each pesticide. Despite CYP2B6 activity being unchanged and increased with endosulfan and methoxychlor, respectively, no change was observed with their mixture, supporting an antagonistic effect. Altogether, our data suggest that CAR and PXR activators endosulfan and methoxychlor can interact together and with other exogenous substrates in human hepatocytes. Their effects on CYP3A4 and CYP2B6 activities could have important consequences if extrapolated to the in vivo situation.

Footnotes

    • Received February 28, 2014.
    • Accepted May 15, 2014.
  • This work was supported by grants from the Agence Nationale de la Recherche (ANR) [contract NISTEC 09-CESA-003-002] and the Ligue 35 Contre le Cancer.

  • dx.doi.org/10.1124/dmd.114.057786.

  • ↵Embedded ImageThis article has supplemental material available at dmd.aspetjournals.org.

  • Copyright © 2014 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 42 (8)
Drug Metabolism and Disposition
Vol. 42, Issue 8
1 Aug 2014
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Rapid CommunicationShort Communication

Differential P450s Modulation by Pesticides

Camille C. Savary, Rozenn Jossé, Arnaud Bruyère, Fabrice Guillet, Marie-Anne Robin and André Guillouzo
Drug Metabolism and Disposition August 1, 2014, 42 (8) 1235-1240; DOI: https://doi.org/10.1124/dmd.114.057786

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Rapid CommunicationShort Communication

Differential P450s Modulation by Pesticides

Camille C. Savary, Rozenn Jossé, Arnaud Bruyère, Fabrice Guillet, Marie-Anne Robin and André Guillouzo
Drug Metabolism and Disposition August 1, 2014, 42 (8) 1235-1240; DOI: https://doi.org/10.1124/dmd.114.057786
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