[en] Imazalil (IMA) is a widely used imidazole-antifungal pesticide and. therefore. a food contaminant. This compound is also used as a drug (enilconazole). As intestine is the first site of exposure to ingested drugs and pollutants, we have investigated the effects of IMA, at realistic intestinal concentrations, on xenobiotic-metabolizing enzymes and efflux pumps by using Caco-2 cells, as a validated in vitro model of the human intestinal absorptive epithelium. For comparison, other conazole fungicides, i.e. ketoconazole, propiconazole and tebuconazole. were also studied. IMA induced cytochrome P450 (CYP) 1A1 activity to the same extent as benzo(a)pyrene (B(a)P) or 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), in a dose-and time-dependent manner. Cell-free aryl hydrocarbon receptor (AhR) binding assay and reporter gene assay suggested that IMA is not an AhR-ligand, implying that IMA-mediated induction should involve an AhR-independent pathway. Moreover, IMA strongly inhibited the CYP3A4 activity in 1,25-vitamin D-3-induced Caco-2 cells. The other fungicides had weak or nil effects on CYP activities. Study of the apical efflux pump activities revealed that ketoconazole inhibited both P-glycoprotein (Pgp) and multidrug resistance-associated protein 2 (MRP-2) or breast cancer resistance protein (BCRP), whereas IMA and other fungicides did not. Our results imply that coingestion of IMA-contaminated food and CYP3A4- or CYP1A1-metabolizable drugs or chemicals could lead to drug bioavailability modulation or toxicological interactions, with possible adverse effects for human health. (C) 2008 Elsevier Ireland Ltd. All rights reserved.
Disciplines :
Pharmacy, pharmacology & toxicology
Author, co-author :
Sergent, Thérèse
Dupont, Isabelle
Jassogne, Coralie
Ribonnet, Laurence
Van Der Heiden, Edwige ; Université de Liège - ULiège > Département de sciences des denrées alimentaires > Département de sciences des denrées alimentaires
Scippo, Marie-Louise ; Université de Liège - ULiège > Département de sciences des denrées alimentaires > Analyse des denrées alimentaires
Muller, Marc ; Université de Liège - ULiège > Département des sciences de la vie > GIGA-R : Biologie et génétique moléculaire
McAlister, Dan
Pussemier, Luc
Larondelle, Yvan
Schneider, Yves-Jacques
Language :
English
Title :
CYP1A1 induction and CYP3A4 inhibition by the fungicide imazalil in the human intestinal Caco-2 cells-Comparison with other conazole pesticides
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