CYP1A1 induction and CYP3A4 inhibition by the fungicide imazalil in the human intestinal Caco-2 cells-comparison with other conazole pesticides.
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.
Sergent
Thérèse
T
Biochimie cellulaire, nutritionnelle & toxicologique, Institut des Sciences de la Vie, Université catholique de Louvain, Croix du Sud 5, B-1348 Louvain-la-Neuve, Belgium.
Dupont
Isabelle
I
Jassogne
Coralie
C
Ribonnet
Laurence
L
van der Heiden
Edwige
E
Scippo
Marie-Louise
ML
Muller
Marc
M
McAlister
Dan
D
Pussemier
Luc
L
Larondelle
Yvan
Y
Schneider
Yves-Jacques
YJ
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000037:antagonists & inhibitors / Q000378:metabolism; D000935:Antifungal Agents / Q000494:pharmacology; D018938:Caco-2 Cells; D002117:Calcitriol / Q000494:pharmacology; D002851:Chromatography, High Pressure Liquid; D019363:Cytochrome P-450 CYP1A1 / Q000096:biosynthesis*; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism; D065692:Cytochrome P-450 CYP3A Inhibitors; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004790:Enzyme Induction; D004791:Enzyme Inhibitors / Q000494:pharmacology* / Q000633:toxicity; D005506:Food Contamination; D005659:Fungicides, Industrial / Q000494:pharmacology* / Q000633:toxicity; D005982:Glutathione Transferase / Q000378:metabolism; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology* / Q000633:toxicity; D007413:Intestinal Mucosa / Q000187:drug effects* / Q000201:enzymology; D007654:Ketoconazole / Q000494:pharmacology; D007700:Kinetics; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D000072317:Polychlorinated Dibenzodioxins / Q000494:pharmacology; D012333:RNA, Messenger / Q000096:biosynthesis; D018336:Receptors, Aryl Hydrocarbon / Q000187:drug effects; D013056:Spectrophotometry, Ultraviolet; D014230:Triazoles / Q000494:pharmacology
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D000935:Antifungal Agents; D002117:Calcitriol; D019363:Cytochrome P-450 CYP1A1; D051544:Cytochrome P-450 CYP3A; D065692:Cytochrome P-450 CYP3A Inhibitors; D004791:Enzyme Inhibitors; D005659:Fungicides, Industrial; D005982:Glutathione Transferase; D007093:Imidazoles; D007654:Ketoconazole; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D009363:Neoplasm Proteins; D000072317:Polychlorinated Dibenzodioxins; D012333:RNA, Messenger; D018336:Receptors, Aryl Hydrocarbon; D014230:Triazoles; C000715087:ABCC2 protein, human; C116614:ABCG2 protein, human; C045950:propiconazole; C087114:tebuconazole; C017435:enilconazole; C510163:CYP3A4 protein, human