title: A novel MDCKII in vitro model for assessing ABCG2-drug interactions and regulation of ABCG2 transport activity in the caprine mammary gland by environmental pollutants and pesticides.
abstract: The ABC efflux transporter ABCG2 represents the main route for active secretion of xenobiotics into milk. Thus, ABCG2 regulation by aryl hydrocarbon receptor (AhR) ligands including ubiquitously environmental pollutants is of great toxicological relevance. However, no adequate in vitro model is as yet available to study AhR-dependent ABCG2 regulation in dairy animals. In this study, we therefore systematically investigated the effect of various environmental contaminants and pesticides on ABCG2 efflux activity in MDCKII cells stably expressing mammary ABCG2 from dairy goats. The AhR-agonists TCDD, Aroclor 1254, prochloraz, and iprodione caused a dose- and time-dependent increase in EROD activity. Moreover, TCDD and prochloraz significantly stimulated ABCG2 transport activity through a dose- and time-dependent induction of transporter gene expression. AhR inhibitors like CH223191 significantly reversed TCDD- and prochloraz-induced stimulation of ABCG2 efflux activity. In contrast, non-AhR activators such as PCB 101 had no significant effect on EROD activity, ABCG2 gene expression or transporter activity. As we identified various anthelmintics including monepantel as potential ABCG2 substrates this regulatory mechanism may result in increased milk residues of potentially harmful xenobiotics. Thus, MDCKII-cABCG2 cells may represent a suitable in vitro model to study mammary ABCG2 secretory activity and its potential regulation by AhR-activating contaminants.
authors.affiliation: Institute of Pharmacology, Pharmacy and Toxicology, Faculty of Veterinary Medicine, Universität Leipzig, An den Tierkliniken 15, 04103 Leipzig, Germany. Electronic address: halwachs@vetmed.uni-leipzig.de.
authors.forename: Sandra
authors.initials: S
authors.lastname: Halwachs
authors.affiliation: Institute of Pharmacology, Pharmacy and Toxicology, Faculty of Veterinary Medicine, Universität Leipzig, An den Tierkliniken 15, 04103 Leipzig, Germany. Electronic address: wassermann@vetmed.uni-leipzig.de.
authors.forename: Louise
authors.initials: L
authors.lastname: Wassermann
authors.affiliation: Institute of Pharmacology, Pharmacy and Toxicology, Faculty of Veterinary Medicine, Universität Leipzig, An den Tierkliniken 15, 04103 Leipzig, Germany. Electronic address: honscha@vetmed.uni-leipzig.de.
authors.forename: Walther
authors.initials: W
authors.lastname: Honscha
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001692:Biological Transport; D019363:Cytochrome P-450 CYP1A1 / Q000378:metabolism; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004785:Environmental Pollutants / Q000008:administration & dosage / Q000633:toxicity*; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D006041:Goats; D061985:Madin Darby Canine Kidney Cells; D008321:Mammary Glands, Animal / Q000187:drug effects* / Q000378:metabolism; D008954:Models, Biological; D010575:Pesticides / Q000633:toxicity*; D013997:Time Factors
chemical_list: D018528:ATP-Binding Cassette Transporters; D004785:Environmental Pollutants; D010575:Pesticides; D019363:Cytochrome P-450 CYP1A1
keywords: Aryl hydrocarbon receptor (AhR); Caprine ABCG2; Dioxin; MDCKII cells; Mammary gland; Pesticides