title: Interaction of mammary bovine ABCG2 with AFB1 and its metabolites and regulation by PCB 126 in a MDCKII in vitro model.
abstract: The ATP-binding cassette efflux transporter ABCG2 plays a key role in the mammary excretion of drugs and toxins in humans and animals. Aflatoxins (AF) are worldwide contaminants of food and feed commodities, while PCB 126 is a dioxin-like PCB which may contaminate milk and dairy products. Both compounds are known human carcinogens. The interactions between AF and bovine ABCG2 (bABCG2) as well as the effects of PCB 126 on its efflux activity have been investigated by means of the Hoechst H33342 transport assay in MDCKII cells stably expressing mammary bABCG2. Both AFB1 and its main milk metabolite AFM1 showed interaction with bABCG2 even at concentrations approaching the legal limits in feed and food commodities. Moreover, PCB 126 significantly enhanced bABCG2 functional activity. Specific inhibitors of either AhR (CH233191) or ABCG2 (Ko143) were able to reverse the PCB 126-induced increase in bABCG2 transport activity, showing the specific upregulation of the efflux protein by the AhR pathway. The incubation of PCB 126-pretreated cells with AFM1 was able to substantially reverse such effect, with still unknown mechanism(s). Overall, results from this study point to AFB1 and AFM1 as likely bABCG2 substrates. The PCB 126-dependent increased activity of the transporter could enhance the ABCG2-mediated excretion into dairy milk of chemicals (i.e., drugs and toxins) potentially harmful to neonates and consumers.
authors.affiliation: Department of Veterinary Sciences, University of Torino, Grugliasco, Italy.
authors.forename: L
authors.initials: L
authors.lastname: Manzini
authors.affiliation: Institute of Veterinary Pharmacology, Pharmacy and Toxicology, Faculty of Veterinary Medicine, University of Leipzig, Leipzig, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Halwachs
authors.affiliation: Department of Veterinary Sciences, University of Torino, Grugliasco, Italy.
authors.forename: F
authors.initials: F
authors.lastname: Girolami
authors.affiliation: Department of Veterinary Sciences, University of Torino, Grugliasco, Italy.
authors.forename: P
authors.initials: P
authors.lastname: Badino
authors.affiliation: Institute of Veterinary Pharmacology, Pharmacy and Toxicology, Faculty of Veterinary Medicine, University of Leipzig, Leipzig, Germany.
authors.forename: W
authors.initials: W
authors.lastname: Honscha
authors.affiliation: Department of Veterinary Sciences, University of Torino, Grugliasco, Italy.
authors.forename: C
authors.identifier: http://orcid.org/0000-0003-0624-7787
authors.initials: C
authors.lastname: Nebbia
mesh_terms: D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2 / Q000187:drug effects / Q000378:metabolism*; D016604:Aflatoxin B1 / Q000378:metabolism*; D000818:Animals; D001562:Benzimidazoles / Q000378:metabolism; D002417:Cattle; D004285:Dogs; D005260:Female; D061985:Madin Darby Canine Kidney Cells / Q000187:drug effects / Q000378:metabolism; D008321:Mammary Glands, Animal / Q000187:drug effects / Q000378:metabolism*; D011078:Polychlorinated Biphenyls / Q000494:pharmacology*
chemical_list: D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D001562:Benzimidazoles; D016604:Aflatoxin B1; D011078:Polychlorinated Biphenyls; C017807:bisbenzimide ethoxide trihydrochloride; C023035:3,4,5,3',4'-pentachlorobiphenyl
keywords: Aflatoxins; Aryl hydrocarbon receptor (AhR); Bovine ABCG2; MDCKII cells; PCB 126