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Interaction of mammary bovine ABCG2 with AFB1 and its metabolites and regulation by PCB 126 in a MDCKII in vitro model
Author(s) -
Manzini L.,
Halwachs S.,
Girolami F.,
Badino P.,
Honscha W.,
Nebbia C.
Publication year - 2017
Publication title -
journal of veterinary pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.527
H-Index - 60
eISSN - 1365-2885
pISSN - 0140-7783
DOI - 10.1111/jvp.12397
Subject(s) - abcg2 , efflux , metabolite , chemistry , multidrug resistance associated protein 2 , atp binding cassette transporter , transporter , pharmacology , excretion , incubation , in vitro , downregulation and upregulation , carcinogen , xenobiotic , biochemistry , biology , gene , enzyme
The ATP ‐binding cassette efflux transporter ABCG 2 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 ABCG 2 ( bABCG 2) 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 bABCG 2. Both AFB 1 and its main milk metabolite AFM 1 showed interaction with bABCG 2 even at concentrations approaching the legal limits in feed and food commodities. Moreover, PCB 126 significantly enhanced bABCG 2 functional activity. Specific inhibitors of either AhR ( CH 233191) or ABCG 2 (Ko143) were able to reverse the PCB 126‐induced increase in bABCG 2 transport activity, showing the specific upregulation of the efflux protein by the AhR pathway. The incubation of PCB 126‐pretreated cells with AFM 1 was able to substantially reverse such effect, with still unknown mechanism(s). Overall, results from this study point to AFB 1 and AFM 1 as likely bABCG 2 substrates. The PCB 126‐dependent increased activity of the transporter could enhance the ABCG 2‐mediated excretion into dairy milk of chemicals (i.e., drugs and toxins) potentially harmful to neonates and consumers.