Functional activity of ABCG2 efflux transporter in the mammary gland of dairy cows and regulation of transporter activity by environmental pollutants

• Applicant: Professor Dr. Walther Honscha, since 1/2016
• Subject Area: Veterinary Medical Science
• Term: from 2013 to 2017
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 247494355

The efflux transporter ABCG2 has been recently identified as the major pathway in secretion of drugs and toxins into milk of humans and mice. No detailed information is so far available on active drug accumulation including ABCG2 in milk of dairy cattle. Thus, in this cooperation project we aim to systematically investigate for the first time the functional ABCG2 secretory activity in the bovine mammary gland. In pharmacokinetic studies, the plasma and milk concentration-time profile of the important veterinary anthelmintic drug monepantel (MNP) is therefore assessed in dairy cows. Moreover, we determine the effect of concurrent administra¬tion of MNP and further ABCG2 drug substrates including enrofloxacin and oxfendazole on the MNP milk excretion rate. In parallel, functional ABCG2 efflux activity is examined in more detail by transepithelial MNP transport studies using polarized MDCKII cells expressing full-length ABCG2 from the lactating bovine mammary gland as adequate in vitro model for the blood-milk barrier. Cells are further co-incubated with MNP and enrofloxacin, oxfendazole or ABCG2 inhibitor fumitremorgin C to test the contribution of ABCG2 to overall drug transport into milk. Interestingly, aryl hydrocarbon receptor (AhR) binding motifs have been identified in the bovine ABCG2 promoter region typically mediating harmful effects of environmental pollutants including dioxins and some pesticides. As potential induction of ABCG2 secretory activity in the mammary gland by these AhR ligands may result in formation of harmful drug milk residues, the effect of selected con¬taminants on functional ABCG2 activity is examined by MNP flux studies using MDCKII-bABCG2 cells.

• DFG Programme: Research Grants
• International Connection: Argentina
• Partner Organisation: Consejo Nacional de Investigaciones Científicas y Técnicas
• Ehemalige Antragstellerin: Dr. Sandra Halwachs, until 12/2015
• Participating Person: Professor Dr. Adrian Luis Lifschitz