1 Scientific RepoRts | 7:41376 | DOI: 10.1038/srep41376 www.nature.com/scientificreports Interactions of retinoids with the ABC transporters p-glycoprotein and Breast Cancer Resistance protein szabolcs tarapcsák 1 , Gábor szalóki 1 , Ágnes telbisz 2 , Zsuzsanna Gyöngy 1 , Krisztina Matúz 3 , Éva Csősz 3 , péter Nagy 1 , Imre J. Holb 4,5 , Ralph Rühl 6 , László Nagy 3 , Gábor szabó 1 & Katalin Goda 1 Retinoids – derivatives of vitamin A – are important cell permeant signaling molecules that regulate gene expression through activation of nuclear receptors. P-glycoprotein (Pgp) and ABCG2 are plasma membrane efux transporters afecting the tissue distribution of numerous structurally unrelated lipophilic compounds. In the present work we aimed to study the interaction of the above ABC transporters with retinoid derivatives. We have found that 13-cis-retinoic acid, retinol and retinyl- acetate inhibited the Pgp and ABCG2 mediated substrate transport as well as the substrate stimulated ATPase activity of these transporters. Interestingly, 9-cis-retinoic acid and AtRA (all-trans retinoic acid), both are stereoisomers of 13-cis-retinoic acid, did not have any efect on the transporters’ activity. Our fuorescence anisotropy measurements revealed that 13-cis-retinoic acid, retinol and retinyl-acetate selectively increase the viscosity and packing density of the membrane. thus, the mixed-type inhibition of both transporters by retinol and ABCG2 by 13-cis-retinoic acid may be the collective result of direct interactions of these retinoids with the substrate binding site(s) and of indirect interactions mediated by their membrane rigidifying efects. P-glycoprotein (Pgp, MDR1, ABCB1) and Breast Cancer Resistance Protein (BCRP, MXR, ABCG2) are mem- bers of the ATP-binding-cassette (ABC) transporter family characterized by their evolutionary conserved ATP-binding domains. ABC transporters form one of the largest protein families and are present in every organ- ism from bacteria to human (for reviews see refs 1, 2, 3). In higher eukaryotes several ABC transporters have important functions in drug metabolizing and drug excreting organs, e.g. in the liver and the kidney, and also play a role in the formation of tissue barriers, including the intestinal epithelium, blood-brain, blood-placenta and blood-testis barriers, suggesting that these proteins are important determinants of the pharmacokinetics of various chemotherapeutic compounds 4 . Since Pgp and ABCG2 is expressed in the apical membrane of entero- cytes, they afect the intestinal absorption of nutrients, drugs, food additives and xenobiotics 5 . In addition, over- expression of Pgp and ABCG2 has also been demonstrated in chemotherapy resistant tumors of various tissue origins (for reviews see refs 6, 7, 8, 9). Of note, ABCG2 is also involved in rather specifc physiological functions e.g. transport of urate 10 , androgens and estrogens 11 , while such roles have not yet been identifed for Pgp. A common structural feature of active ABC transporters is that they contain two nucleotide binding domains (NBDs) responsible for binding and hydrolysis of ATP and at least two transmembrane domains (TMDs) form- ing the drug binding pocket and the drug translocation pathway. Pgp and ABCG2 have particularly wide and 1 Department of Biophysics and Cell Biology, University of Debrecen, Debrecen, H-4002 Egyetem tér 1, P.O.B. 400, Hungary. 2 Institute of Enzymology, Research Centre for Natural Sciences, Hungarian Academy of Sciences, Budapest, H-1117 Magyar tudósok körútja 2, P.O.B. 286, Hungary. 3 Department of Biochemistry and Molecular Biology, University of Debrecen, Debrecen, H-4002 Egyetem tér 1, P.O.B. 400, Hungary. 4 Institute of Horticulture, University of Debrecen, Debrecen, H-4015 Böszörményi út 138, P.O.B. 400, Hungary. 5 Plant Protection Institute, Centre for Agricultural Research, Hungarian Academy of Sciences, Budapest, H-1525 Hermann Ottó út 15, P.O.B. 525, Hungary. 6 MTA-DE, Public Health Research Group of the Hungarian Academy of Sciences, Faculty of Public Health, University of Debrecen, Debrecen, H-4028 Kassai út 26, P.O.B. 400, Hungary. Correspondence and requests for materials should be addressed to K.G. (email: goda@med.unideb.hu) Received: 05 August 2016 Accepted: 20 December 2016 Published: 01 February 2017 OPEN