title: Inhibition of SLC drug transporter activities by environmental bisphenols.
abstract: The plastic component bisphenol A (BPA) is suspected to exert deleterious effects towards human health and targets various cellular and molecular pathways, including activity of ATP-binding cassette drug transporters. The present study was designed to determine whether BPA and some derivatives, like its substitutes bisphenol F (BPF) and bisphenol S (BPS) and the flame retardant tetrabromobisphenol A (TBBPA), may additionally interact with solute carrier (SLC) drug transporters. Activities of the various following SLC transporters were inhibited in a major way (by >60%) by 100μM bisphenols: OCT1 and MATE1 (by BPA and TBBPA), OATP1B1 (by BPA, BPF and TBBPA), OATP1B3 and NTCP (by TBBPA) and OAT3 (by BPA, BPF, BPS and TBBPA); by contrast, activities of other transporters were not impacted (MATE2-K) or were stimulated (notably OCT1 by BPS and OCT2 by BPF). Transporter inhibitions due to bisphenols were concentrations-dependent, with half maximal inhibitory concentrations (IC50) ranging from 0.5μM to 73.5μM. BPA was finally shown to be not transported by OAT3, although inhibiting this transporter in a competitive manner. Taken together, these data indicate that bisphenols interact with SLC transporters, at concentration levels however rather higher than those occurring in humans in response to environmental exposure.
authors.affiliation: Institut de Recherches en Santé, Environnement et Travail (IRSET), UMR INSERM U1085, Faculté de Pharmacie, 2 Avenue du Pr Léon Bernard, 35043 Rennes, France.
authors.forename: Arnaud
authors.initials: A
authors.lastname: Bruyere
authors.affiliation: Institut de Recherches en Santé, Environnement et Travail (IRSET), UMR INSERM U1085, Faculté de Pharmacie, 2 Avenue du Pr Léon Bernard, 35043 Rennes, France.
authors.forename: Céline
authors.initials: C
authors.lastname: Hubert
authors.affiliation: Institut de Recherches en Santé, Environnement et Travail (IRSET), UMR INSERM U1085, Faculté de Pharmacie, 2 Avenue du Pr Léon Bernard, 35043 Rennes, France.
authors.forename: Marc
authors.initials: M
authors.lastname: Le Vee
authors.affiliation: Institut de Recherches en Santé, Environnement et Travail (IRSET), UMR INSERM U1085, Faculté de Pharmacie, 2 Avenue du Pr Léon Bernard, 35043 Rennes, France.
authors.forename: Lisa
authors.initials: L
authors.lastname: Chedik
authors.affiliation: Institut de Recherches en Santé, Environnement et Travail (IRSET), UMR INSERM U1085, Faculté de Pharmacie, 2 Avenue du Pr Léon Bernard, 35043 Rennes, France; EDST-AZM-center-LBA3B, Faculty of Sciences, Rafic Hariri Campus, Lebanese University, Lebanon.
authors.forename: Katia
authors.initials: K
authors.lastname: Sayyed
authors.affiliation: Department of Clinical Pharmacology and Toxicology, University Hospital Zurich, University of Zurich, Rämistrasse 100, 8091 Zurich, Switzerland.
authors.forename: Bruno
authors.initials: B
authors.lastname: Stieger
authors.affiliation: Centre de Pharmacocinétique, Technologie Servier, 25-27 rue Eugène Vignat, 45000 Orléans, France.
authors.forename: Claire
authors.initials: C
authors.lastname: Denizot
authors.affiliation: Centre de Pharmacocinétique, Technologie Servier, 25-27 rue Eugène Vignat, 45000 Orléans, France.
authors.forename: Yannick
authors.initials: Y
authors.lastname: Parmentier
authors.affiliation: Institut de Recherches en Santé, Environnement et Travail (IRSET), UMR INSERM U1085, Faculté de Pharmacie, 2 Avenue du Pr Léon Bernard, 35043 Rennes, France; Pôle Biologie, Centre Hospitalier Universitaire, 2 rue Henri Le Guilloux, 35033 Rennes, France. Electronic address: olivier.fardel@univ-rennes1.fr.
authors.forename: Olivier
authors.initials: O
authors.lastname: Fardel
mesh_terms: D001559:Benzhydryl Compounds / Q000494:pharmacology*; D045744:Cell Line, Tumor; D057809:HEK293 Cells; D006801:Humans; D029362:Organic Anion Transporters, Sodium-Independent / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D027701:Organic Cation Transport Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D010636:Phenols / Q000494:pharmacology*; D011075:Polybrominated Biphenyls / Q000494:pharmacology*; D013450:Sulfones / Q000494:pharmacology*; D000098833:Bisphenol F Compounds; D000098831:Bisphenol S Compounds; D000098826:Bisphenol A Compounds
chemical_list: D001559:Benzhydryl Compounds; D029362:Organic Anion Transporters, Sodium-Independent; D027701:Organic Cation Transport Proteins; D010636:Phenols; D011075:Polybrominated Biphenyls; D013450:Sulfones; C000611646:bisphenol F; D000098833:Bisphenol F Compounds; C543008:bisphenol S; D000098831:Bisphenol S Compounds; C020806:tetrabromobisphenol A; C006780:bisphenol A; D000098826:Bisphenol A Compounds
keywords: Bisphenol A; Bisphenol F; Bisphenol S; Drug transporters; Inhibition; Tetrabromobisphenol A