title: Inhibition of Human Drug Transporter Activities by the Pyrethroid Pesticides Allethrin and Tetramethrin.
abstract: Pyrethroids are widely-used chemical insecticides, to which humans are commonly exposed, and known to alter functional expression of drug metabolizing enzymes. Limited data have additionally suggested that drug transporters, that constitute key-actors of the drug detoxification system, may also be targeted by pyrethroids. The present study was therefore designed to analyze the potential regulatory effects of these pesticides towards activities of main ATP-binding cassette (ABC) and solute carrier (SLC) drug transporters, using transporter-overexpressing cells. The pyrethroids allethrin and tetramethrin were found to inhibit various ABC and SLC drug transporters, including multidrug resistance-associated protein (MRP) 2, breast cancer resistance protein (BCRP), organic anion transporter polypeptide (OATP) 1B1, organic anion transporter (OAT) 3, multidrug and toxin extrusion transporter (MATE) 1, organic cation transporter (OCT) 1 and OCT2, with IC50 values however ranging from 2.6 μM (OCT1 inhibition by allethrin) to 77.6 μM (OAT3 inhibition by tetramethrin) and thus much higher than pyrethroid concentrations (in the nM range) reached in environmentally pyrethroid-exposed humans. By contrast, allethrin and tetramethrin cis-stimulated OATP2B1 activity and failed to alter activities of OATP1B3, OAT1 and MATE2-K, whereas P-glycoprotein activity was additionally moderately inhibited. Twelve other pyrethoids used at 100 μM did not block activities of the various investigated transporters, or only moderately inhibited some of them (inhibition by less than 50%). In silico analysis of structure-activity relationships next revealed that molecular parameters, including molecular weight and lipophilicity, are associated with transporter inhibition by allethrin/tetramethrin and successfully predicted transporter inhibition by the pyrethroids imiprothrin and prallethrin. Taken together, these data fully demonstrated that two pyrethoids, i.e., allethrin and tetramethrin, can act as regulators of the activity of various ABC and SLC drug transporters, but only when used at high and non-relevant concentrations, making unlikely any contribution of these transporter activity alterations to pyrethroid toxicity in environmentally exposed humans.
authors.affiliation: Institut de Recherches en Santé, Environnement et Travail (IRSET), UMR INSERM U1085, Faculté de Pharmacie, 2 Avenue du Pr Léon Bernard, Rennes, France.|Pôle Pharmacie, Centre Hospitalier Universitaire, 2 rue Henri Le Guilloux, 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, 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, Rennes, France.
authors.forename: Marc
authors.initials: M
authors.lastname: Le Vee
authors.affiliation: Department of Clinical Pharmacology and Toxicology, University Hospital Zurich, University of Zurich, Rämistrasse 100, Zurich, Switzerland.
authors.forename: Bruno
authors.initials: B
authors.lastname: Stieger
authors.affiliation: Centre de Pharmacocinétique, Technologie Servier, 25-27 rue Eugène Vignat, Orléans, France.
authors.forename: Claire
authors.initials: C
authors.lastname: Denizot
authors.affiliation: Centre de Pharmacocinétique, Technologie Servier, 25-27 rue Eugène Vignat, 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, Rennes, France.|Pôle Pharmacie, Centre Hospitalier Universitaire, 2 rue Henri Le Guilloux, Rennes, France.
authors.forename: Sophie
authors.initials: S
authors.lastname: Potin
authors.affiliation: Institut de Recherches en Santé, Environnement et Travail (IRSET), UMR INSERM U1085, Faculté de Pharmacie, 2 Avenue du Pr Léon Bernard, Rennes, France.|Pôle Biologie, Centre Hospitalier Universitaire, 2 rue Henri Le Guilloux, Rennes, France.
authors.forename: Olivier
authors.initials: O
authors.lastname: Fardel
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000487:Allethrins / Q000737:chemistry / Q000633:toxicity*; D002460:Cell Line; D004298:Dopamine / Q000378:metabolism; D057809:HEK293 Cells / Q000187:drug effects; D006801:Humans; D000089762:Multidrug Resistance-Associated Protein 2; D027702:Organic Cation Transporter 1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D010575:Pesticides / Q000737:chemistry / Q000633:toxicity*; D011722:Pyrethrins / Q000737:chemistry / Q000633:toxicity*; D000070590:Solute Carrier Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship; D018675:Toxicity Tests
chemical_list: C000715087:ABCC2 protein, human; D018528:ATP-Binding Cassette Transporters; D000487:Allethrins; D000089762:Multidrug Resistance-Associated Protein 2; D027702:Organic Cation Transporter 1; D010575:Pesticides; D011722:Pyrethrins; D000070590:Solute Carrier Proteins; D004298:Dopamine; C009424:tetramethrin