title: Regulation of human hepatic drug transporter activity and expression by diesel exhaust particle extract.
abstract: Diesel exhaust particles (DEPs) are common environmental air pollutants primarily affecting the lung. DEPs or chemicals adsorbed on DEPs also exert extra-pulmonary effects, including alteration of hepatic drug detoxifying enzyme expression. The present study was designed to determine whether organic DEP extract (DEPe) may target hepatic drug transporters that contribute in a major way to drug detoxification. Using primary human hepatocytes and transporter-overexpressing cells, DEPe was first shown to strongly inhibit activities of the sinusoidal solute carrier (SLC) uptake transporters organic anion-transporting polypeptides (OATP) 1B1, 1B3 and 2B1 and of the canalicular ATP-binding cassette (ABC) efflux pump multidrug resistance-associated protein 2, with IC50 values ranging from approximately 1 to 20 μg/mL and relevant to environmental exposure situations. By contrast, 25 μg/mL DEPe failed to alter activities of the SLC transporter organic cation transporter (OCT) 1 and of the ABC efflux pumps P-glycoprotein and bile salt export pump (BSEP), whereas it only moderately inhibited those of sodium taurocholate co-transporting polypeptide and of breast cancer resistance protein (BCRP). Treatment by 25 μg/mL DEPe was next demonstrated to induce expression of BCRP at both mRNA and protein level in cultured human hepatic cells, whereas it concomitantly repressed mRNA expression of various transporters, including OATP1B3, OATP2B1, OCT1 and BSEP. Such changes in transporter expression were found to be highly correlated to those caused by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), a reference activator of the aryl hydrocarbon receptor (AhR) pathway. This suggests that DEPe, which is enriched in known ligands of AhR like polycyclic aromatic hydrocarbons, alters drug transporter expression via activation of the AhR cascade. Taken together, these data established human hepatic transporters as targets of organic chemicals containing in DEPs, which may contribute to their systemic effects through impairing hepatic transport of endogenous compound or drug substrates of these transporters.
authors: 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: Marc
authors: M
authors: Le Vee
authors: 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: Elodie
authors: E
authors: Jouan
authors: Department of Clinical Pharmacology and Toxicology, University Hospital, 8091 Zurich, Switzerland.
authors: Bruno
authors: B
authors: Stieger
authors: 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: Valérie
authors: V
authors: Lecureur
authors: 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.
authors: Olivier
authors: O
authors: Fardel
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000378:metabolism; D002478:Cells, Cultured; D022781:Hepatocytes / Q000187:drug effects* / Q000378:metabolism*; D006801:Humans; D008658:Inactivation, Metabolic; D008099:Liver / Q000187:drug effects* / Q000378:metabolism*; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000378:metabolism; D027361:Organic Anion Transporters / Q000378:metabolism; D029363:Organic Anion Transporters, Sodium-Dependent / Q000378:metabolism; D027702:Organic Cation Transporter 1 / Q000378:metabolism; D061251:Primary Cell Culture; D027981:Symporters / Q000378:metabolism; D013656:Taurocholic Acid / Q000494:pharmacology; D001335:Vehicle Emissions
chemical_list: D018528:ATP-Binding Cassette Transporters; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D027361:Organic Anion Transporters; D029363:Organic Anion Transporters, Sodium-Dependent; D027702:Organic Cation Transporter 1; D027981:Symporters; D013656:Taurocholic Acid; D001335:Vehicle Emissions; C071908:sodium-bile acid cotransporter