title: Alteration of human hepatic drug transporter activity and expression by cigarette smoke condensate.
abstract: Smoking is well-known to impair pharmacokinetics, through inducing expression of drug metabolizing enzymes. In the present study, we demonstrated that cigarette smoke condensate (CSC) also alters activity and expression of hepatic drug transporters, which are now recognized as major actors of hepatobiliary elimination of drugs. CSC thus directly inhibited activities of sinusoidal transporters such as OATP1B1, OATP1B3, OCT1 and NTCP as well as those of canalicular transporters like P-glycoprotein, MRP2, BCRP and MATE1, in hepatic transporters-overexpressing cells. CSC similarly counteracted constitutive OATP, NTCP and OCT1 activities in human highly-differentiated hepatic HepaRG cells. In parallel, CSC induced expression of BCRP at both mRNA and protein level in HepaRG cells, whereas it concomitantly repressed mRNA expression of various transporters, including OATP1B1, OATP2B1, OAT2, NTCP, OCT1 and BSEP, and enhanced that of MRP4. Such changes in transporter gene expression were found to be highly correlated to those caused by 2,3,7,8-tetrachlorodibenzo-p-dioxin, a reference activator of the aryl hydrocarbon receptor (AhR) pathway, and were counteracted, for some of them, by siRNA-mediated AhR silencing. This suggests that CSC alters hepatic drug transporter levels via activation of the AhR cascade. Importantly, drug transporter expression regulations as well as some transporter activity inhibitions occurred for a range of CSC concentrations similar to those required for inducing drug metabolizing enzymes and may therefore be hypothesized to be relevant for smokers. Taken together, these data established human hepatic transporters as targets of cigarette smoke, which could contribute to known alteration of pharmacokinetics and some liver adverse effects caused by smoking.
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, and Faculty of Sciences, Rafic Hariri Campus, Lebanese University, Lebanon.
authors.forename: Katia
authors.initials: K
authors.lastname: Sayyed
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 Le
authors.initials: ML
authors.lastname: Vee
authors.affiliation: EDST-AZM-Center-LBA3B, and Faculty of Sciences, Rafic Hariri Campus, Lebanese University, Lebanon.
authors.forename: Ziad
authors.initials: Z
authors.lastname: Abdel-Razzak
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: Elodie
authors.initials: E
authors.lastname: Jouan
authors.affiliation: Department of Clinical Pharmacology and Toxicology, University Hospital, 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: D018528:ATP-Binding Cassette Transporters / Q000187:drug effects / Q000378:metabolism; D045744:Cell Line, Tumor; D004347:Drug Interactions; D006801:Humans; D008099:Liver / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D034622:RNA Interference / Q000187:drug effects; D012907:Smoking / Q000009:adverse effects*; D000070590:Solute Carrier Proteins / Q000187:drug effects / Q000378:metabolism
chemical_list: D018528:ATP-Binding Cassette Transporters; D000070590:Solute Carrier Proteins
keywords: Aryl hydrocarbon receptor; Cigarette smoke; Drug-drug interactions; Hepatocytes; Transporters