QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: dmd.106.010033v1 34/10/1756    most recent Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Jigorel, E. Articles by Fardel, O. Search for Related Content PubMed PubMed Citation Articles by Jigorel, E. Articles by Fardel, O.

Differential Regulation of Sinusoidal and Canalicular Hepatic Drug Transporter Expression by Xenobiotics Activating Drug-Sensing Receptors in Primary Human Hepatocytes

Institut National de la Santé et de la Recherche Médicale, Faculté de Pharmacie, Rennes, France (E.J., M.L.V., O.F.); Technologie Servier, Orléans, France (C.B-N., Y.P.); and Département Hématologie, Immunologie, et Thérapie Cellulaire, Centre Hospitalier Universitaire Rennes, Rennes, France (O.F.)

Sinusoidal and canalicular hepatic drug transporters constitute key factors involved in drug elimination from liver. Regulation of their expression via activation of xenosensors, such as aryl hydrocarbon receptor (AhR), constitutive androstane receptor (CAR), pregnane X receptor (PXR), and nuclear factor E2-related factor 2 (Nrf2), remains incompletely characterized. The present study was therefore designed to carefully analyze expression of major drug transporters in primary human hepatocytes exposed to dioxin (2,3,7,8-tetrachlorodibenzo-p-dioxin, TCDD) (an AhR activator), rifampicin (RIF) (a PXR activator), phenobarbital (PB) (a CAR activator), and oltipraz (OPZ) (a Nrf2 activator), using mainly reverse transcription-real time polymerase chain reaction assays. With a threshold corresponding to a 1.5-fold factor change in mRNA levels, observed in at least three of seven independent human hepatocyte cultures, efflux transporters such as MDR1, MRP2 and BCRP were up-regulated by PB, RIF, and OPZ, whereas MRP3 was induced by OPZ and RIF. MDR1 and BCRP expression was also increased by TCDD- and RIF-augmented mRNA levels of the influx transporter OATP-C. Bile acid transporters, i.e., bile salt export pump and Na⁺-taurocholate cotransporting polypeptide, and the sinusoidal transporter, OAT2, were down-regulated by all the tested chemicals. Influx transporters such as OCT1, OATP-B, and OATP8 were repressed by PB and TCDD. PB also decreased MRP6 expression, whereas mRNA levels of OCT1 and OATP8 were down-regulated by RIF and OPZ, respectively. Taken together, these data establish a complex pattern of transporter regulation by xenobiotics in human hepatocytes, in addition to interindividual variability in responsiveness. This may deserve further attention with respect to drug-drug interactions and adverse effects of hepatic drugs.

This article has been cited by other articles:

				M. Le Vee, V. Lecureur, A. Moreau, B. Stieger, and O. Fardel Differential Regulation of Drug Transporter Expression by Hepatocyte Growth Factor in Primary Human Hepatocytes Drug Metab. Dispos., November 1, 2009; 37(11): 2228 - 2235. [Abstract] [Full Text] [PDF]

				A. K. Goetz and D. J. Dix Mode of Action for Reproductive and Hepatic Toxicity Inferred from a Genomic Study of Triazole Antifungals Toxicol. Sci., August 1, 2009; 110(2): 449 - 462. [Abstract] [Full Text] [PDF]

				V. Chu, H. J. Einolf, R. Evers, G. Kumar, D. Moore, S. Ripp, J. Silva, V. Sinha, M. Sinz, and A. Skerjanec In Vitro and in Vivo Induction of Cytochrome P450: A Survey of the Current Practices and Recommendations: A Pharmaceutical Research and Manufacturers of America Perspective Drug Metab. Dispos., July 1, 2009; 37(7): 1339 - 1354. [Abstract] [Full Text] [PDF]

				M. L. Vee, V. Lecureur, B. Stieger, and O. Fardel Regulation of Drug Transporter Expression in Human Hepatocytes Exposed to the Proinflammatory Cytokines Tumor Necrosis Factor-{alpha} or Interleukin-6 Drug Metab. Dispos., March 1, 2009; 37(3): 685 - 693. [Abstract] [Full Text] [PDF]

				D. J. Johnson, A. Owen, N. Plant, P. G. Bray, and S. A. Ward Drug-Regulated Expression of Plasmodium falciparum P-Glycoprotein Homologue 1: a Putative Role for Nuclear Receptors Antimicrob. Agents Chemother., April 1, 2008; 52(4): 1438 - 1445. [Abstract] [Full Text] [PDF]

				E. G. van de Kerkhof, I. A. M. de Graaf, A.-L. B. Ungell, and G. M. M. Groothuis Induction of Metabolism and Transport in Human Intestine: Validation of Precision-Cut Slices as a Tool to Study Induction of Drug Metabolism in Human Intestine in Vitro Drug Metab. Dispos., March 1, 2008; 36(3): 604 - 613. [Abstract] [Full Text] [PDF]

				M. Le Vee, P. Gripon, B. Stieger, and O. Fardel Down-Regulation of Organic Anion Transporter Expression in Human Hepatocytes Exposed to the Proinflammatory Cytokine Interleukin 1{beta} Drug Metab. Dispos., February 1, 2008; 36(2): 217 - 222. [Abstract] [Full Text] [PDF]

				L. M. Aleksunes and J. E. Manautou Emerging Role of Nrf2 in Protecting Against Hepatic and Gastrointestinal Disease Toxicol Pathol, June 1, 2007; 35(4): 459 - 473. [Abstract] [Full Text] [PDF]

				B. L. Urquhart, R. G. Tirona, and R. B. Kim Nuclear Receptors and the Regulation of Drug-Metabolizing Enzymes and Drug Transporters: Implications for Interindividual Variability in Response to Drugs J. Clin. Pharmacol., May 1, 2007; 47(5): 566 - 578. [Abstract] [Full Text] [PDF]