Ph.D., Federal Institute of Technology (ETH) Zürich, Switzerland, 1986
Organic Anion Transport, Bile Acid Transport, Transport Physiology, Hepatic Drug Clearance
Drug Transport, Hepatic Drug Clearance, Organic Anion Transport, Bile Acid Transport, Disposition of Perfluoroalkyl substances
Transport proteins control the selective transport of molecules across membranes and are required for the proper function of cells. With regard to pharmacology, transport proteins are involved in the disposition of essentially all drugs and are important determinants of whether dugs will reach their therapeutic targets. Inactivation of transport proteins because of inhibition by other substrates or because of mutations can lead to serious clinical disorders or severe drug-drug interactions. I am mainly interested in three hepatocyte-specific transporters: the Na+/taurocholate cotransporting polypeptide (NTCP; human gene SLC10A1, rodent gene Slc10a1) and the organic anion transporting polypeptides OATP1B1 and 1B3 (SLCO1B1 and SLCO1B3). NTCP is the major transporter for uptake of conjugated bile acids into hepatocytes. Some studies indicate that it might also be involved in drug uptake into human hepatocytes. Recent reports demonstrated that NTCP also functions as a receptor for human hepatitis B and D virus. Most OATPs transport numerous structurally unrelated endo- and xenobiotics into or out of epithelial cells. Moreover, the liver specific OATP1B1 and 1B3 are important transport systems for drug uptake into human hepatocytes. My current research focus is on the following questions: 1) Can these transporters be used for drug-targeting; 2) What are the molecular properties of the broad substrate specificity of OATP1B1 and 1B3; 3) What structural requirements make a compound an OATP substrate; 4) What is the role of these transporters - in particular OATP1B3 - in cancer; and 5) How is uptake mediated by these transporters affected by natural products and environmental contaminants? To answer these questions we are using functional expression systems in combination with molecular biology and computer modeling.
Hagenbuch B. and B. Stieger (2013) The SLCO (former SLC21) Superfamily of Transporters. Mol Aspects Med. 34:396-412.
Zhang, Y., Hays, A., Noblett, A., Thapa, M., Hua, D.H., and Hagenbuch, B. (2013) Transport by OATP1B1 and OATP1B3 Enhances the Cytotoxicity of Epigallocatechin 3-O-gallate and Several Quercetin Derivatives. J. Nat. Prod. 76(3):368-73
Hays, A., Apte, U., and Hagenbuch, B. (2013) Organic Anion Transporting Polypeptides Expressed in Pancreatic Cancer May Serve As Potential Diagnostic Markers and Therapeutic Targets for Early Stage Adenocarcinomas. Pharm Res. DOI:10.1007/s11095-012-0962-7.
Obaidat, A., Roth, M., and Hagenbuch, B. (2012) The Expression and Function of Organic Anion Transporting Polypeptides in Normal Tissues and in Cancer. Annu Rev Pharmacol Toxicol 10;52:135-51.
Roth, M., Obaidat, A., and Hagenbuch, B. (2012) OATPs, OATs and OCTs: The organic anion and cation transporters of the SLCO and SLC22A gene superfamilies. Br J Pharmacol 165:1260-87.
Roth, M., Timmermann, B.N. and Hagenbuch, B. (2011) Interactions of green tea catechins with organic anion transporting polypeptides. Drug Metab. Dispos. 39:920-926.
Obaidat, A., Weiss, J., Wahlgren, B., Manam, R.R., Macherla, V.R., McArthur, K., Chao, T.H., Palladino, M.A., Lloyd, G.K., Potts, B.C., Enna, S.J., Neuteboom, S.T.C. and Hagenbuch, B. (2011) Proteasome regulator marizomib (NPI-0052) exhibits prolonged inhibition, attenuated efflux, and greater cytotoxicity than its reversible analogs. J. Pharmacol. Exp. Ther. 337(2):479-86.
Roth, M., Araya, J.J., Timmermann, B.N. and Hagenbuch, B. (2011) Isolation of modulators of the liver specific Organic Anion Transporting Polypeptides (OATPs) 1B1 and 1B3 from Rollinia emarginata Schlecht (Annonaceae). J. Pharmacol. Exp. Ther. 339(2):624-32.
Hagenbuch, B. (2010) Drug Uptake Systems in Liver and Kidney: A Historic Perspective. Clin. Pharmacol. Ther. 87(1):39-47.
Weaver, Y.M., Ehresman, D.J., Butenhoff, J.L. and Hagenbuch, B. (2010) Roles of rat renal organic anion transporters in transporting perfluorinated carboxylates with different chain lengths. Tox. Sci. 113:305-14.
Gui, C., Obaidat, A., Chaguturu, R. and Hagenbuch, B. (2010) Development of a Cell-based High-throughput Assay to Screen for Inhibitors of Organic Anion Transporting Polypeptides 1B1 and 1B3. Current Chemical Genomics 4:1-8.
Gui, C. and Hagenbuch, B. (2010) Cloning/Characterization of the Canine Organic Anion Transporting Polypeptide 1b4 (Oatp1b4) and Classification of the Canine OATP/SLCO Members. Comp. Biochem. Physiol. C Toxicol. Pharmacol. 151:393-399.
Pacyniak E.K., Roth, M., Hagenbuch, B. and Guo, G.L. (2010) Mechanism of polybrominated diphenyl ether (PBDE) uptake into the liver: PBDE congeners are substrates of human hepatic OATP transporters. Tox. Sci. 115:344-53.
Weaver, Y.M. and Hagenbuch, B. (2010) Several conserved positively charged amino acids in OATP1B1 are involved in binding or translocation of different substrates. J. Membr. Biol. 236:279-90.
Gui, C., Wahlgren, B., Lushington, G.H. and Hagenbuch, B. (2009) Identification, Ki determination and CoMFA analysis of nuclear receptor ligands as competitive inhibitors of OATP1B1-mediated estradiol-17β-glucuronide transport. Pharmacol. Res. 60(1):50-6.
Gui, C. and Hagenbuch, B. (2009) Role of Transmembrane Domain 10 for the Function of Organic Anion Transporting Polypeptide 1B1. Prot. Sci. 18:2298-306.
Gui, C. and Hagenbuch, B. (2008) Amino Acid Residues in Transmembrane Domain 10 of Organic Anion Transporting Polypeptide 1B3 are Critical for Cholecystokinin Octapeptide Transport. Biochemistry 47:9090-9097.
Hagenbuch B. and C. Gui (2008) Xenobiotic transporters of the human organic anion transporting polypeptides (OATP) family. Xenobiotica 38:778-801.
Gui, C., Miao, Y., Thompson, L., Wahlgren, B., Mock, M., Stieger, B. and Hagenbuch, B. (2008) Effect of PXR ligands on transport mediated by human OATP1B1 and OATP1B3. Eur. J. Pharmacol. 584:57-65.
Bruno Hagenbuch, PhD
4093 HLSIC; MS-1018
3901 Rainbow Blvd.
Kansas City, Kansas 66160
F: (913) 588-7501