Ph.D., Federal Institute of Technology (ETH) Zürich, Switzerland, 1986
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, drug transport proteins are involved in the disposition of essentially all drugs and are important determinants of whether dugs will reach their therapeutic targets. Modulation of the function of these drug transporters by other drugs can lead to serious clinical disorders or severe drug-drug interactions. We are mainly working with the hepatocyte-specific organic anion transporting polypeptides OATP1B1 and OATP1B3 which have been shown to mediate the uptake of numerous drugs into hepatocytes. These two transporters are closely related and have a broad and overlapping substrate specificity. This means that both can transport the same substrates, several endogenous compounds and numerous drugs, but with different affinities and capacities. The current research focus in the lab is directed at understanding this multispecificity at the molecular level and at finding selective inhibitors for the two transporters. The expected benefits are improved drug targeting, drug therapy and less unwanted drug-drug interactions. We are using functional expression systems to perform high-throughput screening, photoaffinity labeling to identify interacting amino acids, site-directed mutagenesis to modify the proteins and computer modeling to predict potential modulators. With respect to toxicology with have ongoing collaborations to characterize transporter-mediated disposition of perfluorinated compounds and to further characterize microcystin toxicity in fish.
Steiner, K., Hagenbuch, B. and Dietrich, D.R. (2014) Molecular cloning and functional characterization of a rainbow trout liver Oatp. Toxicol. Appl. Pharmacol. In press.
Nieuweboer, A.J., Hu, S., Gui, C., Hagenbuch, B., Ghobadi Moghaddam-Helmantel, I.M., Gibson, A.A., de Bruijn, P., Mathijssen, R.H., Sparreboom, A. (2014) Influence of drug formulation on OATP1B-mediated transport of paclitaxel. Cancer Res. 74(11):3137-45
Stieger, B. and B. Hagenbuch (2014) Organic Anion-Transporting Polypeptides, in Current Topics in Membranes, 73 Chapter 5, M.O. Bewensee, Editor., 73:205-32.
Boxberger, K.H., Hagenbuch, B. and Lampe, J.N. (2014) Common drugs inhibit human OCT1-mediated neurotransmitter uptake. Drug Metab. Dispos. 42(6):990-5 PMCID: PMC4014663
Ohnishi, S., Hays, A. and Hagenbuch, B. (2014) Cysteine Scanning Mutagenesis of Transmembrane Domain 10 in OATP1B1. Biochemistry 53(14):2261-70 PMCID: PMC4004239
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.
Bruno Hagenbuch, PhD
4093 HLSIC; MS-1018
3901 Rainbow Blvd.
Kansas City, Kansas 66160
F: (913) 588-7501