Bruno Hagenbuch, PhD
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 all drugs and are important determinants of whether drugs 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. Interestingly, inhibitors or modulators of these OATPs act in a substrate-dependent way which can lead to inhibition or stimulation of substrate uptake. Recently we could demonstrate that OATP1B3 interacts with other transporters in human hepatocytes. We currently investigate which transporters interact and what the functional consequence of these interactions is in human hepatocytes. Another research focus is how the function of the sodium-dependent bile acid transporter, NTCP, is affected by amino acid replacements at conserved and non-conserved positions. The hypothesis we are testing is that amino acid replacements at conserved positions likely have either no effect or are detrimental, thus representing a toggle position. However, when amino acids are replaced with every possible other amino acid at non-conserved positions, this likely results in a gradual inhibition or stimulation and therefore represents a rheostat position. Eventually, these results should allow to predict such changes and are directed towards improving precision medicine. With respect to toxicology with have ongoing collaborations to characterize transporter-mediated disposition of perfluorinated compounds that are environmentally stable and have sometimes very long half-lives in humans.
Zhang, Y., Boxberger, K.H., and B. Hagenbuch. (2017) Organic anion transporting polypeptide 1B3 can form homo- and hetero-oligomers. PLoS One. 12:e0180257
Kreznar JH, Keller MP, Traeger LL, Rabaglia ME, Schueler KL, Stapleton DS, Zhao W, Vivas EI, Yandell BS, Broman AT, Hagenbuch B, Attie AD, Rey FE. (2017) Host Genotype and Gut Microbiome Modulate Insulin Secretion and Diet-Induced Metabolic Phenotypes. Cell Rep. 18:1739-1750
Zhao, W., Zitzow, J.D., Weaver, Y., Ehresman, D.J., Chang, S.C., Butenhoff, J.L., and Hagenbuch, B. (2017) Organic Anion Transporting Polypeptides Contribute to the Disposition of Perfluoroalkyl Acids in Humans and Rats. Toxicol. Sci. 156:84-95
Stieger B. and Hagenbuch B. (2016) Recent advances in understanding hepatic drug transport. F1000Res.Oct 6;5:2465
Steiner, K., Zimmermann, L., Hagenbuch, B. and Dietrich, D. (2015) Zebrafish-Oatp mediated transport of Microcystin-congeners. Arch. Toxicol. 90:1129-39
Zhao, W., Zitzow, J.D., Ehresman, D.J., Chang, S.C., Butenhoff, J.L., Forster, J. and Hagenbuch, B. (2015) Na+/taurocholate cotransporting polypeptide (NTCP) and apical sodium-dependent bile acid transporter (ASBT) are involved in the disposition of Perfluoroalkyl Sulfonates (PFASs) in humans and rats. Tox. Sci. 146(2):363-73
Woolbright, B.L., Dorko, K., Antoine, D.J., Clarke, J.I., Gholami, P., Li, F., Kumer, S.C., Schmitt, T.M., Forster, J., Fan, F., Jenkins, R.E., Park, B.K., Hagenbuch, B., Olyaee, M., and Jaeschke, H. (2015) Bile acid-induced necrosis in primary human hepatocytes and in patients with obstructive cholestasis. Toxicol Appl Pharmacol. 2015 283:168-177
Steiner, K., Hagenbuch, B. and Dietrich, D.R. (2014) Molecular cloning and functional characterization of a rainbow trout liver Oatp. Toxicol. Appl. Pharmacol. 280:534-42
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. 74:3137-45
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. 42:990-5 PMCID: PMC4014663
Ohnishi, S., Hays, A. and Hagenbuch, B. (2014) Cysteine Scanning Mutagenesis of Transmembrane Domain 10 in OATP1B1. Biochemistry 53:2261-70 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. 76:368-73
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. 30(9):2260-9
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.