Ph.D., Federal Institute of Technology (ETH) Zürich, Switzerland, 1986
Organic Anion Transport, Bile Acid Transport, Transport Physiology, Hepatic Drug Clearance
Transport proteins are important for the movement of endogenous compounds like nutrients and waste products but also xenobiotics like drugs across cell membranes. I am particularly interested in the structure and function of three transporters expressed in human hepatocytes. The Na+/taurocholate cotransporting polypeptide (NTCP; human SLC10A1 rodents Slc10a1) is the major transporter for uptake of conjugated bile acids into hepatocytes. Recent studies indicate that it can also transport drugs and other xenobiotics and might be involved in their uptake into human hepatocytes. The organic anion transporting polypeptides OATP1B1 and OATP1B3 (human: SLCO1B1 andSLCO1B3; rodent: Slco1b2) transport numerous structurally unrelated endo- and xenobiotics and are important transport systems for drug uptake into hepatocytes. Polymorphisms that affect their function can affect drug disposition.
In order to understand how these transporters move their substrates across the cell membrane and how mutations or other chemicals affect this transport, knowledge of their three dimensional structure is required. So far, none of these transporters have been crystallized and little is known about their structure. In my lab we use biochemical and molecular biology approaches in combination with computer modeling to better understand the structure and function of these important drug transporters with the final goal to help to determine their three dimensional structure.
In addition, we try to elucidate the role OATPs have in cancer. Although OATP1B3 is under normal physiological conditions a liver specific transporter, it is expressed in several cancers such as in pancreatic, prostate, colon and breast cancer. It might be important for the uptake of growth factors that help the cancer to expand but it potentially might also be used to target anticancer drugs to these cancers. We are currently investigating both aspects in the laboratory.
In addition to these projects we are investigating which transporters are involved in the disposition of perfluorinated carboxylates and sulfonates. Recent reports suggest that differential expression of certain transporters is responsible for the gender specific disposition of perfluorinated carbolxylates and we currently investigate whether the same holds true for sulfonates.
Hagenbuch B. and B. Stieger (2012) The SLCO (former SLC21) Superfamily of Transporters. Mol Aspects Med. In press
Roth M, Obaidat A, 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.
Obaidat A., Roth M., and B. Hagenbuch (2012) The Expression and Function of Organic Anion Transporting Polypeptides in Normal Tissues and in Cancer. Annu Rev Pharmacol Toxicol 10;52:135-51.
de Graan A.J., Lancaster C.S., Obaidat A., Hagenbuch B., Elens L., Friberg L.E., de Bruijn P., Hu S., Gibson A.A., Bruun G.H., Corydon T.J., Mikkelsen T.S., Walker A.L., Du G., Loos W.J., van Schaik R.H., Baker S.D., Mathijssen R.H., Sparreboom A. (2012) Influence of Polymorphic OATP1B-Type Carriers on the Disposition of Docetaxel. Clin Cancer Res. 15;18(16):4433-4440.
Pacyniak E., Hagenbuch B., Klaassen C.D., McKeeman L.L., and Guo G.L. (2011) Organic anion transporting polypeptides in the hepatic uptake of PBDE congeners in mice. Toxicol. Appl. Pharmacol. 15;257(1):23-31.
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.
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., Timmermann, B.N. and Hagenbuch, B. (2011) Interactions of green tea catechins with organic anion transporting polypeptides. Drug Metab. Dispos. 39:920-926.
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.
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.
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.
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.
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.Hagenbuch, B. (2010) Drug Uptake Systems in Liver and Kidney: A Historic Perspective. Clin. Pharmacol. Ther. 87(1):39-47.
Bruno Hagenbuch, PhD
4093 HLSIC; MS-1018
3901 Rainbow Blvd.
Kansas City, Kansas 66160
F: (913) 588-7501