Bruno Hagenbuch, Ph.D.

 

Ph.D., Federal Institute of Technology (ETH) Zürich, Switzerland, 1986

Research Interests

Organic Anion Transport, Bile Acid Transport, Transport Physiology, Hepatic Drug Clearance

Transport proteins are important for the transport of endogenous compounds like nutrients and waste products but also xenobiotics like drugs. I am particularly interested in the structure and function of three transporters expressed in human hepatocytes. The Na+/taurocholate cotransporting polypeptide (human NTCP; rodent: Ntcp; SLC10A1/Slc10a1) is the major transporter for uptake of conjugated bile acids into hepatocytes. Recent studies indicate that it might also be involved in drug uptake into human hepatocytes. The organic anion transporting polypeptides OATP1B1 and 1B3 (human: OATPs; rodent: Oatps; SLCO/Slco) transport numerous structurally unrelated endo- and xenobiotics and are important transport systems for drug uptake into human hepatocytes.

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 I try to address 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) Is NTCP a multispecific drug transporter and what is the molecular basis of this multispecificity; 5) What is the role of these transporters in cancer; and 6) How is uptake mediated by these transporters affected by natural products and environmental contaminants?

Selected Publications

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.

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.

Huang, D.Y., Mock, M., Hagenbuch, B., Chan, S., Dmitrovic, J and Kinniburgh, D. (2009) Dynamic cytotoxic response to mycrocystins using microelectronic sensor arrays. Env. Sci. Tech. 43:7803-7809.

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. (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.

 

Contact Information

Bruno Hagenbuch, Ph.D.
Professor
Department of Pharmacology, Toxicology and Therapeutics
The University of Kansas Medical Center
4093 HLSIC; MS1018
3901 Rainbow Boulevard
Kansas City, Kansas 66160
Phone: (913) 588-0028
Fax: (913) 588-7501
Email:bhagenbuch@kumc.edu

Updated 11/12/11