The organic anion transporting polypeptides OATP1B1 and OATP1B3 are two major drug transporters expressed in human hepatocytes. Because of their multispecificity, these two transporters are potential sites of adverse drug-drug interactions. In the previous grant period, we characterized substrate dependent modulation, identified molecular characteristics of the substrate binding sites, and identified several amino acid residues important for OATP1B1- and OATP1B3-mediated substrate transport. However, the molecular mechanisms responsible for their multispecificities remain unclear. Our long term research goal is to understand in detail the mechanism of OATP-mediated transport as an essential prerequisite to understanding, predicting, and preventing OATP-related adverse drug-drug interactions. The rationale for the proposed research is that, because OATP1B1 and OATP1B3 are critically involved in the liver's ability to clear numerous chemicals from the blood, improved mechanistic insights into their individual and overlapping transporter functions will provide a strong scientific framework for improvements in the prediction and prevention of adverse drug-drug interactions, as well as the future design of specific substrates and/or inhibitors of their transport activity. The objective of this application is to identify domains and amino acids that are important for substrate translocation and stimulation, and to characterize the driving force(s) for transport. Our central hypothesis is that OATP1B1 and OATP1B3 transport their substrates via a central pore that includes substrate-specific translocation pathways, and that OATP1B1 and OATP1B3 work as asymmetrical exchangers. We plan to test the hypothesis with two specific aims: 1) Identify and characterize the translocation pathways of OATP1B1 and OATP1B3;and 2) Determine the mechanism of OATP-mediated transport. Completion of these specific aims will explain the substrate dependent effects by identifying amino acids in the different transmembrane domains that influence substrate translocation and will lead us a step closer to the three dimensional structure of these membrane transporters. Furthermore, we will resolve the controversies of the transport mechanism, identify a physiological counter-anion, and explain the allosteric effects that might be due to the oligomeric state of the transporters. This contribution is significant because its results will provide the fundamental understanding required to predict OATP- mediated drug transport, ultimately leading to more effective and efficient therapies in addition to fundamentally advancing the field of organic anion transport.
The proposed research is relevant to public health because a fundamental understanding of the structure/function relationships of OATP1B1 and OATP1B3 will provide the fundamental understanding required to predict OATP-mediated drug transport, ultimately leading to more effective and efficient therapies.
|Nieuweboer, Annemieke J M; Hu, Shuiying; Gui, Chunshan et al. (2014) Influence of drug formulation on OATP1B-mediated transport of paclitaxel. Cancer Res 74:3137-45|
|Stieger, Bruno; Hagenbuch, Bruno (2014) Organic anion-transporting polypeptides. Curr Top Membr 73:205-32|
|Steiner, Konstanze; Hagenbuch, Bruno; Dietrich, Daniel R (2014) Molecular cloning and functional characterization of a rainbow trout liver Oatp. Toxicol Appl Pharmacol 280:534-42|
|Ohnishi, Shuichi; Hays, Amanda; Hagenbuch, Bruno (2014) Cysteine scanning mutagenesis of transmembrane domain 10 in organic anion transporting polypeptide 1B1. Biochemistry 53:2261-70|
|Hagenbuch, Bruno; Stieger, Bruno (2013) The SLCO (former SLC21) superfamily of transporters. Mol Aspects Med 34:396-412|
|Zhang, Yuchen; Hays, Amanda; Noblett, Alexander et al. (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, Amanda; Apte, Udayan; Hagenbuch, Bruno (2013) Organic anion transporting polypeptides expressed in pancreatic cancer may serve as potential diagnostic markers and therapeutic targets for early stage adenocarcinomas. Pharm Res 30:2260-9|
|Roth, Megan; Obaidat, Amanda; Hagenbuch, Bruno (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, Amanda; Roth, Megan; Hagenbuch, Bruno (2012) The expression and function of organic anion transporting polypeptides in normal tissues and in cancer. Annu Rev Pharmacol Toxicol 52:135-51|
|Zeilhofer, Hanns Ulrich; Benke, Dietmar; Yevenes, Gonzalo E (2012) Chronic pain states: pharmacological strategies to restore diminished inhibitory spinal pain control. Annu Rev Pharmacol Toxicol 52:111-33|
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