Pair your accounts.

Export articles to Mendeley

Get article recommendations from ACS based on references in your Mendeley library.

Pair your accounts.

Export articles to Mendeley

Get article recommendations from ACS based on references in your Mendeley library.

You’ve supercharged your research process with ACS and Mendeley!

Click to create an ACS ID

Please note: If you switch to a different device, you may be asked to login again with only your ACS ID.

Please note: If you switch to a different device, you may be asked to login again with only your ACS ID.

Please note: If you switch to a different device, you may be asked to login again with only your ACS ID.

Your Mendeley pairing has expired. Please reconnect
ACS Publications. Most Trusted. Most Cited. Most Read
My Activity

Figure 1Loading Img

High-Speed Screening and QSAR Analysis of Human ATP-Binding Cassette Transporter ABCB11 (Bile Salt Export Pump) To Predict Drug-Induced Intrahepatic Cholestasis

View Author Information
Department of Biomolecular Engineering, Graduate School of Bioscience and Biotechnology, Tokyo Institute of Technology, Yokohama 226-8501, Japan, GS platZ Co. Ltd., Tokyo 103-0027, Japan, BioTec Co. Ltd., Tokyo 113-0034, Japan, Bio Research Laboratories, Nosan Corporation, Tsukuba 300-2615, Japan, and Life Science Systems Department, PLM Solutions Division, Fujitsu Kyushu System Engineering Co. Ltd., Fukuoka 814-8589, Japan
Cite this: Mol. Pharm. 2006, 3, 3, 252–265
Publication Date (Web):April 28, 2006
Copyright © 2006 American Chemical Society

    Article Views





    Other access options


    Abstract Image

    Human ATP-binding cassette transporter ABCB11 (SPGP/BSEP) mediates the elimination of bile salts from liver cells and thereby plays a critical role in the generation of bile flow. In the present study, we have developed in vitro high-speed screening and quantitative structure−activity relationship (QSAR) analysis methods to investigate the interaction of ABCB11 with a variety of drugs. Plasma membrane vesicles prepared from insect cells overexpressing human ABCB11 were used to measure the ATP-dependent transport of [14C]taurocholate. Over 40 different drugs and natural compounds were tested to evaluate their interaction with ABCB11-mediated taurocholate transport. On the basis of the extent of inhibition, we have analyzed the QSAR to identify one set of chemical fragmentation codes closely associated with the inhibition of ABCB11. This approach can be used to predict compounds with a potential risk of drug-induced intrahepatic cholestasis.

    Keywords: ABC transporter; ABCB11; bile salt; intrahepatic cholestasis; troglitazone

    Read this article

    To access this article, please review the available access options below.

    Get instant access

    Purchase Access

    Read this article for 48 hours. Check out below using your ACS ID or as a guest.


    Access through Your Institution

    You may have access to this article through your institution.

    Your institution does not have access to this content. You can change your affiliated institution below.

     Tokyo Institute of Technology.

     GS platZ Co., Ltd.


     BioTec Co., Ltd.

     Nosan Corporation.

     Fujitsu Kyushu System Engineering Co. Ltd.


     Author to whom correspondence should be addressed. Mailing address:  Department of Biomolecular Engineering, Graduate School of Bioscience and Biotechnology, Tokyo Institute of Technology, Nagatsuta 4259-B-60, Yokohama 226-8501, Japan. Tel:  045-924-5800. Fax:  045-924-5838. E-mail:  [email protected].

    Cited By

    This article is cited by 54 publications.

    1. Mohamed Diwan M. AbdulHameed, Ruifeng Liu, Anders Wallqvist. Using a Graph Convolutional Neural Network Model to Identify Bile Salt Export Pump Inhibitors. ACS Omega 2023, 8 (24) , 21853-21861.
    2. Kevin S. McLoughlin, Claire G. Jeong, Thomas D. Sweitzer, Amanda J. Minnich, Margaret J. Tse, Brian J. Bennion, Jonathan E. Allen, Stacie Calad-Thomson, Thomas S. Rush, James M. Brase. Machine Learning Models to Predict Inhibition of the Bile Salt Export Pump. Journal of Chemical Information and Modeling 2021, 61 (2) , 587-602.
    3. Floriane Montanari, Marta Pinto, Narakorn Khunweeraphong, Katrin Wlcek, M. Imran Sohail, Tobias Noeske, Scott Boyer, Peter Chiba, Bruno Stieger, Karl Kuchler, and Gerhard F. Ecker . Flagging Drugs That Inhibit the Bile Salt Export Pump. Molecular Pharmaceutics 2016, 13 (1) , 163-171.
    4. Mathieu Vinken . Adverse Outcome Pathways and Drug-Induced Liver Injury Testing. Chemical Research in Toxicology 2015, 28 (7) , 1391-1397.
    5. Tina Ritschel, Susanne M. A. Hermans, Marieke Schreurs, Jeroen J. M. W. van den Heuvel, Jan B. Koenderink, Rick Greupink, and Frans G. M. Russel . In Silico Identification and in Vitro Validation of Potential Cholestatic Compounds through 3D Ligand-Based Pharmacophore Modeling of BSEP Inhibitors. Chemical Research in Toxicology 2014, 27 (5) , 873-881.
    6. Seva E. Kostrubsky, Stephen C. Strom, Ewa Ellis, Sidney D. Nelson and Abdul E. Mutlib. Transport, Metabolism, and Hepatotoxicity of Flutamide, Drug–Drug Interaction with Acetaminophen Involving Phase I and Phase II Metabolites. Chemical Research in Toxicology 2007, 20 (10) , 1503-1512.
    7. Aki Sakurai,, Yuko Onishi,, Hiroyuki Hirano,, Michel Seigneuret,, Kazuya Obanayama,, Gunwoo Kim,, Ei Leen Liew,, Toshiyuki Sakaeda,, Koh-ichiro Yoshiura,, Norio Niikawa,, Minoru Sakurai, and, Toshihisa Ishikawa. Quantitative Structure−Activity Relationship Analysis and Molecular Dynamics Simulation To Functionally Validate Nonsynonymous Polymorphisms of Human ABC Transporter ABCB1 (P-Glycoprotein/MDR1). Biochemistry 2007, 46 (26) , 7678-7693.
    8. Fatemeh Rezaei, Danny Farhat, Gonca Gursu, Sabrina Samnani, Jyh-Yeuan Lee. Snapshots of ABCG1 and ABCG5/G8: A Sterol’s Journey to Cross the Cellular Membranes. International Journal of Molecular Sciences 2023, 24 (1) , 484.
    9. Aljoša Smajić, Melanie Grandits, Gerhard F. Ecker. Using Jupyter Notebooks for re-training machine learning models. Journal of Cheminformatics 2022, 14 (1)
    10. Hamisha Salim, Alan M. Jones. Angiotensin II receptor blockers (ARBs) and manufacturing contamination: A retrospective National Register Study into suspected associated adverse drug reactions. British Journal of Clinical Pharmacology 2022, 88 (11) , 4812-4827.
    11. Emma Arnesdotter, Eva Gijbels, Bruna dos Santos Rodrigues, Vânia Vilas-Boas, Mathieu Vinken. Adverse Outcome Pathways as Versatile Tools in Liver Toxicity Testing. 2022, 521-535.
    12. Raquel Rodríguez-Pérez, Grégori Gerebtzoff. Identification of bile salt export pump inhibitors using machine learning: Predictive safety from an industry perspective. Artificial Intelligence in the Life Sciences 2021, 1 , 100027.
    13. William A. Murphy, Chitra Saran, Paavo Honkakoski, Kim L.R. Brouwer. Mechanism‐Based Experimental Models for the Evaluation of BSEP Inhibition and DILI. 2021, 261-306.
    14. Sid Bhoopathy, Chris Bode, Vatsala Naageshwaran, Erica Weiskircher-Hildebrandt, Venkata Mukkavilli, Ismael J. Hidalgo. Principles and Experimental Considerations for In Vitro Transporter Interaction Assays. 2021, 339-365.
    15. Lily Dara, Neil Kaplowitz. Drug‐Induced Liver Injury. 2020, 701-713.
    16. Xiaoyang Lu, Lin Liu, Wenya Shan, Limin Kong, Na Chen, Yan Lou, Su Zeng. The Role of the Sodium-taurocholate Co-transporting Polypeptide (NTCP) and Bile Salt Export Pump (BSEP) in Related Liver Disease. Current Drug Metabolism 2019, 20 (5) , 377-389.
    17. Avner Schlessinger, Matthew A. Welch, Herman van Vlijmen, Ken Korzekwa, Peter W. Swaan, Pär Matsson. Molecular Modeling of Drug–Transporter Interactions—An International Transporter Consortium Perspective. Clinical Pharmacology & Therapeutics 2018, 104 (5) , 818-835.
    18. J. Gerry Kenna, Kunal S. Taskar, Christina Battista, David L. Bourdet, Kim L.R. Brouwer, Kenneth R. Brouwer, David Dai, Christoph Funk, Michael J. Hafey, Yurong Lai, Jonathan Maher, Y. Anne Pak, Jenny M. Pedersen, Joseph W. Polli, A. David Rodrigues, Paul B. Watkins, Kyunghee Yang, Robert W. Yucha, . Can Bile Salt Export Pump Inhibition Testing in Drug Discovery and Development Reduce Liver Injury Risk? An International Transporter Consortium Perspective. Clinical Pharmacology & Therapeutics 2018, 104 (5) , 916-932.
    19. Eleni Kotsampasakou, Sankalp Jain, Daniela Digles, Gerhard F. Ecker. Transporters in Hepatotoxicity. 2018, 145-174.
    20. Franck A. Atienzar, Jean-Marie Nicolas. Prediction of Human Liver Toxicity Using In Vitro Assays: Limitations and Opportunities. 2018, 125-150.
    21. Guangyi Yang, Shufan Ge, Rashim Singh, Sumit Basu, Katherine Shatzer, Ming Zen, Jiong Liu, Yifan Tu, Chenning Zhang, Jinbao Wei, Jian Shi, Lijun Zhu, Zhongqiu Liu, Yuan Wang, Song Gao, Ming Hu. Glucuronidation: driving factors and their impact on glucuronide disposition. Drug Metabolism Reviews 2017, 49 (2) , 105-138.
    22. L. Dara, Z.-X. Liu, N. Kaplowitz. Pathogenesis of Idiosyncratic Drug Induced Liver Injury. 2017, 87-100.
    23. Mathieu Vinken. Adverse Outcome Pathways as Tools to Assess Drug-Induced Toxicity. 2016, 325-337.
    24. Toshihisa Ishikawa, Takeaki Fukami, Makoto Nagakura, Hiroyuki Hirano. Current Status and Implications of Transporters: QSAR Analysis Method to Evaluate Drug–Drug Interactions of Human Bile Salt Export Pump (ABCB11/BSEP) and Prediction of Intrahepatic Cholestasis Risk. 2015, 333-347.
    25. Jane A. Barber, Simone H. Stahl, Claire Summers, Gillian Barrett, B. Kevin Park, John R. Foster, J. Gerald Kenna. Quantification of Drug-Induced Inhibition of Canalicular Cholyl-l-Lysyl-Fluorescein Excretion From Hepatocytes by High Content Cell Imaging. Toxicological Sciences 2015, 148 (1) , 48-59.
    26. Marta Pinto, Daniela Digles, Gerhard F. Ecker. Computational models for predicting the interaction with ABC transporters. Drug Discovery Today: Technologies 2014, 12 , e69-e77.
    27. Sean Ekins. Progress in computational toxicology. Journal of Pharmacological and Toxicological Methods 2014, 69 (2) , 115-140.
    28. Sid Bhoopathy, Chris Bode, Vatsala Naageshwaran, Erica A. Weiskircher-Hildebrandt, Ismael J. Hidalgo. Principles and Experimental Considerations for In Vitro Transporter Interaction Assays. 2014, 229-252.
    29. Mathieu Vinken. The adverse outcome pathway concept: A pragmatic tool in toxicology. Toxicology 2013, 312 , 158-165.
    30. Eugenia Ulzurrun, Camilla Stephens, Esperanza Crespo, Francisco Ruiz‐Cabello, Julia Ruiz‐Nuñez, Pablo Saenz‐López, Inmaculada Moreno‐Herrera, Mercedes Robles‐Díaz, Hacibe Hallal, José M. Moreno‐Planas, Maria R. Cabello, M. Isabel Lucena, Raúl J. Andrade. Role of chemical structures and the 1331T>C bile salt export pump polymorphism in idiosyncratic drug‐induced liver injury. Liver International 2013, 33 (9) , 1378-1385.
    31. Kyunghee Yang, Kathleen Köck, Alexander Sedykh, Alexander Tropsha, Kim L.R. Brouwer. An updated review on drug-induced cholestasis: Mechanisms and investigation of physicochemical properties and pharmacokinetic parameters. Journal of Pharmaceutical Sciences 2013, 102 (9) , 3037-3057.
    32. Toshihisa Ishikawa, Joseph Ware. Future Perspectives. 2013, 401-416.
    33. J. Gerry Kenna, Simone H. Stahl, Tobias Noeske. Strategies for Minimisation of the Cholestatic Liver Injury Liability Posed by Drug-Induced Bile Salt Export Pump (BSEP) Inhibition. 2013, 191-223.
    34. Per Artursson, Pär Matsson, Maria Karlgren. In Vitro Characterization of Interactions with Drug Transporting Proteins. 2013, 37-65.
    35. Yurong Lai. The bile salt export pump (BSEP/ABCB11). 2013, 327-352.
    36. Toshihisa Ishikawa, Hikaru Saito, Hiroyuki Hirano, Yutaka Inoue, Yoji Ikegami. Human ABC Transporter ABCG2 in Cancer Chemotherapy: Drug Molecular Design to Circumvent Multidrug Resistance. 2012, 267-278.
    37. Sarah Dawson, Simone Stahl, Nikki Paul, Jane Barber, J. Gerald Kenna. In Vitro Inhibition of the Bile Salt Export Pump Correlates with Risk of Cholestatic Drug-Induced Liver Injury in Humans. Drug Metabolism and Disposition 2012, 40 (1) , 130-138.
    38. Bruno Stieger. The Role of the Sodium-Taurocholate Cotransporting Polypeptide (NTCP) and of the Bile Salt Export Pump (BSEP) in Physiology and Pathophysiology of Bile Formation. 2011, 205-259.
    39. Bruno Stieger. Role of the bile salt export pump, BSEP, in acquired forms of cholestasis. Drug Metabolism Reviews 2010, 42 (3) , 437-445.
    40. Toshihisa Ishikawa, Aki Sakurai, Hiroyuki Hirano, Alexander Lezhava, Minoru Sakurai, Yoshihide Hayashizaki. Emerging New Technologies in Pharamcogenomics: Rapid SNP detection, molecular dynamic simulation, and QSAR analysis methods to validate clinically important genetic variants of human ABC Transporter ABCB1 (P-gp/MDR1). Pharmacology & Therapeutics 2010, 126 (1) , 69-81.
    41. Kristina K. Wolf, Sapana Vora, Lindsey O. Webster, Grant T. Generaux, Joseph W. Polli, Kim L.R. Brouwer. Use of cassette dosing in sandwich-cultured rat and human hepatocytes to identify drugs that inhibit bile acid transport. Toxicology in Vitro 2010, 24 (1) , 297-309.
    42. Jashvant D. Unadkat, Brian J. Kirby, Christopher J. Endres, Joseph K. Zolnerciks. The Impact and In Vitro to In Vivo Prediction of Transporter-Based Drug–Drug Interactions in Humans. 2010, 517-553.
    43. Gerhard F. Ecker. QSAR Studies on ABC Transporter – How to Deal with Polyspecificity. 2009, 195-214.
    44. Sean Ekins. Drug Transporter Pharmacophores. 2009, 215-227.
    45. Yurong Lai. Identification of interspecies difference in hepatobiliary transporters to improve extrapolation of human biliary secretion. Expert Opinion on Drug Metabolism & Toxicology 2009, 5 (10) , 1175-1187.
    46. Hikaru Saito, Masako Osumi, Hiroyuki Hirano, Wangsoo Shin, Ryota Nakamura, Toshihisa Ishikawa. Technical Pitfalls and Improvements for High-speed Screening and QSAR Analysis to Predict Inhibitors of the Human Bile Salt Export Pump (ABCB11/BSEP). The AAPS Journal 2009, 11 (3)
    47. Bruno Stieger. Recent insights into the function and regulation of the bile salt export pump (ABCB11). Current Opinion in Lipidology 2009, 20 (3) , 176-181.
    48. Anna‐Lena Ungell, Per Artursson. An Overview of Caco‐2 and Alternatives for Prediction of Intestinal Drug Transport and Absorption. 2008, 133-159.
    49. S. Koshiba, R. An, H. Saito, K. Wakabayashi, A. Tamura, T. Ishikawa. Human ABC transporters ABCG2 (BCRP) and ABCG4. Xenobiotica 2008, 38 (7-8) , 863-888.
    50. Axel Pähler, Christoph Funk. Chapter 2 Drug-Induced Hepatotoxicity: Learning from Recent Cases of Drug Attrition. 2008, 25-56.
    51. Nadine Zidek, Juergen Hellmann, Peter-Juergen Kramer, Philip G. Hewitt. Acute Hepatotoxicity: A Predictive Model Based on Focused Illumina Microarrays. Toxicological Sciences 2007, 99 (1) , 289-302.
    52. Alan F Hofmann. Biliary secretion and excretion in health and disease: Current concepts. Annals of Hepatology 2007, 6 (1) , 15-27.
    53. Aki Sakurai, Atsuo Kurata, Yuko Onishi, Hiroyuki Hirano, Toshihisa Ishikawa. Prediction of drug-induced intrahepatic cholestasis: in vitro screening and QSAR analysis ofdrugs inhibiting the human bile salt export pump. Expert Opinion on Drug Safety 2007, 6 (1) , 71-86.
    54. Kanako Wakabayashi, Ai Tamura, Hikaru Saito, Yuko Onishi, Toshihisa Ishikawa. Human ABC Transporter ABCG2 in Xenobiotic Protection and Redox Biology. Drug Metabolism Reviews 2006, 38 (3) , 371-391.