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Cited by 92Drug Transport and Resistance MechanismsComputational Drug Discovery MethodsPharmacogenetics and Drug Metabolism

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A New Strategy of High-Speed Screening and Quantitative Structure-Activity Relationship Analysis to Evaluate Human ATP-Binding Cassette Transporter ABCG2-Drug Interactions

Saito, Hikaru, Hirano, Hiroyuki, Nakagawa, Hiroshi, Fukami, Takeaki, Oosumi, Keisuke, Murakami, Kaori, Kimura, Hiroko, Kouchi, Takayuki, Konomi, Mami, Tao, Eriko, Tsujikawa, Noboru, Tarui, Shigeki, Nagakura, Makoto, Osumi, Masako, Ishikawa, Toshihisa·2006·The Journal of Pharmacology and Experimental Therapeutics
DOI 10.1124/jpet.105.099036
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Abstract

The human ATP-binding cassette (ABC) transporter ABCG2 (BCRP/MXR1/ABCP) plays a critical role in cellular protection against xenobiotics as well as pharmacokinetics of drugs in our body. In the present study, we aimed to analyze the quantitative structure-activity relationship (QSAR) latently residing in ABCG2-drug interactions. We first established standard methods for expression of human ABCG2 in insect cells, quality control of plasma membrane samples by using electron microscopy techniques, and high-speed screening of ABCG2 inhibition with test compounds. Plasma membrane vesicles prepared from ABCG2-expressing Sf9 cells were used as a model system to measure the ATP-dependent transport of [3H]methotrexate (MTX). Forty-nine different therapeutic drugs and natural compounds were tested for their ability to inhibit ABCG2-mediated MTX transport. Based on their inhibition profiles, we performed QSAR analysis using chemical fragmentation codes deduced from the structures of test compounds. Multiple linear regression analysis delineated a relationship between the structural components and the extent of ABCG2 inhibition, allowing us to identify one set of structure-specific chemical fragmentation codes that are closely correlated with the inhibition of ABCG2 transport activity. Based on the QSAR analysis data, we predicted the potency of gefitinib to inhibit ABCG2. The validity of our QSAR-based prediction for gefitinib was examined by actual experiments. Our kinetic analysis experiments suggest that the ABCG2-ATP complex binds gefitinib. The present study provides a new strategy for analyzing ABCG2-drug interactions. This strategy is considered to be practical and useful for the molecular designing of new ABCG2 modulators.

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  1. Ahmed-Belkacem A, Pozza A, Munoz-Martinez F, Bates SE, Castanys S, Gamarro F, Di Pietro A, and Perez-Victoria JM (2005) Flavonoid structure-activity studies identify 6-prenylchrysin and tectochrysin as potent and specific inhibitors of breast cancer resistance protein ABCG2. Cancer Res 65: 4852–4860. · DOI
  2. Brehmer D, Greff Z, Godl K, Blencke S, Kurtenbach A, Weber M, Muller S, Klebl B, Cotten M, Keri G, et al. (2005) Cellular targets of gefitinib. Cancer Res 65: 379–382. · DOI
  3. Cooray HC, Janvilisri T, van Veen HW, Hladky SB, and Barrand MA (2004) Interaction of the breast cancer resistance protein with plant polyphenols. Biochem Biophys Res Commun 317: 269–275. · DOI
  4. Doyle LA and Ross DD (2003) Multidrug resistance mediated by the breast cancer resistance protein BCRP (ABCG2). Oncogene 22: 7340–7358. · DOI
  5. Doyle LA, Yang W, Abruzzo LV, Krogmann T, Gao Y, Rishi AK, and Ross DD (1998) A multidrug resistance transporter from human MCF-7 breast cancer cells. Proc Natl Acad Sci USA 95: 15665–15670. · DOI
  6. Ekins S, Kim RB, Leake BF, Dantzig AH, Schuetz EG, Lan LB, Yasuda K, Shepard RL, Winter MA, Schuetz JD, et al. (2002) Application of three-dimensional quantitative structure-activity relationships of P-glycoprotein inhibitors and substrates. Mol Pharmacol 61: 974–981. · DOI
  7. Elkind NB, Szentpetery Z, Apati A, Özvegy-Laczka C, Varady G, Ujhelly O, Szabo K, Homolya L, Varadi A, Buday L, et al. (2005) Multidrug transporter ABCG2 prevents tumor cell death induced by the epidermal growth factor receptor inhibitor Iressa (ZD1839, Gefitinib). Cancer Res 65: 1770–1777. · DOI
  8. Hansch C (1981) The physicochemical approach to drug design and discovery (OSAR). Drug Dev Res 1: 267–309. · DOI
  9. Imai Y, Tsukahara S, Asada S, and Sugimoto Y (2004) Phytoestrogens/flavonoids reverse breast cancer resistance protein/ABCG2-mediated multidrug resistance. Cancer Res 64: 4346–4352. · DOI
  10. Ishikawa T (1989) ATP/Mg2+-dependent cardiac transport system for glutathione S-conjugates: a study using rat heart sarcolemma vesicles. J Biol Chem 264: 17343–17348. · DOI
  11. Ishikawa T, Onishi Y, Hirano H, Oosumi K, Nagakura M, and Tarui S (2004) Pharmacogenomics of drug transporters: a new approach to functional analysis of the genetic polymorphisms of ABCB1 (P-glycoprotein/MDR1). Biol Pharm Bull 27: 939–948. · DOI
  12. Ishikawa T, Sakurai A, Kanamori Y, Nagakura M, Hirano H, Takarada Y, Yamada K, Fukushima K, and Kitajima M (2005) High-speed screening of human ABC transporter function and genetic polymorphisms: new strategies in pharmacogenomics. Methods Enzymol 400: 485–510. · DOI
  13. Jonker JW, Buitelaar M, Wagenaar E, Van Der Valk MA, Scheffer GL, Scheper RJ, Plosch T, Kuipers F, Elferink RP, Rosing H, et al. (2002) The breast cancer resistance protein protects against a major chlorophyll-derived dietary phototoxin and protoporphyria. Proc Natl Acad Sci USA 99: 15649–15654. · DOI · Paper page
  14. Jonker JW, Merino G, Musters S, van Herwaarden AE, Bolscher E, Wagenaar E, Mesman E, Dale TC, and Schinkel AH (2005) The breast cancer resistance protein BCRP (ABCG2) concentrates drugs and carcinogenic xenotoxins into milk. Nat Med 11: 127–129. · DOI
  15. Jonker JW, Smit JW, Brinkhuis RF, Maliepaard M, Beijnen JH, Schellens JH, and Schinkel AH (2000) Role of breast cancer resistance protein in the bioavailability and fetal penetration of topotecan. J Natl Cancer Inst 92: 1651–1656. · DOI
  16. Kawabata S, Oka M, Shiozawa K, Tsukamoto K, Nakatomi K, Soda H, Fukuda M, Ikegami Y, Sugahara K, Yamada Y, et al. (2001) Breast cancer resistance protein directly confers SN-38 resistance of lung cancer cells. Biochem Biophys Res Commun 280: 1216–1223. · DOI
  17. Klopman G, Shi LM, and Ramu A (1997) Quantitative structure-activity relationship of multidrug resistance reversal agents. Mol Pharmacol 52: 323–334. · DOI
  18. Litman T, Brangi M, Hudson E, Fetsch P, Abati A, Ross DD, Miyake K, Resau JH, and Bates SE (2000) The multidrug-resistant phenotype associated with overexpression of the new ABC half-transporter, MXR (ABCG2). J Cell Sci 113: 2011–2021. · DOI
  19. Mitomo H, Kato R, Ito A, Kasamatsu S, Ikegami Y, Kii I, Kudo A, Kobatake E, Sumino Y, and Ishikawa T (2003) A functional study on polymorphism of the ATP-binding cassette transporter ABCG2: critical role of arginine-482 in methotrexate transport. Biochem J 373: 767–774. · DOI
  20. Nakatomi K, Yoshikawa M, Oka M, Ikegami Y, Hayasaka S, Sano K, Shiozawa K, Kawabata S, Soda H, Ishikawa T, et al. (2001) Transport of 7-ethyl-10-hydroxycamptothecin (SN-38) by breast cancer resistance protein ABCG2 in human lung cancer cells. Biochem Biophys Res Commun 288: 827–832. · DOI
  21. Noble ME, Endicott JA, and Johnson LN (2004) Protein kinase inhibitors: insights into drug design from structure. Science (Wash DC) 303: 1800–1805. · DOI
  22. Özvegy-Laczka C, Hegedus T, Varady G, Ujhelly O, Schuetz JD, Varadi A, Keri G, Orfi L, Nemet K, and Sarkadi B. (2004) High-affinity interaction of tyrosine kinase inhibitors with the ABCG2 multidrug transporter. Mol Pharmacol 65: 1485–1495. · DOI
  23. Sarkadi B, Özvegy-Laczka C, Nemet K, and Varadi A (2004) ABCG2—a transporter for all seasons. FEBS Lett 567: 116–120. · DOI
  24. Schmid D, Ecker G, Kopp S, Hitzler M, and Chiba P (1999) Structure-activity relationship studies of propafenone analogs based on P-glycoprotein ATPase activity measurements. Biochem Pharmacol 58: 1447–1456. · DOI
  25. Sesink AL, Arts IC, de Boer VC, Breedveld P, Schellens JH, Hollman PC, and Russel FG (2005) Breast cancer resistance protein (Bcrp1/Abcg2) limits net intestinal uptake of quercetin in rats by facilitating apical efflux of glucuronides. Mol Pharmacol 67: 1999–2006. · DOI
  26. Stewart CF, Leggas M, Schuetz JD, Panetta JC, Cheshire PJ, Peterson J, Daw N, Jenkins JJ 3rd, Gilbertson R, Germain GS, et al. (2004) Gefitinib enhances the antitumor activity and oral bioavailability of irinotecan in mice. Cancer Res 64: 7491–7499. · DOI
  27. Stouch TR and Gudmundsson O (2002) Progress in understanding the structure-activity relationships of P-glycoprotein. Adv Drug Deliv Rev 54: 315–328. · DOI
  28. Yanase K, Tsukahara S, Asada S, Ishikawa E, Imai Y, and Sugimoto Y (2004) Gefitinib reverses breast cancer resistance protein-mediated drug resistance. Mol Cancer Ther 3: 1119–1125. · DOI
  29. Zhang S, Yang X, and Morris ME (2004) Flavonoids are inhibitors of breast cancer resistance protein (ABCG2)-mediated transport. Mol Pharmacol 65: 1208–1216. · DOI

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Metadata

Authors
Saito, H., Hirano, H., Nakagawa, H., Fukami, T., Oosumi, K., Murakami, K., Kimura, H., Kouchi, T., Konomi, M., Tao, E., Tsujikawa, N., Tarui, S., Nagakura, M., Osumi, M., & Ishikawa, T.
Affiliations
Tokyo Institute of Technology (JP)
ORCID
Venue
The Journal of Pharmacology and Experimental Therapeutics
Publisher
Elsevier BV
Published
2006-06
Volume
317
Issue
3
Pages
1114-1124
ISSN
0022-3565 (ISSN-L)
DOI
10.1124/jpet.105.099036
OpenAlex
W2116612040
Cited by
92
References
0
Citations by year
2025: 1 · 2023: 3 · 2022: 1 · 2021: 3 · 2020: 2 · 2019: 2 · 2018: 2 · 2017: 3 · 2016: 3 · 2015: 5 · 2014: 11 · 2013: 11 · 2012: 7
FWCI
3.97
Type
journal article
Language
en
Open access
closed
Licence
Locations
  • Journal of Pharmacology and Experimental Therapeutics (publishedVersion)
  • PubMed (publishedVersion)
Funders
Yakult Honsha
Topics
  • Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
  • Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Drug Discovery › Computational Drug Discovery Methods
  • Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Pharmacogenetics and Drug Metabolism
Keywords
ABCG2, ABC transporters, drug interactions, methotrexate transport, gefitinib, QSAR, plasma membrane vesicles, Sf9 cells
MeSH terms
ATP Binding Cassette Transporter, Subfamily G, Member 2, Animals, Cell Membrane, Cloning, Molecular, Drug Interactions, Pharmaceutical Preparations, Humans, Methotrexate, Microscopy, Electron, Scanning, Neoplasm Proteins, Molecular Structure, Spodoptera, ATP-Binding Cassette Transporters, Quantitative Structure-Activity Relationship

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