Planta Med 2005; 71(2): 135-141
DOI: 10.1055/s-2005-837780
Original Paper
Biochemistry and Molecular Biology
© Georg Thieme Verlag KG Stuttgart · New York

Inhibitory Activity of a Green Tea Extract and some of its Constituents on Multidrug Resistance-Associated Protein 2 Functionality

M. I. Netsch1 , 2 , H. Gutmann1 , S. Luescher1 , S. Brill1 , C. B. Schmidlin2 , M. H. Kreuter2 , J. Drewe1
  • 1Department of Research and Clinical Pharmacology, University Hospital (Universitätsspital), Basel, Switzerland
  • 2Frutarom Switzerland Ltd., R&D Dept. Phytopharmaceuticals, Waedenswil, Switzerland
Further Information

Publication History

Received: April 16, 2004

Accepted: August 21, 2004

Publication Date:
24 February 2005 (online)

Abstract

Green tea extracts (GTE) might modulate ABC transporter gene expression or function. This may be relevant in the treatment of cancer or in influencing intestinal drug permeability. To gain more insight on the influence of a GTE on secretory transport proteins we investigated the influence of GTE and several green tea components on the mRNA expression level of P-glycoprotein (P-gp) and multidrug resistance-associated protein 2 (MRP2) in human gastrointestinal epithelial LS-180 cells. Furthermore, the functional activity of MRP2, using glutathione methylfluorescein (GS-MF) or [3 H]methotrexate (MTX) as substrate, was investigated in canine kidney cells stably overexpressing human MRP2 (MDCK-MRP2). GTE, at a concentration of 0.01 mg/mL, did not increase mRNA expression of P-gp or MRP2 in LS-180 cells. Functional assays in MDCK-MRP2 cells using GS-MF did not show any effect of 0.01 mg/mL GTE on MRP2 activity. In the same cell line the cellular accumulation of MTX (a specific substrate of MRP2) was significantly increased with the MRP-specific inhibitor MK-571 or with 1 mg/mL GTE, but not with 0.1 mg/mL. The green tea components (-)-epigallocatechin gallate, (-)-epigallocatechin, theanine, or caffeine, each in corresponding concentrations to the respective concentration of GTE, did not show any effect on MRP2 function. These data demonstrate that the mRNA expression patterns of P-gp and MRP2 in LS-180 cells are not altered by 0.01 mg/mL of GTE. However, MRP2 function was inhibited by 1 mg/mL GTE, whereas none of the green tea components tested were responsible for this effect.

References

  • 1 Gottesman M M, Pastan I. Biochemistry of multidrug resistance mediated by the multidrug transporter.  Annu Rev Biochem. 1993;  62 385-427
  • 2 Ambudkar S V, Dey S, Hrycyna C A, Ramachandra M, Pastan I, Gottesman M M. Biochemical, cellular, and pharmacological aspects of the multidrug transporter.  Annu Rev Pharmacol Toxicol. 1999;  39 361-98
  • 3 Borst P, Evers R, Kool M, Wijnholds J. A family of drug transporters: the multidrug resistance-associated proteins.  J Natl Cancer Inst. 2000;  92 1295-302
  • 4 Keppler D, Leier I, Jedlitschky G. Transport of glutathione conjugates and glucuronides by the multidrug resistance proteins MRP1 and MRP2.  Biol Chem. 1997;  378 787-91
  • 5 Kim R B, Fromm M F, Wandel C, Leake B, Wood A J, Roden D M. et al . The drug transporter P-glycoprotein limits oral absorption and brain entry of HIV-1 protease inhibitors.  J Clin Invest. 1998;  101 289-94
  • 6 Greiner B, Eichelbaum M, Fritz P, Kreichgauer H P, von Richter O, Zundler J. et al . The role of intestinal P-glycoprotein in the interaction of digoxin and rifampin.  J Clin Invest. 1999;  104 147-153
  • 7 König J, Nies A T, Cui Y, Leier I, Keppler D. Conjugate export pumps of the multidrug resistance protein (MRP) family: localization, substrate specificity, and MRP2-mediated drug resistance.  Biochim Biophys Acta. 1999;  1461 377-94
  • 8 Evers R, Kool M, van Deemter L, Janssen H, Calafat J, Oomen L C. et al . Drug export activity of the human canalicular multispecific organic anion transporter in polarized kidney MDCK cells expressing cMOAT (MRP2) cDNA.  J Clin Invest. 1998;  101 1310-9
  • 9 Cui Y, König J, Buchholz J K, Spring H, Leier I, Keppler D. Drug resistance and ATP-dependent conjugate transport mediated by the apical multidrug resistance protein, MRP2, permanently expressed in human and canine cells.  Mol Pharmacol. 1999;  55 929-37
  • 10 Hooijberg J H, Broxterman H J, Kool M, Assaraf Y G, Peters G J, Noordhuis P. et al . Antifolate resistance mediated by the multidrug resistance proteins MRP1 and MRP2.  Cancer Res. 1999;  59 2532-5
  • 11 Fujiki H. Two stages of cancer prevention with green tea.  J Cancer Res Clin Oncol. 1999;  125 589-97
  • 12 Kostyuk V A, Potapovich A I, Vladykovskaya E N, Hiramatsu M. Protective effects of green tea catechins against asbestos-induced cell injury.  Planta Medica. 2000;  66 762-4
  • 13 Jodoin J, Demeule M, Beliveau R. Inhibition of the multidrug resistance P-glycoprotein activity by green tea polyphenols.  Biochim Biophys Acta. 2002;  1542 149-59
  • 14 Wang E J, Barecki-Roach M, Johnson W W. Elevation of P-glycoprotein function by a catechin in green tea.  Biochem Biophys Res Commun. 2002;  297 412-8
  • 15 Sadzuka Y, Sugiyama T, Hirota S. Modulation of cancer chemotherapy by green tea.  Clin Cancer Res. 1998;  4 153-56
  • 16 Sadzuka Y, Sugiyama T, Sonobe T. Efficacies of tea components on doxorubicin induced antitumor activity and reversal of multidrug resistance.  Toxicol Lett. 2000;  114 155-62
  • 17 Skehan P, Storeng R, Scudiero D, Monks A, McMahon J, Vistica D. et al . New colorimetric cytotoxicity assay for anticancer-drug screening.  J Natl Cancer Inst. 1990;  82 1107-12
  • 18 Luo F R, Paranjpe P V, Guo A, Rubin E, Sinko P. Intestinal transport of irinotecan in Caco-2 cells and MDCK II cells overexpressing efflux transporters Pgp, cMOAT, and MRP1.  Drug Metab Dispos. 2002;  30 763-70
  • 19 Marbeuf-Gueye C, Broxterman H J, Dubru F, Priebe W, Garnier-Suillerot A. Kinetics of anthracycline efflux from multidrug resistance protein-expressing cancer cells compared with P-glycoprotein-expressing cancer cells.  Mol Pharmacol. 1998;  53 141-7
  • 20 Fromm M F, Kauffmann H M, Fritz P, Burk O, Kroemer H K, Warzok R W. et al . The effect of rifampin treatment on intestinal expression of human MRP transporters.  Am J Pathol. 2000;  157 1575-80
  • 21 Schuetz E G, Beck W T, Schuetz J D. Modulators and substrates of P-glycoprotein and cytochrome P4503A coordinately up-regulate these proteins in human colon carcinoma cells.  Mol Pharmacol. 1996;  49 311-8
  • 22 Pfrunder A, Gutmann H, Beglinger C, Drewe J. Gene expression of CYP3A4, ABC-transporters (MDR1 and MRP1-MRP5) and hPXR in three different human colon carcinoma cell lines.  J Pharm Pharmacol. 2003;  55 59-66

Juergen Drewe, MD, MSc

Department of Clinical Pharmacology and Toxicology

University Clinic Basel

Kantonsspital

Petersgraben 4

4031 Basel

Switzerland

Phone: +41-61-265-3848

Fax: +41-61-265 8581

Email: juergen.drewe@unibas.ch