QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: jpet.103.062091v1 309/1/156    most recent Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Chu, X.-Y. Articles by Evers, R. Search for Related Content PubMed PubMed Citation Articles by Chu, X.-Y. Articles by Evers, R.

ABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

Transport of Ethinylestradiol Glucuronide and Ethinylestradiol Sulfate by the Multidrug Resistance Proteins MRP1, MRP2, and MRP3

Department of Drug Metabolism, Merck & Co., Inc., Rahway, New Jersey (X.-Y.C., S.-E.W.H., M.P.B., D.C.E., R.E.); and National Medical Center, Institute of Haematology and Immunology, Budapest, Hungary (B.S.)

Ethinylestradiol (EE) is one of the key constituents of oral contraceptives. Major metabolites of EE in humans are the glucuronide and sulfate conjugates, EE-3-O-glucuronide (EE-G) and EE-3-O-sulfate (EE-S). In the present study, transport of EE-G and EE-S by the human multidrug resistance proteins MRP1, MRP2, and MRP3 was investigated using inside-out membrane vesicles, isolated from Sf9 cells expressing human MRP1, MRP2, or MRP3. Vesicular uptake studies showed that EE-G was not a substrate for MRP1, whereas an ATP-dependent and saturable transport of [³H]EE-G was observed in MRP2 (K_m of 35.1 ± 3.5 µM) and MRP3 (K_m of 9.2 ± 2.3 µM) containing vesicles. EE-S was not transported by either MRP1, MRP2, or MRP3. However, low concentrations of EE-S stimulated MRP2-mediated uptake of ethacrynic acid glutathione. EE-S also stimulated MRP2 and MRP3-mediated uptake of 17-estradiol-17-D-glucuronide. Interestingly, EE-S stimulated strongly MRP2- and MRP3-mediated uptake of EE-G by increasing its apparent transport affinity, whereas no reciprocal stimulation of EE-S uptake by EE-G was observed. These data indicate that EE-S allosterically stimulates MRP2- and MRP3-mediated transport of EE-G and is not cotransported with EE-G. Our studies demonstrate specific active transport of a pharmacologically relevant drug conjugate by human MRP2 and MRP3, involving complex interactions with other organic anions. We also suggest that caution needs to be taken when using only competition studies as screening tools to identify substrates or inhibitors of MRP-mediated transport.

Address correspondence to: Dr. Xiao-Yan Chu, Department of Drug Metabolism, RY80M-112, Merck & Co., Inc., 126 East Lincoln Ave., Rahway, NJ. E-mail: xiaoyan_chu{at}merck.com

This article has been cited by other articles:

				P. M. Gerk, W. Li, V. Megaraj, and M. Vore Human Multidrug Resistance Protein 2 Transports the Therapeutic Bile Salt Tauroursodeoxycholate J. Pharmacol. Exp. Ther., February 1, 2007; 320(2): 893 - 899. [Abstract] [Full Text] [PDF]

				R. G. Deeley, C. Westlake, and S. P. C. Cole Transmembrane Transport of Endo- and Xenobiotics by Mammalian ATP-Binding Cassette Multidrug Resistance Proteins. Physiol Rev, July 1, 2006; 86(3): 849 - 899. [Abstract] [Full Text] [PDF]

				Y.-H. Huang, C.-Y. Lee, P.-J. Tai, C.-C. Yen, C.-Y. Liao, W.-J. Chen, C.-J. Liao, W.-L. Cheng, R.-N. Chen, S.-M. Wu, et al. Indirect Regulation of Human Dehydroepiandrosterone Sulfotransferase Family 1A Member 2 by Thyroid Hormones Endocrinology, May 1, 2006; 147(5): 2481 - 2489. [Abstract] [Full Text] [PDF]

				C. S. Morrow, C. Peklak-Scott, B. Bishwokarma, T. E. Kute, P. K. Smitherman, and A. J. Townsend Multidrug Resistance Protein 1 (MRP1, ABCC1) Mediates Resistance to Mitoxantrone via Glutathione-Dependent Drug Efflux Mol. Pharmacol., April 1, 2006; 69(4): 1499 - 1505. [Abstract] [Full Text] [PDF]

				H.-L. Fang, S. C. Strom, H. Cai, C. N. Falany, T. A. Kocarek, and M. Runge-Morris Regulation of Human Hepatic Hydroxysteroid Sulfotransferase Gene Expression by the Peroxisome Proliferator-Activated Receptor {alpha} Transcription Factor Mol. Pharmacol., April 1, 2005; 67(4): 1257 - 1267. [Abstract] [Full Text] [PDF]

				Z.-S. Chen, Y. Guo, M. G. Belinsky, E. Kotova, and G. D. Kruh Transport of Bile Acids, Sulfated Steroids, Estradiol 17-{beta}-D-Glucuronide, and Leukotriene C4 by Human Multidrug Resistance Protein 8 (ABCC11) Mol. Pharmacol., February 1, 2005; 67(2): 545 - 557. [Abstract] [Full Text] [PDF]

				P. M. Gerk, W. Li, and M. Vore ESTRADIOL 3-GLUCURONIDE IS TRANSPORTED BY THE MULTIDRUG RESISTANCE-ASSOCIATED PROTEIN 2 BUT DOES NOT ACTIVATE THE ALLOSTERIC SITE BOUND BY ESTRADIOL 17-GLUCURONIDE Drug Metab. Dispos., October 1, 2004; 32(10): 1139 - 1145. [Abstract] [Full Text] [PDF]