In addition to its ability to confer resistance to a range of natural product type chemotherapeutic agents, multidrug resistance protein (MRP) has been shown to transport the cysteinyl leukotriene, LTC, and several other glutathione (GSH) S-conjugates. We now demonstrate that its range of potential physiological substrates also includes cholestatic glucuronidated steroids. ATP dependent, osmotically sensitive transport of the naturally occurring conjugated estrogen, 17-estradiol 17-(-D-glucuronide) (E17G), was readily demonstrable in plasma membrane vesicles from populations of MRP-transfected HeLa cells (V 1.4 nmol mg min, K 2.5 µM). The involvement of MRP was confirmed by demonstrating that transport was completely inhibited by a monoclonal antibody specific for an intracellular conformational epitope of the protein. MRP-mediated transport of LTC was competitively inhibited by E17G (K 22 µM), despite the lack of structural similarity between these two substrates. Competitive inhibition of [H]E17G transport was also observed with a number of other cholestatic conjugated steroids. All of these compounds prevented photolabeling of MRP with [H]LTC, demonstrating that the cholestatic steroid and leukotriene conjugates compete either for the same or possibly overlapping sites on the protein. Consistent with the presence of overlapping but non-identical sites, studies using chemotherapeutic drugs to inhibit MRP-mediated E17G transport indicated that daunorubicin had the highest relative potency of the drugs tested, whereas it was the least potent inhibitor of LTC transport. Non-cholestatic steroids glucuronidated at the 3 position of the steroid nucleus, such as 17-estradiol 3-(-D-glucuronide), did not compete for transport of E17G by MRP, nor did they inhibit photolabeling of the protein with [H]LTC. These data identify MRP as a potential transporter of cholestatic conjugated estrogens and demonstrate site-specific requirements for glucuronidation of the steroid nucleus.

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				K.-i. Ito, S. L. Olsen, W. Qiu, R. G. Deeley, and S. P. C. Cole Mutation of a Single Conserved Tryptophan in Multidrug Resistance Protein 1 (MRP1/ABCC1) Results in Loss of Drug Resistance and Selective Loss of Organic Anion Transport J. Biol. Chem., May 4, 2001; 276(19): 15616 - 15624. [Abstract] [Full Text] [PDF]

				E. M. Leslie, K.-i. Ito, P. Upadhyaya, S. S. Hecht, R. G. Deeley, and S. P. C. Cole Transport of the beta -O-Glucuronide Conjugate of the Tobacco-specific Carcinogen 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) by the Multidrug Resistance Protein 1 (MRP1). REQUIREMENT FOR GLUTATHIONE OR A NON-SULFUR-CONTAINING ANALOG J. Biol. Chem., July 20, 2001; 276(30): 27846 - 27854. [Abstract] [Full Text] [PDF]

				Z.-S. Chen, K. Lee, and G. D. Kruh Transport of Cyclic Nucleotides and Estradiol 17-beta -D-Glucuronide by Multidrug Resistance Protein 4. RESISTANCE TO 6-MERCAPTOPURINE AND 6-THIOGUANINE J. Biol. Chem., August 31, 2001; 276(36): 33747 - 33754. [Abstract] [Full Text] [PDF]

				D.-W. Zhang, S. P. C. Cole, and R. G. Deeley Identification of a Nonconserved Amino Acid Residue in Multidrug Resistance Protein 1 Important for Determining Substrate Specificity. EVIDENCE FOR FUNCTIONAL INTERACTION BETWEEN TRANSMEMBRANE HELICES 14 AND 17 J. Biol. Chem., September 7, 2001; 276(37): 34966 - 34974. [Abstract] [Full Text] [PDF]

				K.-i. Ito, C. J. Oleschuk, C. Westlake, M. Z. Vasa, R. G. Deeley, and S. P. C. Cole Mutation of Trp1254 in the Multispecific Organic Anion Transporter, Multidrug Resistance Protein 2 (MRP2) (ABCC2), Alters Substrate Specificity and Results in Loss of Methotrexate Transport Activity J. Biol. Chem., October 5, 2001; 276(41): 38108 - 38114. [Abstract] [Full Text] [PDF]