ATP-dependent 17 beta-estradiol 17-(beta-D-glucuronide) transport by multidrug resistance protein (MRP). Inhibition by cholestatic steroids.
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Loe DW, Almquist KC, Cole SP, Deeley RG
ATP-dependent 17 beta-estradiol 17-(beta-D-glucuronide) transport by multidrug resistance protein (MRP). Inhibition by cholestatic steroids.
J Biol Chem. 1996 Apr 19;271(16):9683-9.
- PubMed ID
- 8621644 [ View in PubMed]
- Abstract
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, LTC4, 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 beta-estradiol 17-(beta-D-glucuronide) (E(2)17 beta G), was readily demonstrable in plasma membrane vesicles from populations of MRP-transfected HeLa cells (Vmax 1.4 nmol mg-1 min-1, K(m) 2.5 micron). 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 LTC4, was competitively inhibited by E(2)17 beta G (K(i(app)) 22 micron), despite the lack of structural similarity between these two substrates. Competitive inhibition of [3H]E(2)17 beta G transport was also observed with a number of other cholestatic conjugated steroids. All of these compounds prevented photolabeling of MRP with [3H]LTC4, 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 E(2)17 beta G transport indicated that daunorubicin had the highest relative potency of the drugs tested, whereas it was the least potent inhibitor of LTC4 transport. Non-cholestatic steroids glucuronidated at the 3 position of the steroid nucleus, such as 17 beta-estradiol 3-(beta-D-glucuronide), did not compete for transport of E(2)17 beta G by MRP, nor did they inhibit photolabeling of the protein with [3H]LTC4. These data identify MRP as a potential transporter of cholestatic conjugated estrogens and demonstrate site-specific requirements for glucuronidation of the steroid nucleus.
DrugBank Data that Cites this Article
- Drug Transporters
Drug Transporter Kind Organism Pharmacological Action Actions Daunorubicin Multidrug resistance-associated protein 1 Protein Humans UnknownSubstrateInhibitorDetails Doxorubicin Multidrug resistance-associated protein 1 Protein Humans UnknownSubstrateInhibitorDetails Vinblastine Multidrug resistance-associated protein 1 Protein Humans UnknownSubstrateInhibitorInducerDetails Vincristine Multidrug resistance-associated protein 1 Protein Humans UnknownSubstrateInhibitorDetails - Binding Properties
Drug Target Property Measurement pH Temperature (°C) Daunorubicin Multidrug resistance-associated protein 1 IC 50 (nM) 8000 N/A N/A Details Doxorubicin Multidrug resistance-associated protein 1 IC 50 (nM) 50000 N/A N/A Details Vinblastine Multidrug resistance-associated protein 1 IC 50 (nM) 30000 N/A N/A Details Vincristine Multidrug resistance-associated protein 1 IC 50 (nM) 70000 N/A N/A Details