Transport of glutathione, glucuronate, and sulfate conjugates by the MRP gene-encoded conjugate export pump.

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Jedlitschky G, Leier I, Buchholz U, Barnouin K, Kurz G, Keppler D

Transport of glutathione, glucuronate, and sulfate conjugates by the MRP gene-encoded conjugate export pump.

Cancer Res. 1996 Mar 1;56(5):988-94.

PubMed ID

8640791 [ View in PubMed

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Abstract

Previous studies have identified the ATP-dependent export of glutathione conjugates as a physiological function of the multidrug resistance protein (MRP). The involvement of MRP in the transport of endogenous and xenobiotic conjugates was investigated further using membrane vesicles from MRP-transfected HeLa cells. The ATP-dependent transport of the glutathione conjugates [(3)H]leukotriene C(4), S-(2,4-dinitrophenyl)-[(3)H]glutathione, and (3)H- labeled oxidized glutathione was characterized by determination of the transport efficiency V(max):K(m) amounting to 1031, 114, and 7.1 ml multiplied by min(-1), respectively. Additional endogenous substrates for MRP-mediated transport included the steroid conjugate 17 beta- glucuronosyl [(3)H]estradiol and the bile salt conjugates [6 alpha-(14)C]glucuronosylhyodeoxycholate and 3 alpha-sulfatolithocholyl [(3)H]taurine. The K(m) value of MRP for 17-beta-glucuronosyl [(3)H]estradiol was 1.5 +/- 0.3 microM, with a V(max):K(m) ratio of 42 ml multiplied by mg protein(-1) multiplied by min(-1), and a K(i) value of 0.7 microM for the leukotriene receptor antagonist MK 571. MRP-mediated ATP-dependent transport was observed for the anticancer drug conjugates glucuronosyl [(3)H]etoposide and monocholoro-mono[(3)H]glutathionyl melphalan, but not for unmodified [(14)C]doxorubicin, [(3)H]daunorubicin, or [(3)H]vinblastine. Our results establish that MRP functions as an ATP-dependent export pump not only for glutathione conjugates but also for glucuronidated and sulfated endogenous as well as exogenous compounds.

DrugBank Data that Cites this Article

Drug Transporters

Drug	Transporter	Kind	Organism	Pharmacological Action	Actions
Glutathione	Multidrug resistance-associated protein 1	Protein	Humans	Unknown	Substrate Inhibitor	Details