The effect of glutathione on the ATPase activity of MRP1 in its natural membranes.

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Hooijberg JH, Pinedo HM, Vrasdonk C, Priebe W, Lankelma J, Broxterman HJ

The effect of glutathione on the ATPase activity of MRP1 in its natural membranes.

FEBS Lett. 2000 Mar 3;469(1):47-51.

PubMed ID

10708754 [ View in PubMed

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Abstract

The transport mechanism by which the multidrug resistance protein 1 (MRP1) effluxes cytotoxic agents out of cells is still not completely understood. However, the cellular antioxidant glutathione (GSH) has been shown to have an important role in MRP1-mediated drug transport. In this study we show that GSH stimulates the ATPase activity of MRP1 in a natural plasma membrane environment. This stimulation was dose-dependent up to 5 mM. The MRP1 substrates vincristine and daunorubicin do not induce MRP1 ATPase activity. In addition, the effect of GSH on the MRP1 ATPase activity is not increased by daunorubicin or by vincristine. In contrast, a GSH conjugate of daunorubicin (WP811) does induce the ATPase activity of MRP1. In the presence of GSH the effect of WP811 was not significantly increased. Finally, (iso)flavonoid-induced MRP1 ATPase activity is not synergistically increased by the presence of GSH. In conclusion, we show that GSH has no apparent influence on the ATPase reaction induced by several MRP1 substrates and/or modulators. The subclasses of molecules had different effects on the MRP1 ATPase activity, which supports the existence of different drug binding sites.

DrugBank Data that Cites this Article

Drug Transporters

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