Effect of the multidrug resistance protein on the transport of the antiandrogen flutamide.

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Grzywacz MJ, Yang JM, Hait WN

Effect of the multidrug resistance protein on the transport of the antiandrogen flutamide.

Cancer Res. 2003 May 15;63(10):2492-8.

PubMed ID

12750271 [ View in PubMed

]

Abstract

Prostate cancer is the most common noncutaneous malignancy of American men. Although it can be initially treated with androgen deprivation therapy, tumors that relapse become resistant to future hormonal manipulation. We previously found that the multidrug resistance protein (MRP), MRP1, is overexpressed in advanced stage and grade human prostate cancer and is negatively regulated by p53. In this study, we sought to determine whether the cellular accumulation of the antiandrogen flutamide, a drug commonly used in the treatment of prostate cancer, is affected by MRP1 expression. There were significant differences between the wild-type and MRP1-overexpressing cells in efflux and accumulation of flutamide and hydroxyflutamide, its active metabolite. In contrast, transport of dihydrotestosterone was not affected by MRP1. Treating the cells with leukotriene D4, a known MRP1 substrate, or VX-710, an MRP1 modulator, restored flutamide and hydroxyflutamide accumulation. Finally, intracellular glutathione depletion with buthionine sulfoximine or energy depletion using 2-deoxy-D-glucose/sodium azide restored flutamide accumulation to that of parental cells while incubating the cells at 4 degrees C abolished MRP1-mediated transport. In summary, these studies indicate that flutamide and hydroxyflutamide but not dihydrotestosterone are transported by MRP1 and that these findings may contribute to our understanding of resistance to hormone refractory prostate cancer.

DrugBank Data that Cites this Article

Drug Transporters

Drug	Transporter	Kind	Organism	Pharmacological Action	Actions
Biricodar	Multidrug resistance-associated protein 1	Protein	Humans	Unknown	Modulator	Details
Flutamide	Multidrug resistance-associated protein 1	Protein	Humans	Unknown	Substrate	Details