This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Grzywacz, M. J. Articles by Hait, W. N. Search for Related Content PubMed PubMed Citation Articles by Grzywacz, M. J. Articles by Hait, W. N.

Effect of the Multidrug Resistance Protein on the Transport of the Antiandrogen Flutamide¹

The Cancer Institute of New Jersey, Departments of Medicine and Pharmacology [M. J. G., J-M. Y., W. N. H.], University of Medicine and Dentistry of New Jersey-Robert Wood Johnson Medical School, New Brunswick, New Jersey 08901

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°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.

This article has been cited by other articles:

				R. G. Deeley, C. Westlake, and S. P. C. Cole Transmembrane Transport of Endo- and Xenobiotics by Mammalian ATP-Binding Cassette Multidrug Resistance Proteins. Physiol Rev, July 1, 2006; 86(3): 849 - 899. [Abstract] [Full Text] [PDF]

				R. Obligacion, M. Murray, and I. Ramzan Drug-Metabolizing Enzymes and Transporters: Expression in the Human Prostate and Roles in Prostate Drug Disposition J Androl, March 1, 2006; 27(2): 138 - 150. [Full Text] [PDF]