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Research Articles: Therapeutics, Targets, and Development

Increase in Mrp1 expression and 4-hydroxy-2-nonenal adduction in heart tissue of Adriamycin-treated C57BL/6 mice

¹ Graduate Center for Toxicology and ² Department of Chemistry and Center of Membrane Sciences, University of Kentucky, Lexington, Kentucky and ³ Prince of Songkhla University, Songkhla, Thailand

Requests for reprints: Mary Vore, Graduate Center for Toxicology, University of Kentucky, 306 Health Sciences Research Building, Lexington, KY 40536. Phone: 859-257-3760; Fax: 859-323-1059. E-mail: maryv{at}uky.edu

Abstract

Multidrug resistance-associated protein 1 (MRP1) mediates the ATP-dependent efflux of endobiotics and xenobiotics, including estradiol 17-(ß-D-glucuronide), leukotriene C₄, and the reduced glutathione conjugate of 4-hydroxy-2-nonenal (HNE), a highly reactive product of lipid peroxidation. Adriamycin is an effective cancer chemotherapeutic drug whose use is limited by cardiotoxicity. Adriamycin induces oxidative stress and production of HNE in cardiac tissue, which may contribute to cardiomyopathy. We investigated the role of Mrp1 in Adriamycin-induced oxidative stress in cardiac tissue. Mice were treated with Adriamycin (20 mg/kg, i.p.), and heart homogenate and sarcolemma membranes were assayed for Mrp1 expression and ATP-dependent transport activity. Expression of Mrp1 was increased at 6 and 24 hours after Adriamycin treatment compared with saline treatment. HNE-adducted proteins were significantly increased (P < 0.001) in the homogenates at 6 hours after Adriamycin treatment and accumulated further with time; HNE adduction of a 190-kDa protein was evident 3 days after Adriamycin treatment. Mrp1 was localized predominately in sarcolemma as shown by confocal and Western blot analysis. Sarcolemma membrane vesicles transported leukotriene C₄ with a K_m and V_max of 51.8 nmol/L and 94.1 pmol/min/mg, respectively, and MK571 (10 µmol/L) inhibited the transport activity by 65%. Exposure of HEK_Mrp1 membranes to HNE (10 µmol/L) significantly decreased the V_max for estradiol 17-(ß-D-glucuronide) transport by 50%. These results show that expression of Mrp1 in the mouse heart is localized predominantly in sarcolemma. Adriamycin treatment increased Mrp1 expression and HNE adduction of Mrp1. Cardiac Mrp1 may play a role in protecting the heart from Adriamycin-induced cardiomyopathy by effluxing HNE conjugates. [Mol Cancer Ther 2006;5(11):2851–60]

Grant support: CA94853 and GM55343.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Received 5/22/06; revised 8/25/06; accepted 9/11/06.

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