Multidrug resistant-associated protein 1 (Mrp1, Abcc1; 190 kDa) mediates the ATP-dependent efflux of endo- and xenobiotics and is expressed in various tissues including heart. In mouse heart, Mrp1 is localized primarily in sarcolemma, where it is thought to mediate efflux of the glutathione conjugate of a highly reactive product of lipid peroxidation, 4-hydroxy-nonenal (HNE). We used Doxorubicin (DOX), an anthracycline chemotherapy drug, as a model to induce oxidative stress and lipid peroxidation that has been demonstrated to be associated with cardiac toxicity. Here, we were able to identify GS-HNE in cardiac mitochondria following DOX treatment. DOX also induced Mrp1 expression in both sarcolemma and cardiac mitochondria. The mitochondrial Mrp1 were capable of mediating ATP-dependent transport of Mrp1 substrates such as estradiol-17\#946;-glucuronide, leukotriene C4 and GS-HNE. The transport activities were inhibited by MK571, a selective Mrp1 inhibitor. Sarcolemma membrane vesicles isolated from DOX-treated mice showed similar transport activities for GS-HNE compared to saline controls. However, GS-HNE transport activity in SMP was increased 2-fold in DOX vs. saline treated-mice. A non-linear regression analysis of sarcolemma membrane vesicle transport from FVB wild-type mice yielded Km and Vmax values of 55.6 \#956;mol/L and 983.5 pmol/min/mg protein, respectively. No Mrp1 transport activity was observed in Mrp1-/- sarcolemma membrane vesicles, indicating that transport of GS-HNE was mediated by Mrp1. Thus, we demonstrate here that functional Mrp1 is localized in sarcolemma and mitochondria following DOX. Mrp1 may serve to protect the heart by mediating efflux of toxic products of oxidative stress such as highly reactive lipid peroxide, HNE from mitochondria and the cardiomyocyte.

Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 917.

100th AACR Annual Meeting-- Apr 18-22, 2009; Denver, CO