Loss of Mrp1 Potentiates Doxorubicin-Induced Cytotoxicity in Neonatal Mouse Cardiomyocytes and Cardiac Fibroblasts

Doxorubicin (DOX) induces dose-dependent cardiotoxicity in part due to its ability to induce oxidative stress. We showed that loss of multidrug resistance-associated protein 1 (Abcc1/Mrp1) potentiates DOX-induced cardiac dysfunction in mice in vivo. Here, we characterized DOX toxicity in cultured cardiomyocytes (CM) and cardiac fibroblasts (CF) derived from C57BL wild type (WT) and Mrp1 null (Mrp1−/−) neonatal mice. CM accumulated more intracellular DOX relative to CF but this accumulation did not differ between genotypes. Following DOX (0.3–4 μM), Mrp1−/− CM, and CF, especially CM, showed a greater decrease in viability and increased apoptosis and DNA damage, demonstrated by higher caspase 3 cleavage, poly (ADP-ribose) polymerase 1 (PARP) cleavage and phosphorylated histone H2AX (γH2AX) levels versus WT cells. Saline- and DOX-treated Mrp1−/− cells had significantly higher intracellular GSH and GSSG compared with WT cells (P