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

Wei Zhang, Daret St Clair, Allan Butterfield, Mary Vore
Toxicological Sciences: An Official Journal of the Society of Toxicology 2016, 151 (1): 44-56
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 < .05), but the redox potential (Eh) of the GSH/GSSG pool did not differ between genotypes in CM and CF, indicating that Mrp1-/- cells maintain this major redox couple. DOX increased expression of the rate-limiting GSH synthesis enzyme glutamate-cysteine ligase catalytic (GCLc) and regulatory subunits (GCLm) to a significantly greater extent in Mrp1-/- versus WT cells, suggesting adaptive responses to oxidative stress in Mrp1-/- cells that were inadequate to afford protection. Expression of extracellular superoxide dismutase (ECSOD/SOD3) was lower (P < .05) in Mrp1-/- versus WT CM treated with saline (62% ± 8% of WT) or DOX (43% ± 12% of WT). Thus, Mrp1 protects CM in particular and CF against DOX-induced toxicity, potentially by regulating extracellular redox states.

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