TY - JOUR T1 - Loss of Multidrug Resistance–Associated Protein 1 Potentiates Chronic Doxorubicin-Induced Cardiac Dysfunction in Mice JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther SP - 280 LP - 287 DO - 10.1124/jpet.115.225581 VL - 355 IS - 2 AU - Wei Zhang AU - Jun Deng AU - Manjula Sunkara AU - Andrew J. Morris AU - Chi Wang AU - Daret St. Clair AU - Mary Vore Y1 - 2015/11/01 UR - http://jpet.aspetjournals.org/content/355/2/280.abstract N2 - Doxorubicin (DOX), an effective cancer chemotherapeutic agent, induces dose-dependent cardiotoxicity, in part due to its ability to cause oxidative stress. We investigated the role of multidrug resistance–associated protein 1 (Mrp1/Abcc1) in DOX-induced cardiotoxicity in C57BL wild-type (WT) mice and their Mrp1 null (Mrp1−/−) littermates. Male mice were administered intraperitoneal DOX (3 or 2 mg/kg body weight) or saline twice a week for 3 weeks and examined 2 weeks after the last dose (protocol A total dose: 18 mg/kg) or for 5 weeks, and mice were examined 48 hours and 2 weeks after the last dose (protocol B total dose: 20 mg/kg). Chronic DOX induced body weight loss and hemotoxicity, adverse effects significantly exacerbated in Mrp1−/− versus WT mice. In the heart, significantly higher basal levels of glutathione (1.41-fold ± 0.27-fold) and glutathione disulfide (1.35-fold ± 0.16-fold) were detected in Mrp1−/− versus WT mice, and there were comparable decreases in the glutathione/glutathione disulfide ratio in WT and Mrp1−/− mice after DOX administration. Surprisingly, DOX induced comparable increases in 4-hydroxynonenal glutathione conjugate concentration in hearts from WT and Mrp1−/− mice. However, more DOX-induced apoptosis was detected in Mrp1−/− versus WT hearts (P < 0.05) (protocol A), and cardiac function, assessed by measurement of fractional shortening and ejection fraction with echocardiography, was significantly decreased by DOX in Mrp1−/− versus WT mice (P < 0.05; 95% confidence intervals of 20.0%–24.3% versus 23.7%–29.5% for fractional shortening, and 41.5%–48.4% versus 47.7%–56.7% for ejection fraction; protocol B). Together, these data indicate that Mrp1 protects the mouse heart against chronic DOX-induced cardiotoxicity. ER -