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Title: Loss of multidrug resistance-associated protein 1 potentiates chronic doxorubicin-induced cardiac dysfunction in mice.

Authors: Zhang, Wei; Deng, Jun; Sunkara, Manjula; Morris, Andrew J; Wang, Chi; St Clair, Daret; Vore, Mary

Published In J Pharmacol Exp Ther, (2015 Nov)

Abstract: 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.

PubMed ID: 26354995 Exiting the NIEHS site

MeSH Terms: Animals; Antibiotics, Antineoplastic/toxicity*; Apoptosis; Cardiotoxicity/metabolism; Cardiotoxicity/pathology; Cardiotoxicity/physiopathology*; Doxorubicin/toxicity*; Glutathione Disulfide/metabolism; Glutathione/analogs & derivatives; Glutathione/metabolism; Leukocyte Count; Mice, Inbred C57BL; Mice, Knockout; Multidrug Resistance-Associated Proteins/genetics*; Myocardial Contraction; Myocardium/metabolism; Myocardium/pathology; Systole; Ventricular Dysfunction, Left/chemically induced; Ventricular Dysfunction, Left/physiopathology

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