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Research ArticleToxicology

Loss of Multidrug Resistance–Associated Protein 1 Potentiates Chronic Doxorubicin-Induced Cardiac Dysfunction in Mice

Wei Zhang, Jun Deng, Manjula Sunkara, Andrew J. Morris, Chi Wang, Daret St. Clair and Mary Vore
Journal of Pharmacology and Experimental Therapeutics November 2015, 355 (2) 280-287; DOI: https://doi.org/10.1124/jpet.115.225581
Wei Zhang
Department of Toxicology and Cancer Biology (W.Z., J.D., D.S.C., M.V.), Division of Cardiovascular Medicine, (M.S., A.J.M), and Markey Cancer Center (C.W.), College of Medicine, University of Kentucky, Lexington, Kentucky
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Jun Deng
Department of Toxicology and Cancer Biology (W.Z., J.D., D.S.C., M.V.), Division of Cardiovascular Medicine, (M.S., A.J.M), and Markey Cancer Center (C.W.), College of Medicine, University of Kentucky, Lexington, Kentucky
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Manjula Sunkara
Department of Toxicology and Cancer Biology (W.Z., J.D., D.S.C., M.V.), Division of Cardiovascular Medicine, (M.S., A.J.M), and Markey Cancer Center (C.W.), College of Medicine, University of Kentucky, Lexington, Kentucky
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Andrew J. Morris
Department of Toxicology and Cancer Biology (W.Z., J.D., D.S.C., M.V.), Division of Cardiovascular Medicine, (M.S., A.J.M), and Markey Cancer Center (C.W.), College of Medicine, University of Kentucky, Lexington, Kentucky
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Chi Wang
Department of Toxicology and Cancer Biology (W.Z., J.D., D.S.C., M.V.), Division of Cardiovascular Medicine, (M.S., A.J.M), and Markey Cancer Center (C.W.), College of Medicine, University of Kentucky, Lexington, Kentucky
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Daret St. Clair
Department of Toxicology and Cancer Biology (W.Z., J.D., D.S.C., M.V.), Division of Cardiovascular Medicine, (M.S., A.J.M), and Markey Cancer Center (C.W.), College of Medicine, University of Kentucky, Lexington, Kentucky
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Mary Vore
Department of Toxicology and Cancer Biology (W.Z., J.D., D.S.C., M.V.), Division of Cardiovascular Medicine, (M.S., A.J.M), and Markey Cancer Center (C.W.), College of Medicine, University of Kentucky, Lexington, Kentucky
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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.

Footnotes

    • Received April 29, 2015.
    • Accepted August 26, 2015.
  • ↵1 Current affiliation: College of Pharmaceutical Sciences, Southwest University, Chongqing, China.

  • This research was supported by the National Institutes of Health National Cancer Institute [Grants R01CA139844 and P30CA177558 (to the Biostatistics and Bioinformatics, Biospecimen and Tissue Procurement and Redox Metabolism Shared Resources of the University of Kentucky Markey Cancer Center)] and by an Institutional Development Award (IDeA) from the National Institute of General Medical Sciences of the National Institutes of Health [P20 GM103527]. W.Z. was supported by the American Heart Association [Predoctoral Fellowship 17060037].

  • dx.doi.org/10.1124/jpet.115.225581.

  • ↵Embedded ImageThis article has supplemental material available at jpet.aspetjournals.org.

  • Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 355 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 355, Issue 2
1 Nov 2015
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Research ArticleToxicology

Mrp1 and Doxorubicin-Induced Cardiac Dysfunction

Wei Zhang, Jun Deng, Manjula Sunkara, Andrew J. Morris, Chi Wang, Daret St. Clair and Mary Vore
Journal of Pharmacology and Experimental Therapeutics November 1, 2015, 355 (2) 280-287; DOI: https://doi.org/10.1124/jpet.115.225581

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Research ArticleToxicology

Mrp1 and Doxorubicin-Induced Cardiac Dysfunction

Wei Zhang, Jun Deng, Manjula Sunkara, Andrew J. Morris, Chi Wang, Daret St. Clair and Mary Vore
Journal of Pharmacology and Experimental Therapeutics November 1, 2015, 355 (2) 280-287; DOI: https://doi.org/10.1124/jpet.115.225581
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