Loss of multidrug resistance-associated protein 1 potentiates chronic doxorubicin-induced cardiac dysfunction in mices

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

Research output: Contribution to journalArticlepeer-review

17 Scopus citations

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 6 0.27-fold) and glutathione disulfide (1.35-fold60.16-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 Mrp12/2 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.

Original languageEnglish
Pages (from-to)280-287
Number of pages8
JournalJournal of Pharmacology and Experimental Therapeutics
Volume355
Issue number2
DOIs
StatePublished - Nov 1 2015

Bibliographical note

Publisher Copyright:
Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics.

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology

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