Elevated glutathione is not sufficient to protect against doxorubicin-induced nuclear damage in heart in multidrug resistance-associated Protein 1 (Mrp1/Abcc1) null mices

Jun Deng, Donna Coy, Wei Zhang, Manjula Sunkara, Andrew J. Morris, Chi Wang, Luksana Chaiswing, Daret St Clair, Mary Vore, Paiboon Jungsuwadee

Research output: Contribution to journalArticlepeer-review

13 Scopus citations

Abstract

Cardiotoxicity is a major dose-limiting adverse effect of doxorubicin (DOX), mediated in part by overproduction of reactive oxygen species and oxidative stress. Abcc1 (Mrp1) mediates the efflux of reduced and oxidized glutathione (GSH, GSSG) and is also a major transporter that effluxes the GSH conjugate of 4-hydroxy-2-nonenal (HNE; GS-HNE), a toxic product of lipid peroxidation formed during oxidative stress. To assess the role of Mrp1 in protecting the heart from DOX-induced cardiac injury, wild-type (WT) and Mrp1 null (Mrp12/2) C57BL/6 littermate mice were administered DOX (15 mg/kg) or saline (7.5 ml/kg) i.v., and heart ventricles were examined at 72 hours. Morphometric analysis by electron microscopy revealed extensive injuries in cytosol, mitochondria, and nuclei of DOX-treated mice in both genotypes. Significantly more severely injured nuclei were observed in Mrp12/2 versusWT mice (P < 0.031). GSH and the GSH/GSSG ratio were significantly increased in treatmentnaïve Mrp12/2 versus WT mice; GSH remained significantly higher in Mrp1-/- versus WT mice after saline and DOX treatment, with no changes in GSSG or GSH/GSSG. GS-HNE, measured by mass spectrometry, was lower in the hearts of treatment-naïve Mrp1-/- versus WT mice (P <0.05). DOX treatment decreased GS-HNE inWT but notMrp1-/- mice, so that GS-HNE was modestly but significantly higher in Mrp1-/- versus WT hearts after DOX. Expression of enzymes mediating GSH synthesis and antioxidant proteins did not differ between genotypes. Thus, despite elevated GSH levels in Mrp1-/- hearts, DOX induced significantly more injury in the nuclei of Mrp1-/- versus WT hearts.

Original languageEnglish
Pages (from-to)272-279
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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