Elevated Glutathione Is Not Sufficient to Protect against Doxorubicin-Induced Nuclear Damage in Heart in Multidrug Resistance–Associated Protein 1 (Mrp1/Abcc1) Null Mice
作者： Jun Deng , Donna Coy , Wei Zhang , Manjula Sunkara , Andrew J. Morris
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摘要: Cardiotoxicity is a major dose-limiting adverse effect of doxorubicin (DOX), mediated in part by overproduction reactive oxygen species and oxidative stress. Abcc1 (Mrp1) mediates efflux reduced oxidized glutathione (GSH, GSSG), also transporter that effluxes the GSH-conjugate 4-hydroxy-2-nonenal (HNE; GS-HNE), toxic product lipid peroxidation formed during To assess role Mrp1 protecting heart from DOX-induced cardiac injury, wild type (WT) null (Mrp1-/-) C57BL/6 littermate mice were administered DOX (15 mg/kg) or saline (7.5 mL/kg) intravenously, ventricles examined at 72 h. Morphometric analysis electron microscopy revealed extensive injuries cytosol, mitochondria, nuclei DOX-treated both genotypes. Significantly more severely injured observed Mrp1-/- vs. WT (p = 0.031). GSH GSH/GSSG ratio significantly increased treatment-naive vs mice; remained higher following treatment, with no changes GSSG GSH/GSSG. GS-HNE, measured mass spectrometry, was lower
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