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首页> 外文期刊>The Journal of Pharmacology and Experimental Therapeutics: Official Publication of the American Society for Pharmacology and Experimental Therapeutics >Elevated Glutathione Is Not Sufficient to Protect against Doxorubicin-Induced Nuclear Damage in Heart in Multidrug Resistance-Associated Protein 1 (Mrp1/Abcc1) Null Mice
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Elevated Glutathione Is Not Sufficient to Protect against Doxorubicin-Induced Nuclear Damage in Heart in Multidrug Resistance-Associated Protein 1 (Mrp1/Abcc1) Null Mice

机译：升高的谷胱甘肽不足以预防多药抗性相关蛋白1（Mrp1 / Abcc1）空小鼠心脏中的阿霉素诱导的核损伤。

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摘要

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 (Mrp1(-/-)) 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 Mrp1(-/-) versus WT mice (P = 0.031). GSH and the GSH/GSSG ratio were significantly increased in treatment-naive Mrp1(-/-) 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-naive Mrp1(-/-) versus WT mice (P < 0.05). DOX treatment decreased GS-HNE in WT but not Mrp1(-/-) 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.
机译：心脏毒性是阿霉素（DOX）的主要剂量限制性不良反应，部分由活性氧的过量产生和氧化应激介导。 Abcc1（Mrp1）介导还原型和氧化型谷胱甘肽（GSH，GSSG）的外排，并且是主要转运蛋白4-羟基-2-壬烯醛（HNE; GS-HNE）的GSH共轭物，脂质过氧化的有毒产物在氧化应激过程中形成。为了评估Mrp1在保护心脏免受DOX诱发的心脏损伤中的作用，对野生型（WT）和Mrp1 null（Mrp1（-/-））C57BL / 6同窝小鼠给予DOX（15 mg / kg）或生理盐水（7.5ml / kg）iv，并且在72小时时检查心室。通过电子显微镜的形态计量学分析显示，两种基因型在接受DOX处理的小鼠的细胞质，线粒体和细胞核中均受到广泛损伤。与WT小鼠相比，在Mrp1（-/-）中观察到的核损伤更为严重（P = 0.031）。与野生型小鼠相比，未治疗的Mrp1（-/-）组的GSH和GSH / GSSG比率显着增加。盐水和DOX处理后，Mrp1（-/-）中的GSH仍然显着高于WT小鼠，GSSG或GSH / GSSG没有变化。 GS-HNE，通过质谱测量，在未治疗的Mrp1（-/-）心脏中比在WT小鼠中更低（P <0.05）。 DOX处理可降低WT小鼠的GS-HNE，但不会降低Mrp1（-/-）小鼠，因此GS-HNE在DOX后与WT心脏相比适中但在Mrp1（-/-）小鼠中显着更高。介导GSH合成的酶和抗氧化蛋白的表达在基因型之间没有差异。因此，尽管在Mrp1（-/-）心脏中GSH含量升高，但与WT心脏相比，DOX显着增加了Mrp1（-/-）核的损伤。

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