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Cyclophosphamide induces a significant increase in iron content in the liver and spleen of mice.
Human & Experimental Toxicology ( IF 2.8 ) Pub Date : 2020-03-04 , DOI: 10.1177/0960327120909880
Y Sheng 1, 2 , Y-J Chen 1, 2 , Z-M Qian 1, 2, 3 , J Zheng 3 , Y Liu 4
Affiliation  

OBJECTIVE Oxidative stress is one of the major mechanisms of cyclophosphamide (CPX)-induced toxicities. However, it is unknown how CPX induces oxidative stress. Based on the available information, we speculated that CPX could increase iron content in the tissues and then induce oxidative stress. METHOD We tested this hypothesis by investigating the effects of CPX on iron and ferritin contents, expression of transferrin receptor 1 (TfR1), ferroportin 1 (Fpn1), iron regulatory proteins (IRPs), hepcidin, and nuclear factor erythroid 2-related factor-2 (Nrf2) in the liver and spleen, and also on reticulocyte count, immature reticulocyte fraction, and hemoglobin (Hb) in the blood in c57/B6 mouse. RESULTS We demonstrated that CPX could induce a significant increase in iron contents and ferritin expression in the liver and spleen, notably inhibit erythropoiesis and Hb synthesis and lead to a reduction in iron usage. The reduced expression in TfR1 and Fpn1 is a secondary effect of CPX-induced iron accumulation in the liver and spleen and also partly associated with the suppressed IRP/iron-responsive element system, upregulation of hepcidin, and downregulation of Nrf2. CONCLUSIONS The reduced iron usage is one of the causes for iron overload in the liver and spleen and the increased tissue iron might be one of the mechanisms for CPX to induce oxidative stress and toxicities.

中文翻译:

环磷酰胺诱导小鼠肝脏和脾脏中铁含量的显着增加。

目的 氧化应激是环磷酰胺(CPX)诱导毒性的主要机制之一。然而,尚不清楚 CPX 如何诱导氧化应激。根据现有信息,我们推测 CPX 可以增加组织中的铁含量,然后诱导氧化应激。方2 (Nrf2) 在肝脏和脾脏中,以及 c57/B6 小鼠血液中的网织红细胞计数、未成熟网织红细胞分数和血红蛋白 (Hb)。结果 我们证明 CPX 可以显着增加肝脏和脾脏中的铁含量和铁蛋白表达,显着抑制红细胞生成和 Hb 合成并导致铁使用量减少。TfR1 和 Fpn1 的表达降低是 CPX 诱导的肝脏和脾脏中铁积累的继发效应,并且部分与抑制的 IRP/铁反应元件系统、铁调素的上调和 Nrf2 的下调有关。结论 铁使用量减少是肝脾铁超负荷的原因之一,组织铁增加可能是CPX诱导氧化应激和毒性的机制之一。和 Nrf2 的下调。结论 铁使用量减少是肝脾铁超负荷的原因之一,组织铁增加可能是CPX诱导氧化应激和毒性的机制之一。和 Nrf2 的下调。结论 铁使用量减少是肝脾铁超负荷的原因之一,组织铁增加可能是CPX诱导氧化应激和毒性的机制之一。
更新日期:2020-04-20
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