Molecular and cellular mechanisms of iron homeostasis and toxicity in mammalian cells
Molecular and cellular mechanisms of iron homeostasis and toxicity in mammalian cells
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DOI：
10.1016/s0162-0134(02)00461-0
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发表时间：
2002-07-25
影响因子：
3.9
通讯作者：
Ward, RJ
中科院分区：
文献类型：
--
作者：
Crichton, RR;Wilmet, S;Ward, RJ
铁是几乎所有生物体的必需金属，因为它参与了大量的含铁酶和蛋白质，但它也是有毒的。本文就铁在肠道的吸收、血清中的转运、细胞内的转运和细胞内铁的贮存等方面的机制作一简要综述。目前的观点涉及铁调节蛋白IRP 1和IRP 2的细胞铁稳态和它们与铁的相互作用的调节元件，影响mRNA的翻译（铁蛋白和红细胞δ-氨基乙酰丙酸合酶）或mRNA的稳定性（转铁蛋白受体）进行了讨论。Fe（II）通过芬顿反应催化羟基自由基形成的潜力意味着铁是潜在有毒的。铁在特定组织和细胞类型（肝脏、巨噬细胞和脑）中的毒性通过适当的细胞和动物模型研究来说明。在肝脏中，高水平的细胞保护酶和抗氧化剂意味着要观察毒性作用，需要大量的铁负载。在网状内皮细胞如巨噬细胞中，细胞铁的相对小的增加（2-3倍）可以影响细胞信号传导，如通过NO产生和核转录因子NF κ B的活化所测量的，以及细胞功能，如通过细胞在刺激时产生活性氧的能力所测量的。大脑中的情况，其中抗氧化防御相对较低，具有高度的区域特异性，其中特定脑区域中的铁积累与许多神经退行性疾病相关。在用三甲基己酰二茂铁或葡萄糖酸铝处理的动物的大脑中，铁和铝分别积累。对于后一种化合物，铁也增加，这可能反映了铝对IRP 2蛋白的影响。螯合疗法可以显着降低脑铝水平，而铁也可以去除，但难度更大。本文综述了螯合疗法在神经退行性疾病的治疗和预防中的应用前景。(C)2002年爱思唯尔科技有限公司All rights reserved.
Iron is an essential metal for almost all living organisms due to its involvement in a large number of iron-containing enzymes and proteins, yet it is also toxic. The mechanisms involved in iron absorption across the intestinal tract, its transport in serum and delivery to cells and iron storage within cells is briefly reviewed. Current views on cellular iron homeostasis involving the iron regulatory proteins IRP1 and IRP2 and their interactions with the iron regulatory elements, affecting either mRNA translation (ferritin and erythroid cell delta-aminolaevulinate synthase) or mRNA stability (transferrin receptor) are discussed. The potential of Fe(II) to catalyse hydroxyl radical formation via the Fenton reaction means that iron is potentially toxic. The toxicity of iron in specific tissues and cell types (liver, macrophages and brain) is illustrated by studies with appropriate cellular and animal models. In liver, the high levels of cyoprotective enzymes and antioxidants, means that to observe toxic effects substantial levels of iron loading are required. In reticuloendothelial cells, such as macrophages, relatively small increases in cellular iron (2-3-fold) can affect cellular signalling, as measured by NO production and activation of the nuclear transcription factor NFkappaB, as well as cellular function, as measured by the capacity of the cells to produce reactive oxygen species when stimulated. The situation in brain, where anti-oxidative defences are relatively low, is highly regionally specific, where iron accumulation in specific brain regions is associated with a number of neurodegenerative diseases. In the brains of animals treated with either trimethylhexanoylferrocene or aluminium gluconate, iron and aluminium accumulate, respectively. With the latter compound, iron also increases, which may reflect an effect of aluminium on the IRP2 protein. Chelation therapy can reduce brain aluminium levels significantly, while iron can also be removed, but with greater difficulty. The prospects for chelation therapy in the treatment and possible prevention of neurodegenerative diseases is reviewed. (C) 2002 Elsevier Science Inc. All rights reserved.