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5-氨基乙酰丙酸对铁蛋白的氧化损伤。

Oxidative damage to ferritin by 5-aminolevulinic acid.

作者信息

Rocha Maria E M, Dutra Fernando, Bandy Brian, Baldini Regina L, Gomes Suely L, Faljoni-Alário Adelaide, Liria Cleber W, Miranda M Terêsa M, Bechara Etelvino J H

机构信息

Departamento de Bioqui;mica, Instituto de Qui;mica, Universidade de São Paulo, Av. Prof. Lineu Prestes 748, CEP 05508-900, São Paulo, SP, Brazil.

出版信息

Arch Biochem Biophys. 2003 Jan 15;409(2):349-56. doi: 10.1016/s0003-9861(02)00633-1.

Abstract

5-Aminolevulinic acid (ALA), a heme precursor overproduced in various porphyric disorders, has been implicated in iron-mediated oxidative damage to biomolecules and cell structures. From previous observations of ferritin iron release by ALA, we investigated the ability of ALA to cause oxidative damage to ferritin apoprotein. Incubation of horse spleen ferritin (HoSF) with ALA caused alterations in the ferritin circular dichroism spectrum (loss of a alpha-helix content) and altered electrophoretic behavior. Incubation of human liver, spleen, and heart ferritins with ALA substantially decreased antibody recognition (51, 60, and 28% for liver, spleen, and heart, respectively). Incubation of apoferritin with 1-10mM ALA produced dose-dependent decreases in tryptophan fluorescence (11-35% after 5h), and a partial depletion of protein thiols (18% after 24h) despite substantial removal of catalytic iron. The loss of tryptophan fluorescence was inhibited 35% by 50mM mannitol, suggesting participation of hydroxyl radicals. The damage to apoferritin had no effect on ferroxidase activity, but produced a 61% decrease in iron uptake ability. The results suggest a local autocatalytic interaction among ALA, ferritin, and oxygen, catalyzed by endogenous iron and phosphate, that causes site-specific damage to the ferritin protein and impaired iron sequestration. These data together with previous findings that ALA overload causes iron mobilization in brain and liver of rats may help explain organ-specific toxicities and carcinogenicity of ALA in experimental animals and patients with porphyria.

摘要

5-氨基酮戊酸(ALA)是一种在各种卟啉症中过量产生的血红素前体,它与铁介导的生物分子和细胞结构的氧化损伤有关。基于先前对ALA释放铁蛋白中铁的观察,我们研究了ALA对铁蛋白脱辅基蛋白造成氧化损伤的能力。将马脾铁蛋白(HoSF)与ALA一起孵育会导致铁蛋白圆二色光谱发生变化(α-螺旋含量丧失)并改变电泳行为。将人肝、脾和心脏铁蛋白与ALA一起孵育会大幅降低抗体识别能力(肝、脾和心脏铁蛋白分别降低51%、60%和28%)。将脱铁铁蛋白与1-10mM的ALA一起孵育会导致色氨酸荧光呈剂量依赖性降低(5小时后降低11-35%),并且尽管大量去除了催化铁,但蛋白质巯基仍部分耗竭(24小时后降低18%)。50mM甘露醇可抑制35%的色氨酸荧光丧失,这表明羟基自由基参与其中。对脱铁铁蛋白的损伤对铁氧化酶活性没有影响,但会使铁摄取能力降低61%。结果表明,在内源性铁和磷酸盐的催化下,ALA、铁蛋白和氧气之间存在局部自催化相互作用,这种相互作用会对铁蛋白蛋白质造成位点特异性损伤并损害铁螯合。这些数据与先前关于ALA过载会导致大鼠脑和肝中铁动员的研究结果一起,可能有助于解释ALA在实验动物和卟啉症患者中的器官特异性毒性和致癌性。

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