ABSTRACT

Objectives: Prooxidant properties of iron-binding hydroxypyridone compounds including deferiprone and mimosine were analyzed.

Methods: Hydroxypyridone/iron-dependent production of reactive oxygen species was evidenced by the inactivation of aconitase, the most sensitive enzyme to oxidative stress in permeabilized yeast cells.

Results and Discussion: Deferiprone and mimosine produced reactive oxygen species in the presence of ferrous sulfate. The inactivation required sodium azide the inhibitor of catalase, and addition of TEMPOL, a scavenger of superoxide radical, protected aconitase from the inactivation, suggesting that the superoxide radical produced from the hydroxypyridone/iron complex is responsible for the inactivation of aconitase. A principal role of superoxide radical was further supported by the finding that the hydroxypyridone/iron complex can inactivate aconitase in the presence of cyanide the inhibitor of superoxide dismutase. Deferiprone and mimosine stimulated the Fe²⁺ oxidation, resulting in the one-electron reduction of oxygen to form superoxide anion, which can inactivate aconitase by oxidizing the prosthetic iron-sulfur cluster. Mimosine further stimulated the ascorbate/iron-dependent formation of 8-hydroxy-2′-deoxyguanosine in DNA.

Conclusion: Biological toxicity of mimosine and deferiprone reported previously can be accounted for by the prooxidant properties of hydroxypyridone compounds: coordination complex with iron generates reactive oxygen species resulting in the disturbance of mitochondrial energy metabolism and DNA damage.

摘要

目的：分析了铁结合羟基吡啶酮化合物（包括去铁酮和含羞草碱）的抗氧化性能。

方法：羟基磷灰石/铁依赖于活性氧的产生是通过乌头酸酶失活来证明的，乌头酸酶是通透性酵母细胞中对氧化应激最敏感的酶。

结果与讨论：在硫酸亚铁存在下，去铁酮和含羞草产生了活性氧。灭活需要叠氮化钠作为过氧化氢酶的抑制剂，并且加入TEMPOL（超氧化物自由基的清除剂）可保护乌头酸酶免于灭活，这表明由羟基吡啶酮/铁络合物产生的超氧化物基团是乌头酸酶的失活的原因。发现羟基吡啶酮/铁络合物可以在超氧化物歧化酶抑制剂氰化物存在下使乌头酸酶失活，这进一步证明了超氧自由基的主要作用。去铁酮和含羞草碱刺激了Fe ²⁺氧化，导致氧的单电子还原形成超氧阴离子，该超氧阴离子可通过氧化假体铁硫簇而使乌头酸酶失活。Mimosine进一步刺激了DNA中抗坏血酸/铁依赖的8-羟基-2'-脱氧鸟苷的形成。

结论：以前报道的含羞草碱和去铁酮的生物毒性可以由羟基吡啶酮化合物的促氧化作用来解释：配位配合物与铁产生活性氧，从而导致线粒体能量代谢紊乱和DNA损伤。