Synchrotron radiation induced X-ray emission studies of the antioxidant mechanism of the organoselenium drug ebselen
Synchrotron radiation induced X-ray emission studies of the antioxidant mechanism of the organoselenium drug ebselen
复制标题
DOI：
10.1007/s00775-012-0879-y
复制
发表时间：
2012-04-01
影响因子：
3
通讯作者：
Giles, Gregory I.
中科院分区：
文献类型：
--
作者：
Aitken, Jade B.;Lay, Peter A.;Giles, Gregory I.
同步辐射诱导的X射线发射（SRIXE）光谱被用来映射细胞摄取的有机硒为基础的抗氧化剂药物依布硒啉使用分化的ND 15细胞作为神经元模型。用硬X射线微探针束获得的细胞SRIXE谱（12.8-keV），在K-α线处显示出硒的荧光的大增强（11.2-keV），在60至240分钟的时间段内用依布硒啉（10 μ M）处理后。细胞元素含量的依赖性变化是K，Cl和Ca物质流出的氧化应激的特征。SRIXE细胞硒分布图显示，依布硒啉主要定位于一个谨慎的区域的细胞，通过比较与K和P元素的地图，假设对应于内质网。基于这些发现，假设依布硒啉氧化还原催化的主要结果是诱导细胞应激。提出了依布硒啉的作用机制，即通过增加抗氧化基因的表达，使细胞对药物诱导的应激作出反应。这一假设得到以下观察结果的支持：依布硒啉还调节过渡金属Mn、Cu、Fe和Zn的体内平衡，过渡金属摄取的增加与抗氧化剂金属酶表达的已知诱导时间平行。
Synchrotron radiation induced X-ray emission (SRIXE) spectroscopy was used to map the cellular uptake of the organoselenium-based antioxidant drug ebselen using differentiated ND15 cells as a neuronal model. The cellular SRIXE spectra, acquired using a hard X-ray microprobe beam (12.8-keV), showed a large enhancement of fluorescence at the K-alpha line for Se (11.2-keV) following treatment with ebselen (10 mu M) at time periods from 60 to 240 min. Drug uptake was quantified and ebselen was shown to induce time-dependent changes in cellular elemental content that were characteristic of oxidative stress with the efflux of K, Cl, and Ca species. The SRIXE cellular Se distribution map revealed that ebselen was predominantly localized to a discreet region of the cell which, by comparison with the K and P elemental maps, is postulated to correspond to the endoplasmic reticulum. On the basis of these findings, it is hypothesized that a major outcome of ebselen redox catalysis is the induction of cellular stress. A mechanism of action of ebselen is proposed that involves the cell responding to drug-induced stress by increasing the expression of antioxidant genes. This hypothesis is supported by the observation that ebselen also regulated the homeostasis of the transition metals Mn, Cu, Fe, and Zn, with increases in transition metal uptake paralleling known induction times for the expression of antioxidant metalloenzymes.