Synchrotron radiation induced X-ray emission studies of the antioxidant mechanism of the organoselenium drug ebselen
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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 Kα line for Se (11.2-keV) following treatment with ebselen (10 μM) 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.
KeywordsAntioxidant Drug Ebselen Organoselenium Synchrotron-radiation-induced X-ray emission
Antioxidant response element
Reactive oxygen species
Synchrotron-radiation-induced X-ray emission
We are grateful for financial support provided by a University of Sydney Postdoctoral Fellowship (G.I.G), Australian Research Council (ARC) Discovery grants (P.A.L., H.H.H., and P.K.W.), including an ARC Australian Professorial Fellowship (to P.A.L), an ARC QEII Fellowship (to H.H.H.), and an ARC Australian Research Fellowship (to P.K.W.), a National Heart Foundation Grant-in-Aid (to P.K.W), and an Australian Synchrotron Research Program (ASRP) grant for access to the Advanced Photon Source facilities. The ASRP was funded by the Commonwealth of Australia under the Major National Research Facilities Program. The use of Advanced Photon Source facilities was supported by the US Department of Energy, Basic Energy Sciences, Office of Science, under contract number W-31-109-Eng-38.
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