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Synchrotron radiation induced X-ray emission studies of the antioxidant mechanism of the organoselenium drug ebselen

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Abstract

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.

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Abbreviations

ARE:

Antioxidant response element

ER:

Endoplasmic reticulum

GPx:

Glutathione peroxidase

GSH:

Reduced glutathione

GSSG:

Oxidized glutathione

ROS:

Reactive oxygen species

SOD:

Superoxide dismutase

SRIXE:

Synchrotron-radiation-induced X-ray emission

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Acknowledgments

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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Authors and Affiliations

  1. School of Chemistry, The University of Sydney, Sydney, NSW, 2006, Australia

    Jade B. Aitken & Peter A. Lay

  2. Discipline of Neurosurgery, Australian School of Advanced Medicine, Macquarie University, Ground Floor, 2 Technology Place, Sydney, NSW, 2109, Australia

    T. T. Hong Duong

  3. Discipline of Pathology, Bosch Research Institute, Sydney Medical School, The University of Sydney, Sydney, NSW, 2006, Australia

    Roshanak Aran & Paul K. Witting

  4. School of Chemistry and Physics, University of Adelaide, Adelaide, SA, 5005, Australia

    Hugh H. Harris

  5. X-ray Science Division, Argonne National Laboratory, Argonne, IL, 60439, USA

    Barry Lai & Stefan Vogt

  6. Department of Pharmacology and Toxicology, University of Otago, PO Box 913, Dunedin, New Zealand

    Gregory I. Giles

  7. Australian Synchrotron, Clayton, VIC, 3168, Australia

    Jade B. Aitken

  8. Institute of Materials Structure Science, KEK, Tsukuba, Ibaraki, 305-0801, Japan

    Jade B. Aitken

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  1. Jade B. Aitken
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Correspondence to Peter A. Lay or Gregory I. Giles.

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Aitken, J.B., Lay, P.A., Duong, T.T.H. et al. Synchrotron radiation induced X-ray emission studies of the antioxidant mechanism of the organoselenium drug ebselen. J Biol Inorg Chem 17, 589–598 (2012). https://doi.org/10.1007/s00775-012-0879-y

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  • DOI: https://doi.org/10.1007/s00775-012-0879-y

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