Original Paper

JBIC Journal of Biological Inorganic Chemistry

, Volume 17, Issue 4, pp 589-598

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

  • Jade B. AitkenAffiliated withSchool of Chemistry, The University of SydneyAustralian SynchrotronInstitute of Materials Structure Science, KEK
  • , Peter A. LayAffiliated withSchool of Chemistry, The University of Sydney Email author 
  • , T. T. Hong DuongAffiliated withDiscipline of Neurosurgery, Australian School of Advanced Medicine, Macquarie University
  • , Roshanak AranAffiliated withDiscipline of Pathology, Bosch Research Institute, Sydney Medical School, The University of Sydney
  • , Paul K. WittingAffiliated withDiscipline of Pathology, Bosch Research Institute, Sydney Medical School, The University of Sydney
  • , Hugh H. HarrisAffiliated withSchool of Chemistry and Physics, University of Adelaide
  • , Barry LaiAffiliated withX-ray Science Division, Argonne National Laboratory
  • , Stefan VogtAffiliated withX-ray Science Division, Argonne National Laboratory
  • , Gregory I. GilesAffiliated withDepartment of Pharmacology and Toxicology, University of Otago Email author 

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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.

Keywords

Antioxidant Drug Ebselen Organoselenium Synchrotron-radiation-induced X-ray emission