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

Authors

  • Jade B. Aitken
    • School of ChemistryThe University of Sydney
    • Australian Synchrotron
    • Institute of Materials Structure Science, KEK
    • School of ChemistryThe University of Sydney
  • T. T. Hong Duong
    • Discipline of Neurosurgery, Australian School of Advanced MedicineMacquarie University
  • Roshanak Aran
    • Discipline of Pathology, Bosch Research Institute, Sydney Medical SchoolThe University of Sydney
  • Paul K. Witting
    • Discipline of Pathology, Bosch Research Institute, Sydney Medical SchoolThe University of Sydney
  • Hugh H. Harris
    • School of Chemistry and PhysicsUniversity of Adelaide
  • Barry Lai
    • X-ray Science DivisionArgonne National Laboratory
  • Stefan Vogt
    • X-ray Science DivisionArgonne National Laboratory
    • Department of Pharmacology and ToxicologyUniversity of Otago
Original Paper

DOI: 10.1007/s00775-012-0879-y

Cite this article as:
Aitken, J.B., Lay, P.A., Duong, T.T.H. et al. J Biol Inorg Chem (2012) 17: 589. doi:10.1007/s00775-012-0879-y

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

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

Copyright information

© SBIC 2012