Skip Navigation



ToxSci Advance Access published online on May 18, 2005
Toxicological Sciences, doi:10.1093/toxsci/kfi205
This Article
Right arrow Advance Access manuscript (PDF) Freely available
Right arrow All Versions of this Article:
86/2/354    most recent
kfi205v1
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrowRequest Permissions
Right arrow Disclaimer
Google Scholar
Right arrow Articles by Ho, H. K.
Right arrow Articles by Bruschi, S. A.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Ho, H. K.
Right arrow Articles by Bruschi, S. A.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?

Toxicological Sciences © The Author 2005. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please email: journals.permissions@oupjournals.org
Received March 2, 2005
Accepted May 9, 2005

In Vitro Toxicology

Nrf2 Activation Involves An Oxidative-Stress Independent Pathway In Tetrafluoroethylcysteine-Induced Cytotoxicity

Han K. Ho 1*, Collin C. White 2, Carolina Fernandez 2, Nelson Fausto 3, Terrance J. Kavanagh 2, Sidney D. Nelson 1, and Sam A. Bruschi 1

1 Department of Medicinal Chemistry, University of Washington, Seattle, Washington 98195
2 Department of Environmental and Occupational Health Sciences, University of Washington, Seattle, Washington 98195
3 Department of Pathology, University of Washington, Seattle, Washington 98195

* To whom correspondence should be addressed.
Han K. Ho, E-mail: hankiat{at}u.washington.edu


  Abstract

Tetrafluoroethylcysteine (TFEC), a metabolite of the industrial gas tetrafluoroethylene, can cause both nephrotoxicity and limited hepatotoxicity in animal models and this is associated with the covalent modification of specific intramitochondrial proteins including heat shock protein 60 (HSP60), mitochondrial HSP70 (mtHSP70), aspartate aminotransferase (AST), aconitase and _-ketoglutarate dehydrogenase ({alpha}KGDH). Using the murine TAMH cell line as a useful in vitro model for TFEC toxicity, we demonstrate a rapid and sustained induction of Nrf2, a member of the "cap-and-collar" transcription factor family, following exposure to cytotoxic concentrations of TFEC. A functional correlate was also established with the rapid translocation of cytosolic Nrf2 into the nucleus. In addition, transcriptional and translational upregulation of known Nrf2 regulated genes including glutamate cysteine ligase (GCL), both catalytic and modulatory subunits), heme oxygenase-1, and glutathione S-transferase (GST) isoforms were detected. While Nrf2 activation is often linked to perturbation of cellular thiol status and/or oxidative stress, we were unable to detect any significant depletion of cellular glutathione or oxidation of mitochondrial membrane cardiolipin, or increases in reactive oxygen species (ROS). These data suggest Nrf2 activation is likely independent of classical oxidative stress or, at best, a result of a transient, low-level redox stress. Moreover, supporting evidence indicates an early endoplasmic reticular (ER) stress response after TFEC treatment, with a time-dependent upregulation of the ER responsive genes gadd34, gadd45, gadd153 and ndr1. These findings suggest an alternative pathway for Nrf2 activation, i.e. Nrf2 phosphorylation through ER-mediated protein kinases such as PKR-like endoplasmic reticular kinase (PERK). Overall, the results implicate a role for Nrf2 in the cellular response to TFEC toxicity, and suggest a previously unrecognized role for the ER in this model of mitochondrially-initiated cytotoxicity.

Keywords: Tetrafluoroethylcysteine; mitochondrial dysfunction; Nrf2; oxidative stress; ER stress.
Add to CiteULike CiteULike   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us    What's this?


This article has been cited by other articles:


Home page
 Molecular Cancer TherapeuticsHome page
C. Mitchell, M. A. Park, G. Zhang, S. I. Han, H. Harada, R. A. Franklin, A. Yacoub, P.-L. Li, P. B. Hylemon, S. Grant, et al.
17-Allylamino-17-demethoxygeldanamycin enhances the lethality of deoxycholic acid in primary rodent hepatocytes and established cell lines
Mol. Cancer Ther., February 1, 2007; 6(2): 618 - 632.
[Abstract] [Full Text] [PDF]

Home page
 Drug Metab. Dispos.Home page
M. S. Ko, S. J. Lee, J. W. Kim, J. W. Lim, and S. G. Kim
DIFFERENTIAL EFFECTS OF THE OXIDIZED METABOLITES OF OLTIPRAZ ON THE ACTIVATION OF CCAAT/ENHANCER BINDING PROTEIN-{beta} AND NF-E2-RELATED FACTOR-2 FOR GSTA2 GENE INDUCTION
Drug Metab. Dispos., August 1, 2006; 34(8): 1353 - 1360.
[Abstract] [Full Text] [PDF]


Disclaimer: Please note that abstracts for content published before 1996 were created through digital scanning and may therefore not exactly replicate the text of the original print issues. All efforts have been made to ensure accuracy, but the Publisher will not be held responsible for any remaining inaccuracies. If you require any further clarification, please contact our Customer Services Department.