Skip Navigation



ToxSci Advance Access published online on September 8, 2005
Toxicological Sciences, doi:10.1093/toxsci/kfi318
This Article
Right arrow Advance Access manuscript (PDF) Freely available
Right arrow All Versions of this Article:
88/2/602    most recent
kfi318v1
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 Kennette, W.
Right arrow Articles by Koropatnick, J.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Kennette, W.
Right arrow Articles by Koropatnick, J.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?

© 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 July 28, 2005
Accepted September 6, 2005

Systems Toxicology

Basal and Zinc-Induced Metallothionein in Resistance to Cadmium, Cisplatin, Zinc, and tertbutyl Hydroperoxide: Studies using MT Knockout and Antisense-Downregulated MT in Mammalian Cells

Wendy Kennette 1, Olga M. Collins 1, Rudolfs K. Zalups 2, and Jim Koropatnick 3*

1 Cancer Research Laboratory Program, London Regional Cancer Program, London Health Sciences Centre, London, Ontario, Canada N6A 4L6
2 Division of Basic Medical Sciences, Mercer University School of Medicine, Macon, Georgia, USA
3 Cancer Research Laboratory Program, London Regional Cancer Program, London Health Sciences Centre, London, Ontario, Canada N6A 4L6; Departments of Oncology, Physiology and Pharmacology, Pathology, and Microbiology and Immunology, University of Western Ontario, Canada N6A 4L6; Lawson Health Research Institute, London, Ontario, Canada N6A 4L6

* To whom correspondence should be addressed.
Jim Koropatnick, E-mail: JKOROPAT{at}UWO.CA


  Abstract

Metallothioneins (MTs) mediate resistance to metal and non-metal toxicants. To differentiate the role of MTs from other protective factors, resistance to zinc (Zn), cadmium (Cd), tertbutyl hydroperoxide (tBH), and cisplatin (CDDP) was compared in renal cell lines from wild type (MT-WT) and MT-1/MT-2 knockout (MT-KO) mice. MT-WT cells were more resistant to tBH than MT-KO cells but, unexpectedly, were more sensitive to Zn, Cd, and CDDP. Thus, basal expression of MT conferred resistance to tBH, but not to Cd or CDDP. Pretreatment with Zn increased MT expression and enhanced resistance to Cd and CDDP only in MT-WT cells, indicating a critical role for MT in this form of resistance. By contrast, Zn-pretreatment increased resistance to subsequent Zn exposure, but did not alter resistance to tBH, regardless of MT-status. Therefore, Zn-induced resistance to subsequent exposure to Zn (but not to Cd or CDDP) was mediated by non-MT factors, and neither Zn-induced MT nor other factors affected tBH sensitivity. Furthermore, antisense down-regulation of MT in human HeLa cells reduced basal MT levels and resistance to TBH, but not to Cd or CDDP. Therefore, basal MT alone can mediate resistance to TBH (but not to Cd or CDDP) in mouse and human cells. These data suggest that MT can mediate resistance to toxicants by different mechanisms, some of which correlate with the cellular content of MT protein. Moreover, resistance to some agents (Cd and CDDP) can be enhanced by inducing MT. Resistance to other agents (tBH) requires only basal (non-induced) MT levels.

Keywords: metallothionein; knockout; antisense; drug sensitivity; drug resistance; cisplatin; cadmium; reactive oxygen species; tertbutyl hydroperoxide; zinc.
Add to CiteULike CiteULike   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us    What's this?




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.