Document Detail


Metallothionein blocks oxidative DNA damage in vitro.
MedLine Citation:
PMID:  22914987     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
The role of metallothionein (MT) in mitigation of oxidative DNA damage (ODD) induced by either cadmium (Cd) or the direct oxidant hydrogen peroxide (H(2)O(2)) was systematically examined using MT-I/II double knockout (MT-null) or MT-competent wild-type (WT) cells. Both toxicants were much more lethal to MT-null cells (Cd LC(50) = 6.6 μM; H(2)O(2) LC(50) = 550 μM) than to WT cells (Cd LC(50) = 16.5 μM; H(2)O(2) LC(50) = 930 μM). Cd induced concentration-related MT increases in WT cells, while the basal levels were undetectable and not increased by Cd in MT-null cells. ODD, measured by the immuno-spin trapping method, was minimally induced by sub-toxic Cd levels (1 or 5 μM; 24 h) in WT cells, but markedly increased in MT-null cells (>430 %). Similarly, ODD was induced to higher levels by lower concentrations of H(2)O(2) in MT-null cells than WT cells. Transfection of MT-I into MT-null cells reduced both Cd- and H(2)O(2)-induced cytolethality and ODD. Cd increased the expression of the oxidant defense genes, HO-1, and GSTa2 to a much greater extent in MT-null cells than in WT. Cd or H(2)O(2) exposure increased the expression of key transport genes, Mrp1 and Mrp2, in WT cells but not in MT-null cells. MT protects against Cd- and H(2)O(2)-induced ODD in MT-competent cells possibly by multiple mechanisms, potentially including direct metal ion sequestration and sequestration of oxidant radicals by MT. MT-deficient cells appear to adapt to Cd primarily by turning on oxidant response systems, while MT-competent cells activate MT and transport systems.
Authors:
Wei Qu; Jingbo Pi; Michael P Waalkes
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Publication Detail:
Type:  Journal Article     Date:  2012-08-23
Journal Detail:
Title:  Archives of toxicology     Volume:  87     ISSN:  1432-0738     ISO Abbreviation:  Arch. Toxicol.     Publication Date:  2013 Feb 
Date Detail:
Created Date:  2013-01-24     Completed Date:  2013-07-02     Revised Date:  2014-02-04    
Medline Journal Info:
Nlm Unique ID:  0417615     Medline TA:  Arch Toxicol     Country:  Germany    
Other Details:
Languages:  eng     Pagination:  311-21     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
Animals
Cadmium Chloride / toxicity
Cell Line
Cell Survival / drug effects
DNA Damage*
Embryonic Stem Cells / drug effects*,  metabolism
Gene Expression / drug effects
Gene Expression Regulation / drug effects
Gene Knockdown Techniques
Glutathione Transferase / genetics
Heme Oxygenase-1 / genetics,  metabolism
Hydrogen Peroxide / toxicity
Isoenzymes / genetics
Membrane Proteins / genetics,  metabolism
Metallothionein / deficiency,  genetics,  metabolism*
Mice
Mice, Knockout
Multidrug Resistance-Associated Proteins / genetics,  metabolism
Oxidants / toxicity*
Oxidative Stress / drug effects*
Transfection
Grant Support
ID/Acronym/Agency:
ZIA ES102925-01/ES/NIEHS NIH HHS; ZIA ES102925-02/ES/NIEHS NIH HHS; ZIA ES102925-03/ES/NIEHS NIH HHS
Chemical
Reg. No./Substance:
0/Isoenzymes; 0/Membrane Proteins; 0/Multidrug Resistance-Associated Proteins; 0/Oxidants; 0/multidrug resistance-associated protein 1; 0/multidrug resistance-associated protein 2; 9038-94-2/Metallothionein; BBX060AN9V/Hydrogen Peroxide; EC 1.14.99.3/Heme Oxygenase-1; EC 1.14.99.3/Hmox1 protein, mouse; EC 2.5.1.18/Glutathione Transferase; EC 2.5.1.18/glutathione S-transferase alpha; J6K4F9V3BA/Cadmium Chloride
Comments/Corrections

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