Carcinogenesis Advance Access published online on May 19, 2006
Carcinogenesis, doi:10.1093/carcin/bgl076
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1 Brown University, Department of Pathology and Laboratory Medicine, 70 Ship Street, Room 507, Providence, RI 02912; Present address: Draeger Medical Systems Inc., Danvers, MA 01923
* To whom correspondence should be addressed. Recent epidemiological and risk assessment studies have found a very high risk of lung cancer among chromium(VI)-exposed workers even at permissible levels of exposure. However, mechanistic views on the key genotoxic role of transient Cr(V) intermediates were more consistent with the threshold or highly non-linear (heavy dose) models of genetic damage by intracellular Cr(VI). In this work, we examined the production of mutagenic DNA lesions during metabolism of Cr(VI) by its dominant reducer ascorbate (vitamin C) under conditions promoting increased yield of transient Cr forms. We found that slow reductive activation of Cr(VI) by limited concentrations of ascorbate resulted in a greater yield of DCFH-oxidizing Cr intermediates but these species were unable to cause DNA strand breaks. Cr(VI)-ascorbate reactions generated a high number of Cr-DNA adducts that were responsible for all mutagenic responses detected in Cr(VI)-treated pSP189 shuttle plasmids following their replication in human cells. Mutagenicity of DNA damage resulting from the reactions with increased stability of Cr intermediates was approximately 4-times lower relative to the conditions lacking detectable Cr(V) formation. Unlike other reactions, slow reduction of Cr(VI) with ascorbate produced Cr-DNA adducts that were more resistant to dissociation by chelators, suggesting multicoordinate binding of Cr(III) to DNA. Overall, our findings do not support the possibility that increased Cr(V) formation at depleted ascorbate levels modeling heavy dose exposures causes higher levels of mutagenic DNA damage.
Received March 23, 2006
Revised May 10, 2006
Accepted May 15, 2006
CARCINOGENESIS
Lower mutagenicity but higher stability of Cr-DNA adducts formed during gradual chromate activation with ascorbate
George Quievryn 1,
Joseph Messer 2,
and
Anatoly Zhitkovich 3 *
2 Brown University, Department of Pathology and Laboratory Medicine, 70 Ship Street, Room 507, Providence, RI 02912; Present address: Genzyme Inc., Framingham, MA 01701
3 Brown University, Department of Pathology and Laboratory Medicine, 70 Ship Street, Room 507, Providence, RI 02912
Anatoly Zhitkovich, E-mail: anatoly_zhitkovich{at}brown.edu
Abstract 
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  M. Reynolds and A. Zhitkovich Cellular vitamin C increases chromate toxicity via a death program requiring mismatch repair but not p53 Carcinogenesis, July 1, 2007; 28(7): 1613 - 1620. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Reynolds, L. Stoddard, I. Bespalov, and A. Zhitkovich Ascorbate acts as a highly potent inducer of chromate mutagenesis and clastogenesis: linkage to DNA breaks in G2 phase by mismatch repair Nucleic Acids Res., January 28, 2007; 35(2): 465 - 476. [Abstract] [Full Text] [PDF]
|
|