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ToxSci Advance Access originally published online on January 18, 2006
Toxicological Sciences 2006 90(2):432-439; doi:10.1093/toxsci/kfj108
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© The Author 2006. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Dithiol Compounds at Low Concentrations Increase Arsenite Toxicity

Kun-Yan Jan*, Tsing-Cheng Wang*, Balakrishnan Ramanathan* and Jia-Ran Gurr{dagger},1

* Institute of Cellular and Organismic Biology, Academia Sinica, Taipei 11529, Taiwan, ROC; and {dagger} Hsing Wu College, No. 101, Sec. 1, Fenliao Rd., Linkou Township, Taipei County 24452, Taiwan, ROC

Received November 14, 2005; accepted January 6, 2006

Inorganic trivalent arsenicals are vicinal thiol-reacting agents, and dithiothreitol (DTT) is a well-known dithiol agent. Interestingly, both decreasing and increasing effects of DTT on arsenic trioxide–induced apoptosis have been reported. We now provide data to show that, at high concentrations, DTT, dimercaptosuccinic acid (DMSA), and dimercaptopropanesulfonic acid (DMPS) decreased arsenic trioxide–induced apoptosis in NB4 cells, a human promyelocytic leukemia cell line. In contrast, at low concentrations DTT, DMSA, and DMPS increased the arsenic trioxide–induced apoptosis. DTT at a high concentration (3 mM) decreased, whereas at a low concentration (0.1 mM), it increased the cell growth inhibition of arsenic trioxide, methylarsonous acid (MMAIII), and dimethylarsinous acid (DMAIII) in NB4 cells. DMSA and DMPS are currently used as antidotes for acute arsenic poisoning. These two dithiol compounds also show an inverse-hormetic effect on arsenic toxicity in terms of DNA damage, micronucleus induction, apoptosis, and colony formation in experiments using human epithelial cell lines derived from arsenic target tissues such as the kidney and bladder. With the oral administration of dithiols, the concentrations of these dithiol compounds in the human body are likely to be low. Therefore, the present results suggest the necessity of reevaluating the therapeutic effect of these dithiol compounds for arsenic poisoning.

Key Words: arsenite; oxidative damage; DNA damage; dithiols; cellular antioxidant capacity.


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