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Preparation of DMMTAV and DMDTAV Using DMAV for Environmental Applications: Synthesis, Purification, and Confirmation

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Dithiol compounds at low concentrations increase arsenite toxicity.

Kun-Yan Jan¹, Tsing-Cheng Wang, Balakrishnan Ramanathan

¹Institute of Cellular and Organismic Biology, Academia Sinica, Taipei 11529, Taiwan, ROC.

Toxicological Sciences : an Official Journal of the Society of Toxicology

|January 20, 2006

Summary

Dithiothreitol (DTT), dimercaptosuccinic acid (DMSA), and dimercaptopropanesulfonic acid (DMPS) exhibit inverse-hormetic effects on arsenic toxicity. Low concentrations increase arsenic-induced apoptosis, while high concentrations decrease it, suggesting a need to reevaluate their therapeutic use.

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Area of Science:

Biochemistry
Toxicology
Cell Biology

Background:

Inorganic trivalent arsenicals are thiol-reacting agents.
Dithiothreitol (DTT) is a dithiol agent with reported conflicting effects on arsenic trioxide-induced apoptosis.
Dimercaptosuccinic acid (DMSA) and dimercaptopropanesulfonic acid (DMPS) are used as antidotes for arsenic poisoning.

Purpose of the Study:

To investigate the dose-dependent effects of DTT, DMSA, and DMPS on arsenic trioxide-induced apoptosis and toxicity.
To evaluate the inverse-hormetic effects of these dithiol compounds on arsenic toxicity in relevant human cell lines.

Main Methods:

NB4 human promyelocytic leukemia cells and human epithelial cell lines from arsenic target tissues (kidney, bladder) were used.
Experiments assessed apoptosis, cell growth inhibition, DNA damage, micronucleus induction, and colony formation.
Varying concentrations of DTT, DMSA, and DMPS were tested in conjunction with arsenic trioxide, methylarsonous acid (MMA(III)), and dimethylarsinous acid (DMA(III)).

Main Results:

High concentrations of DTT, DMSA, and DMPS decreased arsenic trioxide-induced apoptosis in NB4 cells.
Low concentrations of DTT, DMSA, and DMPS increased arsenic trioxide-induced apoptosis.
DTT showed a concentration-dependent effect on cell growth inhibition by arsenic compounds.
Dithiol compounds exhibited inverse-hormetic effects on various measures of arsenic toxicity in epithelial cells.

Conclusions:

Dithiol compounds like DTT, DMSA, and DMPS display an inverse-hormetic effect on arsenic toxicity, with low doses enhancing and high doses mitigating toxicity.
The findings suggest that the therapeutic efficacy of these dithiols for arsenic poisoning may need reevaluation, considering potential low in vivo concentrations after oral administration.