Dithiol compounds at low concentrations increase arsenite toxicity.
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 (MMA(III)), and dimethylarsinous acid (DMA(III)) 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.
Jan
Kun-Yan
KY
Institute of Cellular and Organismic Biology, Academia Sinica, Taipei 11529, Taiwan, ROC.
Wang
Tsing-Cheng
TC
Ramanathan
Balakrishnan
B
Gurr
Jia-Ran
JR
D017209:Apoptosis; D018053:Arsenites / Q000633:toxicity*; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000187:drug effects / Q000473:pathology; D002470:Cell Survival / Q000187:drug effects; D004249:DNA Damage; D004229:Dithiothreitol / Q000633:toxicity*; D004347:Drug Interactions; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D048629:Micronuclei, Chromosome-Defective; D004113:Succimer / Q000633:toxicity*; D013438:Sulfhydryl Compounds / Q000032:analysis; D014494:Unithiol / Q000633:toxicity*
D018053:Arsenites; D013438:Sulfhydryl Compounds; D014494:Unithiol; D006861:Hydrogen Peroxide; D004113:Succimer; D005978:Glutathione; C015001:arsenite; D004229:Dithiothreitol