Inorganic and Dimethylated Arsenic Species Induce Cellular p53

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Abstract

Arsenic compounds are known for their ability both to cause and to treat human cancers, although the molecular mechanisms underlying these actions are incompletely understood. The simplest explanation is that arsenic causes DNA damage that leads to mutations. However, the majority of scientific evidence indicates that arsenic is not a genotoxin or DNA-damaging agent. DNA damage typically leads to cellular responses designed to minimize the replication of damaged DNA, such as the induction of p53, and p53 induction has therefore been used as an indicator of DNA damage. Because this approach can be applied to human cells and does not rely on a specific, heritable mutation occurring at a particular site, it seemed possible that this method could detect DNA damage that was undetectable using other techniques. To examine the genotoxic potential of arsenic compounds, therefore, seven of these compounds (sodium arsenite, sodium arsenate, methyloxoarsine, iododimethylarsine, disodium methyl arsonate, dimethylarsinic acid, and arsenic trioxide) were tested for their ability to increase the cellular level of p53 as measured by ELISA. Of this group, arsenic trioxide was the strongest inducer of cellular p53, while dimethylarsinic acid, iododimethylarsine, and sodium arsenite also caused p53 induction in a dose- and time-dependent manner. Sodium arsenate, as well as the two monomethyl compounds tested, methyloxoarsine and disodium methyl arsonate, did not cause detectable increases in cellular p53. Our results indicate, therefore, that cells respond to several of these arsenic compounds as they do to chemicals that damage DNA, suggesting that exposure of cells to these compounds does in fact cause DNA damage. Such damage could then result in mutations and the observed development of cancer.

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