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INVESTIGATIONS INTO THE MODE OF ACTION OF ARSENIC
Citation:
KLIGERMAN, A. D. INVESTIGATIONS INTO THE MODE OF ACTION OF ARSENIC. Presented at The 4th Conference on Molecular Mechanisms of Metal Toxicity and Carcinogenicity, Morgantown, WV, September 24 - 27, 2006.
Description:
Arsenic is a ubiquitous metalloid to which there is significant human exposure through the air, water, and food. That arsenic can induce cancer in humans has been known since the late 17th century, yet how arsenic induces cancer has been the subject of a myriad of scientific investigations. Various modes of action (MOA) have been proposed for arsenic¿s carcinogenicity including changes in DNA methylation, disruption of cell signaling, inhibition of DNA repair, regenerative cell proliferation, and the induction of DNA damage. In this presentation, a review is given of my laboratory¿s previous studies on the ability of arsenicals to cause DNA damage, the relative inability of these arsenicals to induce point mutations, and the involvement of arsenicals in spindle disruption. Also, new data will be presented that shows that reduced glutathione (GSH) can chemically reduce inactive pentavalent arsenicals to trivalent arsenicals, which can disrupt tubulin polymerization. In addition, evidence is presented that reactive oxygen species (ROS) are most likely not involved in this tubulin disruption. Lastly, a testable hypothesis is presented on how arsenic may induce stable chromosome aberrations (CAs) that can lead to cancer, thus, supporting a role for genetic damage in the MOA for arsenic.