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THE ROLE OF VALENCE AND METHYLATION STATE ON THE ACTIVITY OF ARSENIC DURING MITOSIS
Citation:
Kligerman, A D., C L. Doerr, AND A H. Tennant. THE ROLE OF VALENCE AND METHYLATION STATE ON THE ACTIVITY OF ARSENIC DURING MITOSIS. Presented at Environmental Mutatgenesis Society, Pittsburgh, PA, Oct 2-6, 2005.
Description:
Trivalent methylated arsenicals are much more potent DNA damaging agents, clastogens, and large deletion mutagens than are their inorganic and pentavalent counterparts. Previously we had noticed that many of the arsenicals induced "c-type" anaphases characteristic of spindle poisons. In the present study. we exposed human lvmphoblasts for 6 h to six arsenicals: sodium arsenate (NaAs5), sodium arsenite (NaAs3), monomethvlarsonic acid (MMA5), monomelhvlarsonous acid (MMA3), dimethylarsinic acid (DMA5), and dimelhylarsinous acid (DMA3). Slides were then prepared, and the mitotic indices (MI) were calculated. NaAs5 caused a small but significant increase in MI. MMA5 also caused only slight increase in MI that just reached statistical significance. In contrast. DMA5 caused a highly significant increase in MI producing~75% the MI of demecolcine, the positive control. NaAs3 had no significant effect on MI and was quite toxic. MMA3 induced more than a twofold increase in MI compared to the control. DMA3 gave inconsistent results. We also exposed each arsenical directly to tubulin and spectropholometrically measured the effect on polymerization. None of the pentavalent arsenicals had a substantial effect on polymerization of tubulin. In contrast. NaAs3 inhibited polymerization at 1mM and above, and MMA3 and DMA3 at 10 ?M and above. Taken together. these results give a complex picture of how arsenicals may affect cells. Some arc cytotoxic, which may prevent the cells from cycling, thereby reducing the MI. Simultaneously, at lower concentrations, these same arsenicals may react with the spindle and cause an apparent increase in Ml by arresting the cells at metaphase or anaphase. Thus. the metabolites of arsenic are active not only as chromosome breaking and DNA damaging agents but can also interfere with cell division. They can effect this through interaction with the spindle potentially leading to aneuploidy, a common driving force in genomic instability and ultimately in minor formation.