Oxidation and methylation status determine the effects of arsenic on the mitotic apparatus.
We investigated the spindle inhibitory properties of six arsenicals differing in their methylation or oxidation state. Human lymphoblasts were exposed for 6 h to either sodium arsenate (NaAs(V)), sodium arsenite (NaAs(III)), monomethylarsonic acid (MMA(V)), monomethylarsonous acid (MMA(III)), dimethylarsinic acid (DMA(V)), or dimethylarsinous acid (DMA(III)). After exposure slides were prepared, and the mitotic indices (MI) were assessed. We also exposed tubulin directly to each arsenical and spectrophotometrically measured its effect on polymerization. NaAs(V) caused a small but significant increase in MI. MMA(V) also caused only a slight increase in MI that just reached statistical significance. In contrast, DMA(V) caused a significant increase in MI, producing approximately 75% the MI of demecolcine and approximately 4 times the MI of the control. NaAs(III) had no significant effect on MI and was quite toxic. MMA(III) induced more than a twofold increase in MI compared to the control, which was about 40% that caused by demecolcine. On a micromolar basis, MMA(III) was the most potent of the arsenicals tested. DMA(III) gave inconsistent results. None of the pentavalent arsenicals had a substantial effect (either inhibition or enhancement) on GTP-induced polymerization of tubulin. In contrast, NaAs(III) inhibited polymerization at concentrations of 1 mM and above and MMA(III) and DMA(III) at 10 microM and above. Taken together, these results present a complex picture of how arsenicals may affect cells. These studies demonstrate that the metabolites of arsenic are active not only as chromosome breaking and DNA damaging agents but can also interfere with cell division via tubulin disruption.
Kligerman
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Environmental Carcinogenesis Division, National Health and Environmental Effects Research Laboratory, US Environmental Protection Agency, Research Triangle Park, North Carolina 27711, USA. kligerman.andrew@epa.gov
Doerr
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Tennant
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D000782:Aneuploidy; D001151:Arsenic / Q000633:toxicity*; D001152:Arsenicals; D018053:Arsenites / Q000633:toxicity; D002101:Cacodylic Acid / Q000633:toxicity; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008214:Lymphocytes / Q000187:drug effects*; D008745:Methylation; D008940:Mitotic Index; D009942:Organometallic Compounds / Q000633:toxicity; D010084:Oxidation-Reduction; D017670:Sodium Compounds / Q000633:toxicity; D008941:Spindle Apparatus / Q000187:drug effects*; D013329:Structure-Activity Relationship; D013997:Time Factors; D014404:Tubulin / Q000378:metabolism; D050257:Tubulin Modulators / Q000633:toxicity
D001152:Arsenicals; D018053:Arsenites; D009942:Organometallic Compounds; D017670:Sodium Compounds; D014404:Tubulin; D050257:Tubulin Modulators; C406082:monomethylarsonous acid; C017947:sodium arsenite; D002101:Cacodylic Acid; D001151:Arsenic