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Oxidation and methylation status determine the effects of arsenic on the mitotic apparatus

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Abstract

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 (NaAsV), sodium arsenite (NaAsIII), monomethylarsonic acid (MMAV), monomethylarsonous acid (MMAIII), dimethylarsinic acid (DMAV), or dimethylarsinous acid (DMAIII). 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. NaAsV caused a small but significant increase in MI. MMAV also caused only a slight increase in MI that just reached statistical significance. In contrast, DMAV caused a significant increase in MI, producing ∼75% the MI of demecolcine and ∼4 times the MI of the control. NaAsIII had no significant effect on MI and was quite toxic. MMAIII induced more than a twofold increase in MI compared to the control, which was about 40% that caused by demecolcine. On a micromolar basis, MMAIII was the most potent of the arsenicals tested. DMAIII gave inconsistent results. None of the pentavalent arsenicals had a substantial effect (either inhibition or enhancement) on GTP-induced polymerization of tubulin. In contrast, NaAsIII inhibited polymerization at concentrations of 1 mM and above and MMAIII and DMAIII at 10 μM 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.

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Abbreviations

DMAIII:

dimethylarsinous acid

DMAV:

dimethylarsinic acid

MI:

mitotic index

MMAIII:

monomethylarsonous acid

MMAV:

monomethylarsinic acid

NaAsIII:

sodium arsenite

NaAsV:

sodium arsenate

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Kligerman, A.D., Doerr, C.L. & Tennant, A.H. Oxidation and methylation status determine the effects of arsenic on the mitotic apparatus. Mol Cell Biochem 279, 113–121 (2005). https://doi.org/10.1007/s11010-005-8283-3

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