Methylated trivalent arsenic species are genotoxic

被引:429
作者
Mass, MJ [1 ]
Tennant, A
Roop, BC
Cullen, WR
Styblo, M
Thomas, DJ
Kligerman, AD
机构
[1] US EPA, Environm Carcinogenesis Div MD68, Natl Hlth & Enivironm Effects Res Lab, Off Res & Dev, Res Triangle Pk, NC 27711 USA
[2] Univ N Carolina, Dept Pediat, Chapel Hill, NC 27599 USA
[3] Univ British Columbia, Dept Chem, Vancouver, BC V5Z 1M9, Canada
[4] Univ N Carolina, Dept Pediat, Chapel Hill, NC 27599 USA
[5] US EPA, Off Res & Dev, Natl Hlth & Environm Effects Res Lab, Div Environm Toxicol, Res Triangle Pk, NC 27711 USA
关键词
D O I
10.1021/tx000251l
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
The reactivities of methyloxoarsine (MAsIII) and iododimethylarsine (DMAsIII), two methylated trivalent arsenicals, toward supercoiled phi X174 RFI DNA were assessed using a DNA nicking assay. The induction of DNA damage by these compounds in vitro in human peripheral lymphocytes was assessed using a single-cell gel (SCG, "comet") assay. Both methylated trivalent arsenicals were able to nick and/or completely degrade phi X174 DNA in vitro in 2 h incubations at 37 degreesC (pH 7.4) depending on concentration. MAsIII was effective at nicking phi X174 DNA at 30 mM; however, at 150 muM DMAsIII, nicking could be observed. Exposure of (phi X174 DNA to sodium arsenite (iAs(III); from 1 nM up to 300 mM), sodium arsenate (from 1 muM to 1 M), and the pentavalent arsenicals, monomethylarsonic acid (from 1 muM to 3 M) and dimethylarsinic acid (from 0.1 to 300 mM), did not nick or degrade phi X174 DNA under these conditions. In the SCG assay in human lymphocytes, methylated trivalent arsenicals were much more potent than any other arsenicals that were tested. On the basis of the slopes of the concentration-response curve for the tail moment in the SCG assay, MAsIII and DMAsIII were 77 and 386 times more potent than iAs(III), respectively. Because methylated trivalent arsenicals were the only arsenic compounds that were observed to damage naked DNA and required no exogenously added enzymatic or chemical activation systems, they are considered here to be direct-acting forms of arsenic that are genotoxic, though they are not, necessarily, the only genotoxic species of arsenic that could exist.
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页码:355 / 361
页数:7
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