DNA damage induced by methylated trivalent arsenicals is mediated by reactive oxygen species
被引:193
作者:
Nesnow, S
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US EPA, Div Environm Carcinogenesis, Natl Hlth & Environm Effects Res Lab, Off Res & Dev, Res Triangle Pk, NC 27711 USAUS EPA, Div Environm Carcinogenesis, Natl Hlth & Environm Effects Res Lab, Off Res & Dev, Res Triangle Pk, NC 27711 USA
Nesnow, S
[1
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Roop, BC
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机构:US EPA, Div Environm Carcinogenesis, Natl Hlth & Environm Effects Res Lab, Off Res & Dev, Res Triangle Pk, NC 27711 USA
Roop, BC
Lambert, G
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机构:US EPA, Div Environm Carcinogenesis, Natl Hlth & Environm Effects Res Lab, Off Res & Dev, Res Triangle Pk, NC 27711 USA
Lambert, G
Kadiiska, M
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机构:US EPA, Div Environm Carcinogenesis, Natl Hlth & Environm Effects Res Lab, Off Res & Dev, Res Triangle Pk, NC 27711 USA
Kadiiska, M
Mason, RP
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机构:US EPA, Div Environm Carcinogenesis, Natl Hlth & Environm Effects Res Lab, Off Res & Dev, Res Triangle Pk, NC 27711 USA
Mason, RP
Cullen, WR
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机构:US EPA, Div Environm Carcinogenesis, Natl Hlth & Environm Effects Res Lab, Off Res & Dev, Res Triangle Pk, NC 27711 USA
Cullen, WR
Mass, MJ
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机构:US EPA, Div Environm Carcinogenesis, Natl Hlth & Environm Effects Res Lab, Off Res & Dev, Res Triangle Pk, NC 27711 USA
Mass, MJ
机构:
[1] US EPA, Div Environm Carcinogenesis, Natl Hlth & Environm Effects Res Lab, Off Res & Dev, Res Triangle Pk, NC 27711 USA
[2] NIEHS, Lab Pharmacol & Chem, Res Triangle Pk, NC 27709 USA
[3] Univ British Columbia, Dept Chem, Vancouver, BC, Canada
Arsenic is a human carcinogen; however, the mechanisms of arsenic's induction of carcinogenic effects have not been identified clearly. We have shown previously that monomethylarsonous acid (MMA(III)) and dimethylarsinous acid (DMA(III)) are genotoxic and can damage supercoiled phiX174 DNA and the DNA in peripheral human lymphocytes in culture. These trivalent arsenicals are biomethylated forms of inorganic arsenic and have been detected in the urine of subjects exposed to arsenite and arsenate. We show here by molecular, chemical, and physical methods that reactive oxygen species (ROS) are intermediates in the DNA-damaging activities of MMA(III) and DMA(III). Using the phiX174 DNA nicking assay we found that the ROS inhibitors Tiron, melatonin, and the vitamin E analogue Trolox inhibited the DNA-nicking activities of both MMA(III) and DMA(III) at low micromolar concentrations. The spin trap agent 5,5-dimethyl-1-pyrroline-N-oxide (DMPO) also was effective at preventing the DNA nicking induced by MMA(III) and DMA(III.) ESR spectroscopy studies using DMPO identified a radical as a ROS intermediate in the DNA incubations with DMA(III). This radical adduct was assigned to the DMPO-hydroxyl free radical adduct on the basis of comparison of the observed hyperfine splitting constants and line widths with those reported in the literature. The formation of the DMPO-hydroxyl free radical adduct was dependent on time and the presence of DMA(III) and was completely inhibited by Tiron and Trolox and partially inhibited by DMSO. Using electrospray mass spectrometry, micromolar concentrations of DMA(v) were detected in the DNA incubation mixtures with DMA(III). These data are consistent with the conclusions that the DNA-damaging activity of DMA(III) is an indirect genotoxic effect mediated by ROS-formed concomitantly with the oxidation of DMA(III) to DMA(v).
机构:
Univ Nebraska, Med Ctr, Dept Pathol & Microbiol, Nebraska Med Ctr 983135, Omaha, NE 68198 USAUniv Nebraska, Med Ctr, Dept Pathol & Microbiol, Nebraska Med Ctr 983135, Omaha, NE 68198 USA
Cohen, SM
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Arnold, LL
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机构:Univ Nebraska, Med Ctr, Dept Pathol & Microbiol, Nebraska Med Ctr 983135, Omaha, NE 68198 USA
Arnold, LL
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Uzvolgyi, E
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机构:Univ Nebraska, Med Ctr, Dept Pathol & Microbiol, Nebraska Med Ctr 983135, Omaha, NE 68198 USA
Uzvolgyi, E
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Cano, M
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机构:Univ Nebraska, Med Ctr, Dept Pathol & Microbiol, Nebraska Med Ctr 983135, Omaha, NE 68198 USA
Cano, M
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John, MS
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机构:Univ Nebraska, Med Ctr, Dept Pathol & Microbiol, Nebraska Med Ctr 983135, Omaha, NE 68198 USA
John, MS
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Yamamoto, S
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机构:Univ Nebraska, Med Ctr, Dept Pathol & Microbiol, Nebraska Med Ctr 983135, Omaha, NE 68198 USA
Yamamoto, S
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Lu, XF
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机构:Univ Nebraska, Med Ctr, Dept Pathol & Microbiol, Nebraska Med Ctr 983135, Omaha, NE 68198 USA
Lu, XF
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Le, XC
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机构:Univ Nebraska, Med Ctr, Dept Pathol & Microbiol, Nebraska Med Ctr 983135, Omaha, NE 68198 USA
机构:
Univ Gottingen, Med Inst Gen Hyg & Environ Hlth, D-37073 Gottingen, GermanyUniv Gottingen, Med Inst Gen Hyg & Environ Hlth, D-37073 Gottingen, Germany
机构:
Univ Nebraska, Med Ctr, Dept Pathol & Microbiol, Nebraska Med Ctr 983135, Omaha, NE 68198 USAUniv Nebraska, Med Ctr, Dept Pathol & Microbiol, Nebraska Med Ctr 983135, Omaha, NE 68198 USA
Cohen, SM
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Arnold, LL
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机构:Univ Nebraska, Med Ctr, Dept Pathol & Microbiol, Nebraska Med Ctr 983135, Omaha, NE 68198 USA
Arnold, LL
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Uzvolgyi, E
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机构:Univ Nebraska, Med Ctr, Dept Pathol & Microbiol, Nebraska Med Ctr 983135, Omaha, NE 68198 USA
Uzvolgyi, E
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Cano, M
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机构:Univ Nebraska, Med Ctr, Dept Pathol & Microbiol, Nebraska Med Ctr 983135, Omaha, NE 68198 USA
Cano, M
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John, MS
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机构:Univ Nebraska, Med Ctr, Dept Pathol & Microbiol, Nebraska Med Ctr 983135, Omaha, NE 68198 USA
John, MS
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Yamamoto, S
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机构:Univ Nebraska, Med Ctr, Dept Pathol & Microbiol, Nebraska Med Ctr 983135, Omaha, NE 68198 USA
Yamamoto, S
;
Lu, XF
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机构:Univ Nebraska, Med Ctr, Dept Pathol & Microbiol, Nebraska Med Ctr 983135, Omaha, NE 68198 USA
Lu, XF
;
Le, XC
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机构:Univ Nebraska, Med Ctr, Dept Pathol & Microbiol, Nebraska Med Ctr 983135, Omaha, NE 68198 USA
机构:
Univ Gottingen, Med Inst Gen Hyg & Environ Hlth, D-37073 Gottingen, GermanyUniv Gottingen, Med Inst Gen Hyg & Environ Hlth, D-37073 Gottingen, Germany