Involvement of DNA Conformational Change Induced by Rearrangement of Copper-coordination Geometry in Oxidative DNA Damages Caused by Copper and Dopamine

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Oxidative DNA damages involve reduction-oxidation reactions between certain metals and compounds, and result in genetic abnormalities leading to diseases including cancer and neurodegenerative disorders. Here, we report that DNA damages mediated by combination of a neurotransmitter dopamine and copper accompany a unique DNA conformational change. Copper (II) [Cu(II)] was shown as bound to consecutive guanines (G-G) of DNA, by demonstrating the G-G selective inhibition of restriction enzymes. When dopamine was added to calf thymus DNA in the presence of Cu(II), DNA guanines were oxidized. UV and ^1H NMR analyses suggested that dopamine was oxidized to the quinone form in the presence of Cu(II). The circular dichroism experiments showed DNA spectral changes under the conditions of oxidative DNA damage, indicating a conformational change of the DNA strand by dopamine and copper. The DNA conformational change was suppressed by adding a Cu(I)-specific chelator bathocuproine. Therefore, the conformational change can be explained by a rearrangement of the copper-coordination geometry in DNA through Cu(II) reduction to Cu(I). Thus, changes in DNA conformation could be involved in metal-mediated genotoxicity as well as oxidative damage but via different mechanism.
公益社団法人日本薬学会の論文
2009-04-01