Ohkuma Y, Kawanishi S
Department of Hygiene, Mie University School of Medicine, Tsu, Japan.
Arch Biochem Biophys. 2001 May 1;389(1):49-56. doi: 10.1006/abbi.2001.2302.
The mechanism of DNA damage by a metabolite of the carcinogen o-anisidine in the presence of metals was investigated by the DNA sequencing technique using 32P-labeled human DNA fragments. The o-anisidine metabolite, o-aminophenol, caused DNA damage in the presence of Cu(II). The DNA damage was inhibited by catalase and bathocuproine, suggesting the involvement of H2O2 and Cu(I). The formation of 8-oxo-7,8-dihydro-2'-deoxyguanosine by o-aminophenol increased in the presence of Cu(II). We conclude that Cu(II)-mediated oxidative DNA damage by this o-anisidine metabolite seems to be relevant for the expression of the carcinogenicity of o-anisidine. o-Aminophenol plus Cu(II) caused preferential DNA damage at the 5'-site guanine of GG and GGG sequences. When CuZn-SOD or Mn-SOD was added, the DNA damage was enhanced and its predominant cleavage sites were changed into thymine and cytosine residues. We consider that SOD may increase the frequency of mutations due to DNA damage induced by o-aminophenol and thus increase its carcinogenic potential.
采用32P标记的人DNA片段测序技术，研究了致癌物邻甲氧基苯胺的一种代谢物在金属存在下造成DNA损伤的机制。邻甲氧基苯胺代谢物邻氨基苯酚在Cu(II)存在下会导致DNA损伤。过氧化氢酶和2,9 - 二甲基菲咯啉能抑制这种DNA损伤，这表明H2O2和Cu(I)参与其中。在Cu(II)存在下，邻氨基苯酚导致的8 - 氧代 - 7,8 - 二氢 - 2'-脱氧鸟苷生成增加。我们得出结论，这种邻甲氧基苯胺代谢物通过Cu(II)介导的氧化性DNA损伤似乎与邻甲氧基苯胺致癌性的表达有关。邻氨基苯酚加Cu(II)会在GG和GGG序列的5'-鸟嘌呤位点造成优先的DNA损伤。当添加铜锌超氧化物歧化酶（CuZn-SOD）或锰超氧化物歧化酶（Mn-SOD）时，DNA损伤会增强，其主要切割位点会变为胸腺嘧啶和胞嘧啶残基。我们认为超氧化物歧化酶可能会增加由邻氨基苯酚诱导的DNA损伤导致的突变频率，从而增加其致癌潜力。
