The mechanism for the formation of hotspots in relation to evaluation of carcinogenic risks of environmental chemicals

我们已经证明，在Cu（II）、NADH和/或CYP450还原酶存在的情况下，许多环境化学物质及其代谢物，包括苯[a]蒽、儿茶素、丙卡嗪、多柔比星、乙苯、双酚a、苯二胺和硝基呋喃酮，会对特定的DNA碱基序列造成损伤，包括与p53基因热点互补的5 ‘-ACG-3’序列。大豆异黄酮被认为是癌症化学预防剂，但最近的研究表明，它们会诱发女性生殖器官的癌症。大豆异黄酮促进了人类乳腺癌细胞的增殖，而其代谢物诱导了位点特异性DNA损伤，特别是p53基因的5‘-ACG-3’序列。这些发现表明大豆异黄酮通过DNA损伤引发癌变，通过细胞增殖促进癌变。从酒精中提取的Salsolinol也能诱导细胞增殖和位点特异性DNA损伤。因此，salsolinol和大豆异黄酮引起乳腺癌的方式相似。用于染料生产的邻苯胺和邻二苯胺是膀胱致癌物。我们已经证明，在Cu（II）和细胞色素P450存在的情况下，o-茴香胺和o-二苯胺诱导p53基因5‘-ACG-3’序列的位点特异性DNA损伤。与邻苯二胺的致癌性和靶器官的多样性相一致，邻苯二胺比邻苯二胺更有效地诱导损伤。我们已经证明了各种各样的环境化学物质在癌症相关基因热点的连续碱基上特异性地诱导DNA损伤。连续碱基的DNA损伤称为簇状DNA损伤，这种DNA损伤难以修复，可能导致突变。我们的研究结果表明，热点地区的DNA损伤有助于环境化学物质诱导的致癌作用。在这项研究中，我们建立了一个新的系统来检测热点区域的簇DNA损伤。这一系统将有助于深入评估环境化学品的潜在风险和预防癌症。少

We have demonstrated that numerous environmental chemicals and their metabolites, including benz[a]anthracene, catechins, procarbazine, doxorubicin, ethylbenzene, bisphenol A, phenylenediamine, and nitrofurazone induced damage to specific DNA base sequences, including the 5 '-ACG-3' sequence complementary to a hotspot of the p53 gene, in the presence of Cu(II), NADH and/or CYP450 reductase. The soy isoflavones are considered to be cancer chemopreventive agents, but recent studies have indicated they induce cancers of female reproductive organs. The soy isoflavones enhanced the proliferation of human breast cancer cells, whereas their metabolites induced site-specific DNA damage particularly at the 5'-ACG-3' sequence of the p53 gene. These findings indicate that soy isoflavones cause carcinogenesis through initiation via DNA damage and promotion via cell proliferation. Salsolinol, derived from alcohol, also induced both cell proliferation and site-specific DNA damage. Thus, salsolinol a … More ppears to cause breast cancer in a similar manner to soy isoflavones. o-Anisidine and o-dianisidine, used in the production of dyes, are urinary bladder carcinogens. We have demonstrated that o-anisidine and o-dianisidine induced site-specific DNA damage at the 5'-ACG-3' sequence of the p53 gene in the presence of Cu(II) and cytochrome P450. o-Dianisidine induced damage much more efficiently than o-anisidine, in consistent with their carcinogenicity and diversity of their target organs.We have demonstrated that a wide variety of environmental chemicals induce DNA damage specifically at consecutive bases of hotspots of cancer-relevant genes. DNA damage at consecutive bases, referred to as cluster DNA damage, is difficult to be repaired, and thus such DNA damage may lead to mutation. Our findings suggest that DNA damage at the hotspots contributes to carcinogenesis induced by environmental chemicals. In this study, we have established a new system to examine cluster DNA damage at hotspots. This system would provide an insight into the evaluation of the potential risk of environmental chemicals and cancer prevention. Less