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

我们已经证明，在铜(II)、NADH和/或细胞色素P450还原酶的存在下，许多环境化学品及其代谢物，包括苯并[a]菲、儿茶素、原卡巴肼、阿霉素、乙苯、双酚A、苯二胺和呋喃西林，会引起特定DNA碱基序列的损伤，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的化学预防药物，但最近的研究表明，它们会诱发女性生殖器官癌症。大豆异黄酮能促进人乳腺癌细胞的增殖，而其代谢产物可诱导特定部位的DNA损伤，尤其是在p53基因的5‘-ACG-3’序列上。这些发现表明，大豆异黄酮通过DNA损伤引发致癌，通过细胞增殖促进致癌。从酒精中提取的丹参素也能诱导细胞增殖和特异性DNA损伤。因此，丹参素a…更多的梨会导致乳腺癌，其方式与大豆异黄酮类似。用于生产染料的邻氨基苯甲胺和邻二苯甲胺是膀胱癌的致癌物。我们已经证明，在铜(II)和细胞色素P450存在的情况下，邻氨基苯甲胺和邻二苯甲胺可以诱导p53基因5‘-ACG-3’序列的特异性DNA损伤。与其致癌性和靶器官的多样性相一致，O-二苯甲胺比邻氨基苯甲胺更有效地诱导DNA损伤。我们已经证明，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，很难修复，因此这种DNA损伤可能导致突变。我们的发现表明，热点区域的DNA损伤导致了环境化学物质的致癌作用。在这项研究中，我们建立了一种新的系统来检测热点区域的簇DNA损伤。这一系统将为评估环境化学品和癌症预防的潜在风险提供洞察力。较少

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