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

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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