Mechanisms of DNA damage induced by environmental factors and cancer chemoprevention

我们研究了由环境因素和间接DNA损伤介导的直接DNA损伤机制，并研究了由硝酸氧化物（NO）和反应性氧化物物种释放的炎症细胞，如单胞菌和中性菌。本研究中的主要发现已被归纳为后续。（1）作为膳食因素、异环胺和氨基酸代谢物导致DNA损伤在金属存在中。抗氧化剂，如β-胡萝卜素、维生素E （α-碳酚）、N-乙酰胆碱素和黄酮类化合物，以及在金属存在中诱导氧化DNA损伤，建议这些抗氧化剂可以作为抗氧化剂发挥作用。苯唑醇过氧化物，一种食品附加物，诱导特定序列在Cu（I）中对GG序列的5'G造成的DNA损伤。作为实用性和空气污染因子，toluene、O-toluidine和硝基苯的代谢物，可能与实用性癌症相关，并通过光激活引起DNA损伤。在添加剂中，一个quinolone抗生素，nalidoxic acid和lomefloxacin通过电子转移和单氧的生成引起DNA光损伤，相应地。以下是一个发现，即这些药物可以作为原始光素发挥作用的结论。（3） Concerning indirect DNA damage by inflammatory factors， oxidative DNA damage in human cultured cells was induced by simultaneous generation of NO superoxide （OイイD22イイD2イイD1-イエD1）。文化细胞中8-氧化物G的形成被明显地增加了，因为暴露，没有从碳原镍化合物激活的宏观物质释放，并表明炎症可以通过间接机制对DNA造成中度损害。在这些发现的基础上，由环境因素参与诱导的碳生成由氧化应激介导的直接DNA损伤和由炎症细胞介导的间接DNA损伤。

We have investigated the mechanisms of direct DNA damage induced by environmental factors and indirect DNA damage mediated by nitric oxide (NO) and reactive oxygen species released from inflammatory cells, such as monocytes and neutrophils. The main findings in this study are summarized as follows. (1) As dietary factors, heterocyclic amines and amino acid metabolite caused DNA damage in the presence of metal ions. Antioxidants, such as β-carotene, vitamin E (α-tocophorol), N-acetylcystein and flavonoids, induced oxidative DNA damage in the presence of metal ions, suggesting that these antioxidants can act as prooxidants. Benzoyl peroxide, a food additive, induced sequence-specific DNA damage at the 5'G of GG sequence in the presence of Cu(I). As occupational and air pollutant factors, metabolites of toluene, o-toluidine and nitrobenzene, which may be associated with occupational cancer, caused DNA damage mediated by photoactivation of endogenous molecules. In addition, a quinolone antibacterials, nalidixic acid and lomefloxacin caused DNA photodamage through electron transfer and the generation of singlet oxygen, respectively. This findings suggests that these drugs can act as exogenous photocarcinogens.(3) Concerning indirect DNA damage by inflammatory factors, oxidative DNA damage in human cultured cells was induced by simultaneous generation of NO superoxide (OィイD22ィエD2ィイD1-ィエD1). The formation of 8-oxodG in cultured cells was significantly increased by exposure to NO released from macrophages activated by carcinogenic nickel compounds, indicating that inflammation can mediate DNA damage through an indirect mechanism. On the basis of these findings, carcinogenesis induced by environmental factors involves direct DNA damage mediated by oxidative stress and indirect DNA damage mediated by inflammatory cells.