Mechanisms of DNA damage induced by environmental factors and cancer chemoprevention

环境因素诱导的DNA损伤机制与癌症化学预防

基本信息

批准号：
09470101
负责人：
KAWANISHI Shosuke
金额：
$ 8.19万
依托单位：
Mie University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
1997
资助国家：
日本
起止时间：
1997 至 1999
项目状态：
已结题

项目摘要

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.

我们已经研究了由环境因素引起的直接DNA损伤的机制以及由一氧化氮（NO）介导的间接DNA损伤和由炎症细胞（例如单核细胞和中性粒细胞）释放的活性氧。这项研究的主要发现总结如下。（1）作为饮食因素，杂环胺和氨基酸代谢产物在金属离子存在下引起DNA损伤。抗氧化剂，例如β-胡萝卜素，维生素E（α-托罗尔），N-乙酰基脊髓和类黄酮，在金属离子存在下会诱导氧化性DNA损伤，这表明这些抗氧化剂可以用作验证者。苯甲酰过氧化苯甲酰是GG序列在Cu（i）存在下的5'g GG序列的食物添加剂特异性DNA损伤。作为占用和空气污染物因素，可能与职业癌有关的甲苯，O-甲硅烷和硝基苯代谢产生了内源性分子的光激活介导的DNA损伤。此外，分别通过电子转移和单线氧的产生引起了喹诺酮抗菌，奈替二酸和lomefloxacin引起DNA光损伤。 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 were induced by simple generation of NO superoxide (OixodG in cultured cells was significantly increased by exposure to NO released from macrophages activated by carcinogenic nickel compounds, indicating that injection can mediate DNA damage through an indirect机制。根据这些发现，环境因素引起的致癌作用涉及由氧化应激介导的直接DNA损伤和炎症细胞介导的间接DNA损伤。