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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.

我们研究了环境因素引起的直接DNA损伤和炎症细胞（如单核细胞和中性粒细胞）释放的一氧化氮（NO）和活性氧介导的间接DNA损伤的机制。本研究的主要发现总结如下。(1)杂环胺和氨基酸代谢产物作为膳食因素，在金属离子存在下引起DNA损伤。抗氧化剂如β-胡萝卜素、维生素E（α-胡萝卜素）、N-乙酰半胱氨酸和黄酮类化合物在金属离子存在下诱导氧化性DNA损伤，表明这些抗氧化剂可以作为促氧化剂。食品添加剂过氧化苯甲酰在Cu（I）存在下可引起GG序列5 ′ G处的DNA序列特异性损伤。甲苯、邻甲苯胺和硝基苯作为职业性和大气污染物，其代谢产物可通过内源性分子的光活化作用引起DNA损伤，可能与职业性癌症有关。此外，喹诺酮类抗菌药萘啶酸和洛美沙星分别通过电子转移和单线态氧的产生引起DNA光损伤。这一发现表明，这些药物可以作为外源性光致癌物。(3)关于炎症因子引起的间接DNA损伤，人培养细胞中的氧化DNA损伤是由同时产生的NO超氧化物（OイD22 D2イD1-D1）引起的。8-oxodG在培养的细胞中的形成显着增加暴露于从致癌镍化合物激活的巨噬细胞释放的NO，表明炎症可以通过间接机制介导DNA损伤。在这些发现的基础上，由环境因素引起的癌变涉及由氧化应激介导的直接DNA损伤和由炎性细胞介导的间接DNA损伤。