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Analysis of the human DNA damage by dietary factors via reactive oxygen species and cancer prevention

饮食因素通过活性氧对人类 DNA 损伤的分析与癌症预防

基本信息

批准号：
12670318
负责人：
MURATA Mariko
金额：
$ 1.92万
依托单位：
Mie University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2000
资助国家：
日本
起止时间：
2000 至 2001
项目状态：
已结题

项目摘要

Dietary factor is estimated to have the largest proportion (35 %) in the causation of human cancer. We revealed that vitamin A (retinol) and its derivative (retinal) caused cellular DNA cleavage and significantly induced 8-oxo-7, 8-dihydro-2'-deoxyguanosine (8-oxodG) formation in HL-60 cells but not in H_2O_2 -resistant HP100 cells, suggesting the involvement of H_2O_2. The superoxide generation during autoxidation of retinoids was significantly correlated with the formation of 8-oxodG. Retinol and retinal have prooxidant abilities, which might lead to carcinogenesis of the supplements of β-carotene (J. Biol. Chem. 275, 2003, 2000). Vegetables like broccoli and cauliflower contain substantial quantities of isothiocyanates, and isothiocyanates were proposed as promising chemopreventive agents for human cancers. However, we revealed that isothiocyanates significantly induced 8-oxodG formation through generation of superoxide by the yield of SH group from isothiocyanates (Free Radic. Biol … More . Med. 28, 797, 2000). DNA adduct formation is thought to be a major cause of DNA damage by carcinogenic aromatic amines. We investigated the ability of several aromatic amines and N-hydroxy metabolite to cause oxidative DNA damage. The N-hydroxy metabolites of 4-aminobiphenyl (4-ABP) (Free Radic. Biol. Med. 30, 765-773, 2001), heterocyclic amines PhIP (Carcinogenesis in press) and aminophenylnorharman (Mutat. Res. 494, 63-72, 2001) were found to cause Cu(II)-mediated DNA damage, and addition of the endogenous reductant NADH led to dramatic enhancement of this process. We conclude that, in addition to DNA adduct formation, oxidative DNA damage may play an important role in the carcinogenic process of these aromatic amines. Potassium bromate (KBrO_3), a food additive, induces renal-cell tumors in rats. We showed that KBrO_3 induced 8-oxodG formation. We speculated that reduction of KBrO_3 by SH compounds like GSH and Cys yields bromine oxides and bromine radicals, which are the reactive species that cause guanine oxidation, leading to renal carcinogenesis of KBrO_3 (Chem. Res. Toxicol. 14, 678-685, 2001). Less

据估计，饮食因素在人类癌症的病因中所占比例最大（35%）。我们发现，维生素 A（视黄醇）及其衍生物（视黄醛）可引起细胞 DNA 裂解，并显着诱导 HL-60 细胞中 8-oxo-7, 8-二氢-2'-脱氧鸟苷 (8-oxodG) 的形成，但在 H_2O_2 抗性 HP100 细胞中则不然，表明 H_2O_2 参与其中。类维生素A自动氧化过程中超氧化物的产生与8-oxodG的形成显着相关。视黄醇和视黄醛具有促氧化能力，补充β-胡萝卜素可能会导致致癌(J. Biol. Chem. 275, 2003, 2000)。西兰花和花椰菜等蔬菜含有大量的异硫氰酸盐，异硫氰酸盐被认为是人类癌症的有前途的化学预防剂。然而，我们发现异硫氰酸酯通过由异硫氰酸酯产生 SH 基团产生超氧化物，显着诱导 8-oxodG 形成（Free Radic. Biol … More . Med. 28, 797, 2000）。 DNA 加合物的形成被认为是致癌芳香胺造成 DNA 损伤的主要原因。我们研究了几种芳香胺和 N-羟基代谢物引起氧化 DNA 损伤的能力。 4-氨基联苯 (4-ABP) (Free Radic. Biol. Med. 30, 765-773, 2001)、杂环胺 PhIP (Carcinogenesis in press) 和氨基苯基去哈尔曼 (Mutat. Res. 494, 63-72, 2001) 的 N-羟基代谢物被发现会引起 Cu(II) 介导的 DNA 损伤，并且内源性还原剂 NADH 的添加显着增强了这一过程。我们的结论是，除了DNA加合物的形成之外，DNA氧化损伤可能在这些芳香胺的致癌过程中发挥重要作用。食品添加剂溴酸钾 (KBrO_3) 可诱发大鼠肾细胞肿瘤。我们发现 KBrO_3 诱导 8-oxodG 形成。我们推测，GSH和Cys等SH化合物还原KBrO_3会产生溴氧化物和溴自由基，它们是引起鸟嘌呤氧化的活性物质，导致KBrO_3肾癌发生(Chem. Res. Toxicol. 14, 678-685, 2001)。较少的