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）会引起细胞 DNA 裂解，并显着诱导 8-oxo-7, 8-二氢。 -2'-脱氧鸟苷 (8-oxodG) 在 HL-60 细胞中形成，但在 H_2O_2 抗性 HP100 细胞中不形成，表明参与H_2O_2. 类视黄醇自动氧化过程中超氧化物的生成与 8-oxodG 的形成显着相关。视黄醇和视黄醛具有促氧化能力，这可能导致补充 β-胡萝卜素的致癌作用 (J. Biol. Chem. 275, 2003, 2000）西兰花和花椰菜等蔬菜含有大量异硫氰酸盐。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，我们发现异硫氰酸盐通过异硫氰酸盐中 SH 基团的产量产生超氧化物，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。芳香胺和 N-羟基代谢物会导致氧化性 DNA 损伤）和氨基苯甲哈尔曼（Mutat. Res. 494, 63-72， 2001）被发现会引起 Cu(II) 介导的 DNA 损伤，并且内源性还原剂 NADH 的添加导致了这一过程的显着增强。我们得出的结论是，除了 DNA 加合物的形成之外，氧化性 DNA 损伤可能在其中发挥着重要作用。这些芳香胺的致癌过程食品添加剂溴酸钾 (KBrO_3) 会诱发大鼠肾细胞肿瘤我们发现 KBrO_3 会诱导 8-oxodG。我们推测，SH 类化合物 GSH 和 Cys 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）。更少