Mechanisms of DNA damage induced by morin, an inhibitor of amyloid β-peptide aggregation
Mechanisms of DNA damage induced by morin, an inhibitor of amyloid β-peptide aggregation
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β-淀粉样蛋白肽聚集抑制剂桑色素诱导的 DNA 损伤机制
DOI：
10.1080/10715762.2018.1562179
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发表时间：
2019
影响因子：
3.3
通讯作者：
Oikawa Shinji
中科院分区：
文献类型：
--
作者：
Mori Yurie;Kato Shinya;Fujisawa Yutaka;Ohnishi Shiho;Hiraku Yusuke;Kawanishi Shosuke;Murata Mariko;Oikawa Shinji
桑色素是一种潜在的淀粉样蛋白β-肽聚集的抑制剂。这种聚集与阿尔茨海默病的发病机制有关。同时，在金属离子存在的情况下，桑色素被发现具有诱变性，并表现出膜脂过氧化和DNA链断裂。为了阐明桑色素诱导DNA损伤的分子机制，我们检测了桑色素加铜(II)处理后32P-5‘末端标记的人DNA片段的DNA损伤及其位点特异性。在桑色素+铜(II)处理的小牛胸腺DNA中，也检测到了DNA氧化损伤的指示剂8-氧-7，8-二氢-2‘-脱氧鸟苷(8-oxodG)的形成。在铜(II)存在下，桑色素诱导的DNA链断裂和碱基修饰具有剂量依赖性。桑色素加铜(II)优先在胸腺嘧啶和鸟嘌呤残基引起哌啶不稳定损伤。甲硫氨酸、过氧化氢酶和铜(I)螯合剂对DNA损伤均有抑制作用。典型的·OH清除剂乙醇、甘露醇和甲酸钠对桑色素加铜(II)诱导的DNA损伤无抑制作用。加入超氧化物歧化酶后，DNA损伤不受抑制。此外，桑色素加铜(II)可促进小牛胸腺DNA片段中8-oxodG的形成。我们的结论是，在铜(II)存在的情况下，桑色素通过铜(I)/铜(II)氧化还原循环和H_2O_2的产生而发生自氧化，产生铜(I)-氢过氧化氢，从而导致DNA氧化损伤。
Morin is a potential inhibitor of amyloid β-peptide aggregation. This aggregation is involved in the pathogenesis of Alzheimer’s disease. Meanwhile, morin has been found to be mutagenic and exhibits peroxidation of membrane lipids concurrent with DNA strand breaks in the presence of metal ions. To clarify a molecular mechanism of morin-induced DNA damage, we examined the DNA damage and its site specificity on32P-5′-end-labeled human DNA fragments treated with morin plus Cu(II). The formation of 8-oxo-7,8-dihydro-2′-deoxyguanosine (8-oxodG), an indicator of oxidative DNA damage, was also determined in calf thymus DNA treated with morin plus Cu(II). Morin-induced DNA strand breaks and base modification in the presence of Cu(II) were dose dependent. Morin plus Cu(II) caused piperidine-labile lesions preferentially at thymine and guanine residues. The DNA damage was inhibited by methional, catalase and Cu(I)-chelator bathocuproine. The typical •OH scavengers ethanol, mannitol and sodium formate showed no inhibitory effect on DNA damage induced by morin plus Cu(II). When superoxide dismutase was added to the solution, DNA damage was not inhibited. In addition, morin plus Cu(II) increased 8-oxodG formation in calf thymus DNA fragments. We conclude that morin undergoes autoxidation in the presence of Cu(II) via a Cu(I)/Cu(II) redox cycle and H2O2generation to produce Cu(I)-hydroperoxide, which causes oxidative DNA damage.