Spontaneous mutagenesis in Csb(m/m)Ogg1⁻(/)⁻ mice is attenuated by dietary resveratrol.
Spontaneous mutagenesis in Csb(m/m)Ogg1⁻(/)⁻ mice is attenuated by dietary resveratrol.
复制标题
饮食中的白藜芦醇可减弱 Csb(m/m)Ogg1⁻(/)⁻ 小鼠的自发诱变。
作者：
Markus Fusser;G. Nesse;A. Khobta;N. Xia;Huige Li;A. Klungland;B. Epe
氧化性DNA修饰，如7，8-二氢-8-氧代鸟嘌呤（8-oxoG），显然在所有活细胞中内源性产生。Csb（m/m）Ogg 1 β（/）C3小鼠中8-oxoG修复缺陷导致这些病变的基础水平升高和自发突变频率增加，如果细胞增殖受到刺激，自发突变会引发肝脏中的肿瘤发生。在此，我们描述了植物抗毒素白藜芦醇，无论是连续7天/管饲（100毫克/公斤体重）或3-9个月的饮食（0.04%自由采食），减少内源性氧化DNA碱基损伤的Csb（m/m）Ogg 1（/）rmb小鼠的肝脏中的20-30%（P < 0.01）。在野生型动物中也观察到小但一致的作用。在BigBlue® Csb（m/m）Ogg 1 β（/）β小鼠的lacI基因中测定的自发突变频率同时被白藜芦醇降低至相似的程度。从机制上讲，这种保护是由抗氧化防御系统的诱导引起的，因为（i）从所有白藜芦醇处理的动物中分离的肝细胞对单链断裂的产生和H2O的细胞杀伤不太敏感，（ii）超氧化物歧化酶1和2的信使RNA水平（SOD 1和SOD 2）血红素加氧酶-1和谷胱甘肽过氧化物酶在短期治疗后显著上调，（iii）主要归因于氧化碱基修饰8-oxoG（G：C至T：A颠换）比归因于自发脱氨基的G：C至A：T转换受到更强烈的抑制。因此，结果表明，内源性氧化DNA损伤引起的自发体细胞突变率可以通过应用外源性试剂来降低。
Oxidative DNA modifications such as 7,8-dihydro-8-oxoguanine (8-oxoG) are generated endogenously in apparently all living cells. The defect of the repair of 8-oxoG in Csb(m/m)Ogg1⁻(/)⁻ mice results in elevated basal levels of these lesions and increased frequencies of spontaneous mutations, which initiate tumorigenesis in the liver if cell proliferation is stimulated. Here, we describe that the phytoalexin resveratrol, applied either for 7 days per gavage (100 mg/kg body wt) or for 3-9 months in the diet (0.04% ad libitum), reduces the endogenous oxidative DNA base damage in the livers of the Csb(m/m)Ogg1⁻(/)⁻ mice by 20-30% (P < 0.01). A small but consistent effect is also observed in the wild-type animals. The spontaneous mutation frequencies determined in the lacI gene of BigBlue® Csb(m/m)Ogg1⁻(/)⁻ mice are concomitantly reduced by resveratrol to similar extents. Mechanistically, the protection is caused by an induction of the antioxidant defense system since (i) hepatocytes isolated from all resveratrol-treated animals were less susceptible to the generation of single-strand breaks and to cell killing by H₂O₂, (ii) messenger RNA levels of superoxide dismutases 1 and 2 (SOD1 and SOD2) heme oxygenase-1 and glutathione peroxidase were significantly upregulated after the short-term treatment and (iii) mutations primarily ascribed to the oxidative base modification 8-oxoG (G:C to T:A transversions) were more strongly suppressed than G:C to A:T transitions ascribed to spontaneous deamination. The results thus demonstrate that spontaneous somatic mutation rates resulting from endogenous oxidative DNA damage can be reduced by application of an exogenous agent.
影响因子：
158.5
作者：
Lichtenstein, P;Holm, NV;Hemminki, K
通讯作者：
Hemminki, K