DNA Damage Research Group, Institute of Life Science, College of Medicine, Swansea University, SA2 8PP, UK.
Toxicol Sci. 2012 Aug;128(2):387-97. doi: 10.1093/toxsci/kfs152. Epub 2012 Apr 26.
Oxidative stress contributes to many disease etiologies including ageing, neurodegeneration, and cancer, partly through DNA damage induction (genotoxicity). Understanding the i nteractions of free radicals with DNA is fundamental to discern mutation risks. In genetic toxicology, regulatory authorities consider that most genotoxins exhibit a linear relationship between dose and mutagenic response. Yet, homeostatic mechanisms, including DNA repair, that allow cells to tolerate low levels of genotoxic exposure exist. Acceptance of thresholds for genotoxicity has widespread consequences in terms of understanding cancer risk and regulating human exposure to chemicals/drugs. Three pro-oxidant chemicals, hydrogen peroxide (H(2)O(2)), potassium bromate (KBrO(3)), and menadione, were examined for low dose-response curves in human lymphoblastoid cells. DNA repair and antioxidant capacity were assessed as possible threshold mechanisms. H(2)O(2) and KBrO(3), but not menadione, exhibited thresholded responses, containing a range of nongenotoxic low doses. Levels of the DNA glycosylase 8-oxoguanine glycosylase were unchanged in response to pro- oxidant stress. DNA repair-focused gene expression arrays reported changes in ATM and BRCA1, involved in double-strand break repair, in response to low-dose pro-oxidant exposure; however, these alterations were not substantiated at the protein level. Determination of oxidatively induced DNA damage in H(2)O(2)-treated AHH-1 cells reported accumulation of thymine glycol above the genotoxic threshold. Further, the H(2)O(2) dose-response curve was shifted by modulating the antioxidant glutathione. Hence, observed pro- oxidant thresholds were due to protective capacities of base excision repair enzymes and antioxidants against DNA damage, highlighting the importance of homeostatic mechanisms in "genotoxic tolerance."
氧化应激导致多种疾病的发生，包括衰老、神经退行性变和癌症，部分原因是通过诱导 DNA 损伤（遗传毒性）。了解自由基与 DNA 的相互作用是识别突变风险的基础。在遗传毒理学中，监管机构认为大多数遗传毒物在剂量和诱变反应之间呈线性关系。然而，允许细胞耐受低水平遗传毒性暴露的内稳态机制，包括 DNA 修复，是存在的。遗传毒性的阈值接受在理解癌症风险和监管人类接触化学物质/药物方面具有广泛的影响。三种促氧化剂化学品，过氧化氢（H₂O₂）、溴酸钾（KBrO₃）和甲萘醌，在人淋巴母细胞中被检测到低剂量反应曲线。DNA 修复和抗氧化能力被评估为可能的阈值机制。H₂O₂和 KBrO₃，但不是甲萘醌，表现出有阈值的反应，包含一系列非遗传毒性的低剂量。8-氧鸟嘌呤糖苷酶的 DNA 糖苷酶水平在应对促氧化剂应激时没有变化。针对 DNA 修复的基因表达谱报告称，在低剂量促氧化剂暴露下，ATM 和 BRCA1 的基因表达发生变化，这两种基因参与双链断裂修复；然而，这些变化在蛋白质水平上没有得到证实。在 H₂O₂处理的 AHH-1 细胞中检测到氧化性诱导的 DNA 损伤，报告了胸腺嘧啶二醇在遗传毒性阈值以上的积累。此外，通过调节抗氧化剂谷胱甘肽，H₂O₂的剂量反应曲线发生了移位。因此，观察到的促氧化剂阈值是由于碱基切除修复酶和抗氧化剂对 DNA 损伤的保护能力，突出了内稳态机制在“遗传毒性耐受”中的重要性。
