Inorganic arsenic is considered a human carcinogen based principally on epidemiological evidence. Unlike most initiating chemicals, arsenic is inactive or extremely weak in its ability to directly induce gene mutations. Arsenite has been shown, however, to enhance mutagenicity when present with other agents such as UV radiation. Synergistic potentiation of chromosomal damage has been shown with co-treatment with DNA-crosslinking agents. Arsenite at low concentrations is known to be highly selective in reacting with closely spaced (vicinal) dithiol groups in proteins. Poly(ADP-ribose) polymerase (PARP) is known to contain such vicinal dithiol groups. Stimulation of PARP is an immediate response of eukaryotic cells to DNA strand breaks and has been implicated in DNA repair. The effect of treatment with sodium arsenite on PARP activity was assessed as followsMolt-3 cells (a human T-cell lymphoma-derived cell line) in culture were treated for 24 h with concentrations of sodium arsenite ranging from 2.5 up to 25 microM. Speciation of inorganic arsenic and cell viability were determined. Cell cycle kinetics were measured by flow cytometry. Poly(ADP-ribose) synthesis was assayed using a palindromic decameric deoxynucleotide to stimulate enzyme activity. Results show that arsenite decreases PARP activity in a dose-dependent manner with an approximately 50% decrease in enzyme activity at 10 microM arsenite and 80% viability. The percent of cells in S-phase increases with increasing concentration of arsenite. These results provide further indication that arsenite may potentiate genetic damage through reaction with dithiols in DNA repair proteins such as PARP, perhaps resulting in interference with normal repair function.

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主要根据流行病学证据,无机砷被认为是人类致癌物。与大多数起始化学物质不同,砷在直接诱导基因突变的能力方面没有活性或极弱。然而,当与其他试剂 (例如紫外线辐射) 一起存在时,亚砷酸盐可以增强诱变性。与DNA交联剂共同处理已显示出染色体损伤的协同增强作用。众所周知,低浓度的亚砷酸盐在与蛋白质中紧密间隔的 (相邻) 二硫醇基团反应中具有很高的选择性。聚 (ADP-核糖) 聚合酶 (PARP) 已知包含此类邻二硫醇基团。刺激PARP是真核细胞对DNA链断裂的立即反应,并与DNA修复有关。用亚砷酸钠处理对PARP活性的影响进行评估,因为followsMolt-3培养物中的细胞 (人类T细胞淋巴瘤衍生的细胞系) 用2.5至25微米的亚砷酸钠浓度处理24小时。确定了无机砷的形态和细胞活力。通过流式细胞术测量细胞周期动力学。使用回文十聚脱氧核苷酸刺激酶活性测定聚 (ADP-核糖) 合成。结果表明,亚砷酸盐以剂量依赖性方式降低PARP活性,在10微米亚砷酸盐和80% 活力下酶活性降低约50%。S期细胞百分比随亚砷酸盐浓度的增加而增加。这些结果进一步表明,亚砷酸盐可能通过与DNA修复蛋白 (例如PARP) 中的二硫醇反应来增强遗传损伤,从而可能导致对正常修复功能的干扰。

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