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首页> 外文期刊>Biochemistry >Gentoxicity and Mutagenicity of Chromium(VI)/Ascorbate-Generated DNA Adducts in Human and Bacterial Cells
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Gentoxicity and Mutagenicity of Chromium(VI)/Ascorbate-Generated DNA Adducts in Human and Bacterial Cells

机译：铬（VI）/抗坏血酸产生的DNA加合物在人和细菌细胞中的遗传毒性和致突变性

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Reduction of carcinogenic Cr(VI) by vitamin C generates ascorbate-Cr(III)-DNA cross-links, binary Cr(III)-DNA adducts, and can potentially cause oxidative DNA damage by intermediate reaction products. Here, we examined the mutational spectrum and the importance of different forms of DNA damage in genotoxicity and mutagenicity of Cr(VI) activated by physiological concentrations of ascrobate. Reduction of Cr(VI) led to a dose-dependent formation of both mutagenic and replication-blocking DNA lesions as detected by propagation of the pSP189 plasmids in human fibroblasts. Disruption of Cr-DNA binding abolished mutagenic responses and normalized the yield of replicated plasmids, indicating that Cr-DNA adducts were responsible for both mutagencity and genotoxicity of Cr(VI). The absence of DNA breaks and abasic sites confirmed for lack of a significant production of hydroxyl radicals and Cr(V)-peroxo complexes in Cr(VI)-ascorbate reactions. Ascorbate-Cr(III)-DNA cross-links were much more mutagenic than smaller Cr(III)-DNA adducts and accounted for more than 90% of Cr(VI) mutagenicity. Ternary adducts were also several times more potent in the inhibition of replication than binary complexes. The Cr(VI)-induced mutational spectrum consisted of an approximately equal number of deletions and G/C-targated point mutations (51% G/C - > T/A and 30% G/C - > A/T). In Escherichia coli cells, Cr(VI)-induced DNA adducts were only highly gentoxic but not mutagenic under either normal or SOS-induced conditions. Lower toxicity and high mutagenicity of ascorbate - Cr(III)-DNA adducts in human cells may result from the recruitment of an error-prone bypass DNA polymerase(s) to the stalled replication forks. Our results suggest that phosphotriester-type DNA adducts could play a more important role in human than bacterial mutagenesis.
机译：维生素C还原致癌的Cr（VI）会生成抗坏血酸-Cr（III）-DNA交联键，二价Cr（III）-DNA加合物，并可能通过中间反应产物引起DNA氧化损伤。在这里，我们检查了突变谱和不同形式的DNA损伤的重要性在由生理浓度的抗坏血酸激活的Cr（VI）的遗传毒性和致突变性中。 Cr（VI）的还原导致诱变和复制阻断DNA损伤的剂量依赖性形成，如通过在人成纤维细胞中传播pSP189质粒所检测到的。 Cr-DNA结合的破坏消除了诱变反应，并使复制质粒的产量正常化，表明Cr-DNA加合物对Cr（VI）的致突变性和遗传毒性都有影响。 DNA断裂和无碱基位点的缺乏证实在Cr（VI）-抗坏血酸反应中缺乏大量的羟基自由基和Cr（V）-peroxo配合物。抗坏血酸-Cr（III）-DNA交联比较小的Cr（III）-DNA加合物更具致突变性，占Cr（VI）致突变性的90％以上。三元加合物对复制的抑制作用也比二元复合物强几倍。 Cr（VI）诱导的突变谱由大约相等数量的缺失和G / C污染点突变组成（51％G / C-> T / A和30％G / C-> A / T）。在大肠杆菌细胞中，Cr（VI）诱导的DNA加合物在正常或SOS诱导的条件下仅具有高度的遗传毒性，而没有致突变性。抗坏血酸-Cr（III）-DNA加合物在人细胞中的较低毒性和高致突变性可能是由于将容易出错的旁路DNA聚合酶募集到停滞的复制叉中引起的。我们的结果表明，磷酸三酯型DNA加合物在人类中的作用比细菌诱变更为重要。

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