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首页> 美国卫生研究院文献>Environmental Health Perspectives >Reductive activation with cysteine represents a chromium(III)-dependent pathway in the induction of genotoxicity by carcinogenic chromium(VI).
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Reductive activation with cysteine represents a chromium(III)-dependent pathway in the induction of genotoxicity by carcinogenic chromium(VI).

机译：半胱氨酸的还原活化代表致癌性铬（VI）致遗传毒性的铬（III）依赖性途径。

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摘要

Induction of DNA damage by carcinogenic hexavalent chromium compounds [Cr(VI)] results from its reduction to lower oxidation states. Reductive metabolism of Cr(VI) generates intermediate Cr(V/IV)species, organic radicals, and finally Cr(III), which forms stable complexes with many biological ligands, including DNA. To determine the biological significance of different reaction products, we examined genotoxic responses and the formation of DNA damage during reduction of Cr(VI) by its biological reducer, cysteine. We have found that cysteine-dependent activation of Cr(VI) led to the formation of Cr-DNA and cysteine-Cr-DNA adducts as well as interstrand DNA cross-links. The yield of binary and ternary DNA adducts was relatively constant at different concentrations of Cr(VI) and averaged approximately 54 and 45%, respectively. Interstrand DNA cross-links accounted on average for 1% of adducts, and their yield was even less significant at low Cr(VI) concentrations. Reduction of Cr(VI) in several commonly used buffers did not induce detectable damage to the sugar-phosphate backbone of DNA. Replication of Cr(VI)-modified plasmids in intact human fibroblasts has shown that cysteine-dependent metabolism of Cr(VI) resulted in the formation of mutagenic and replication-blocking DNA lesions. Selective elimination of Cr-DNA adducts from Cr(VI)-treated plasmids abolished all genotoxic responses, indicating that nonoxidative, Cr(III)-dependent reactions were responsible for the induction of both mutagenicity and replication blockage by Cr(VI). The demonstration of the mutagenic potential of Cr-DNA adducts suggests that these lesions can be explored in the development of specific and mechanistically important biomarkers of exposure to toxic forms of Cr.
机译：致癌的六价铬化合物[Cr（VI）]引起的DNA损伤是由于其还原成较低的氧化态而引起的。 Cr（VI）的还原代谢产生中间的Cr（V / IV）物种，有机自由基，最后生成Cr（III），与许多生物配体（包括DNA）形成稳定的复合物。为了确定不同反应产物的生物学意义，我们检查了遗传毒性反应和通过其生物还原剂半胱氨酸还原Cr（VI）期间DNA损伤的形成。我们发现，Cr（VI）的半胱氨酸依赖性激活导致Cr-DNA和半胱氨酸-Cr-DNA加合物的形成以及链间DNA交联。在不同浓度的Cr（VI）下，二元和三元DNA加合物的收率相对恒定，分别平均约为54％和45％。链间DNA交联平均占加合物的1％，在低Cr（VI）浓度下其收率甚至更低。在几种常用的缓冲液中还原Cr（VI）不会引起对DNA糖磷酸骨架的可检测到的破坏。 Cr（VI）修饰的质粒在完整的人类成纤维细胞中的复制显示，Cr（VI）的半胱氨酸依赖性代谢导致诱变和复制受阻DNA损伤的形成。从Cr（VI）处理的质粒中选择性消除Cr-DNA加合物消除了所有的遗传毒性反应，表明非氧化性，Cr（III）依赖性反应是导致Cr（VI）诱变和复制受阻的原因。 Cr-DNA加合物诱变潜力的证明表明，可以通过开发特定的和具有机械重要性的生物标志物来接触这些毒性形式的Cr，从而探索这些损伤。

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