Faculty of Pharmacy, Apotex Centre, University of Manitoba, Winnipeg, Manitoba, Canada.
J Inorg Biochem. 2011 Jun;105(6):833-8. doi: 10.1016/j.jinorgbio.2011.02.007. Epub 2011 Feb 26.
Cadmium (Cd(2+)) is a highly toxic and carcinogenic metal that is an environmental and occupational hazard. DNA topoisomerase II is an essential nuclear enzyme and its inhibition can result in the formation of genotoxic and recombinogenic DNA double strand breaks. In this study we showed that cadmium chloride strongly inhibited the DNA decatenation activity of human topoisomerase IIα in the low micromolar concentration range and that its inhibitory effects were reduced by glutathione. Because the activity of topoisomerase II is strongly inhibited by thiol-reactive compounds this result suggested that cadmium may be binding to critical topoisomerase II cysteine thiols. Cadmium, however, did not stabilize DNA-topoisomerase II covalent complexes, as measured by the lack of formation of DNA double strand breaks. Hence, it is not likely to be a topoisomerase II poison. Consistent with the idea that cadmium cytotoxicity may be modulated by glutathione levels, buthionine sulfoximine pretreatment to decrease glutathione levels resulted in a greatly increased cadmium-induced cytotoxicity in K562 cells. The results of this study suggest that cadmium may exert some of its cell growth inhibitory, and possibly its toxicity and carcinogenicity, by inhibiting topoisomerase IIα through reaction with critical cysteine thiols.
镉（Cd(2+)）是一种剧毒和致癌的金属，对环境和职业健康构成威胁。DNA 拓扑异构酶 II 是一种必需的核酶，其抑制作用可导致遗传毒性和重组性 DNA 双链断裂的形成。在这项研究中，我们表明氯化镉在低微摩尔浓度范围内强烈抑制人拓扑异构酶 IIα 的 DNA 解链活性，而谷胱甘肽可降低其抑制作用。由于拓扑异构酶 II 的活性被巯基反应性化合物强烈抑制，因此这一结果表明镉可能与关键的拓扑异构酶 II 半胱氨酸巯基结合。然而，镉并没有稳定 DNA-拓扑异构酶 II 共价复合物，如缺乏 DNA 双链断裂的形成所表明的那样。因此，它不太可能是拓扑异构酶 II 的毒物。与谷胱甘肽水平可能调节镉细胞毒性的观点一致，用丁硫氨酸亚砜亚胺预处理降低谷胱甘肽水平会导致 K562 细胞中镉诱导的细胞毒性大大增加。这项研究的结果表明，镉可能通过与关键的半胱氨酸巯基反应抑制拓扑异构酶 IIα 来发挥其部分细胞生长抑制作用，并且可能具有毒性和致癌性。
