Institut fur Lebensmittelchemie, Westfalische Wilhelms-Universitat Munster, Corrensstrasse 45, 48149 Munster, Germany.
Chem Res Toxicol. 2010 Feb 15;23(2):432-42. doi: 10.1021/tx900444w.
Water-soluble and particulate cadmium compounds are carcinogenic to humans. While direct interactions with DNA are unlikely to account for carcinogenicity, induction of oxidative DNA damage and interference with DNA repair processes might be more relevant underlying modes of action (recently summarized, for example, in Joseph , P. (2009) Tox. Appl. Pharmacol. 238 , 271 - 279). The present study aimed to compare genotoxic effects of particulate CdO and soluble CdCl(2) in cultured human cells (A549, VH10hTert). Both cadmium compounds increased the baseline level of oxidative DNA damage. Even more pronounced, both cadmium compounds inhibited the nucleotide excision repair (NER) of BPDE-induced bulky DNA adducts and UVC-induced photolesions in a dose-dependent manner at noncytotoxic concentrations. Thereby, the uptake of cadmium in the nuclei strongly correlated with the repair inhibition of bulky DNA adducts, indicating that independent of the cadmium compound applied Cd(2+) is the common species responsible for the observed repair inhibition. Regarding the underlying molecular mechanisms in human cells, CdCl(2) (as shown before by Meplan, C., Mann, K. and Hainaut, P. (1999) J. Biol. Chem. 274 , 31663 - 31670 ) and CdO altered the conformation of the zinc binding domain of the tumor suppressor protein p53. In further studies applying only CdCl(2), cadmium decreased the total nuclear protein level of XPC, which is believed to be the principle initiator of global genome NER. This led to diminished association of XPC to sites of local UVC damage, resulting in decreased recruitment of further NER proteins. Additionally, CdCl(2) strongly disturbed the disassembly of XPC and XPA. In summary, our data indicate a general nucleotide excision repair inhibition by cadmium compounds, which is most likely caused by a diminished assembly and disassembly of the NER machinery. These data reveal new insights into the mechanisms involved in cadmium carcinogenesis and provide further evidence that DNA repair inhibition may be one predominant mechanism in cadmium induced carcinogenicity.
水溶性和颗粒态的镉化合物对人类具有致癌性。虽然与 DNA 的直接相互作用不太可能导致致癌性，但诱导氧化 DNA 损伤和干扰 DNA 修复过程可能是更相关的潜在作用模式（最近有综述，例如，Joseph，P.（2009）Tox. Appl. Pharmacol. 238，271-279）。本研究旨在比较颗粒态 CdO 和可溶性 CdCl2 在培养的人细胞（A549，VH10hTert）中的遗传毒性作用。两种镉化合物均增加了氧化 DNA 损伤的基线水平。更明显的是，两种镉化合物均以剂量依赖的方式在非细胞毒性浓度下抑制 BPDE 诱导的大体积 DNA 加合物和 UVC 诱导的光损伤的核苷酸切除修复（NER）。因此，镉在核内的摄取与大体积 DNA 加合物的修复抑制强烈相关，表明独立于应用的镉化合物，Cd2+是导致观察到的修复抑制的共同物种。关于人细胞中的潜在分子机制，CdCl2（如 Meplan，C.，Mann，K.和 Hainaut，P.（1999）J. Biol. Chem. 274，31663-31670 之前所示）和 CdO 改变了肿瘤抑制蛋白 p53 的锌结合域的构象。在进一步仅应用 CdCl2 的研究中，镉降低了 XPC 的总核蛋白水平，XPC 被认为是全球基因组 NER 的主要启动子。这导致 XPC 与局部 UVC 损伤部位的结合减少，从而减少了进一步的 NER 蛋白的募集。此外，CdCl2 强烈干扰 XPC 和 XPA 的解组装。总之，我们的数据表明镉化合物普遍抑制核苷酸切除修复，这很可能是由于 NER 机制的组装和拆卸减少所致。这些数据揭示了镉致癌作用中涉及的机制的新见解，并提供了进一步的证据，表明 DNA 修复抑制可能是镉诱导致癌性的主要机制之一。
