Recent advances in metal carcinogenicity
Recent advances in metal carcinogenicity
复制标题
DOI：
10.1351/pac200072061007
复制
发表时间：
2000-06-01
影响因子：
1.8
通讯作者：
Hartwig, A
中科院分区：
文献类型：
--
作者：
Hartwig, A
镍、铬、砷、钴和镉化合物的致癌性早已被认识到。然而，肿瘤形成的机制还不是很清楚。致癌潜力取决于金属种类；主要决定因素是氧化态和溶解度。两种作用模式似乎占主导地位：诱导DNA氧化损伤和与DNA修复过程的相互作用，导致与各种DNA损伤剂联合作用的遗传毒性增强。核苷酸切除修复(NER)在低浓度、无细胞毒性的镍(II)、镉(II)、钴(II)和砷(III)时受到抑制；氧化DNA碱基修饰的修复受到镍(II)和镉(II)的干扰。修复抑制的一个原因似乎是锌(II)和镁(II)的置换。潜在的敏感靶点是存在于几种DNA修复酶中的所谓锌指结构，如哺乳动物的XPA蛋白和细菌的甲酰胺基嘧啶-DNA糖基酶(FPG蛋白)；详细的研究表明，每种锌指蛋白对有毒金属离子都具有独特的敏感性。综上所述，有毒金属离子可能通过诱导DNA氧化损伤和降低对内源和外源诱变剂诱导的DNA损伤的修复能力来降低遗传稳定性，从而增加肿瘤形成的风险。
The carcinogenicity of nickel, chromium, arsenic,cobalt, and cadmium compounds has long been recognized. Nevertheless, the mechanisms involved in tumor formation are not well understood. The carcinogenic potential depends on metal species; major determinants are oxidation state and solubility. Two modes of action seem to be predominant: the induction of oxidative DNA damage and the interaction with DNA repair processes, leading to an enhancement of genotoxicity in combination with a variety of DNA-damaging agents. Nucleotide excision repair (NER) is inhibited at low, non-cytotoxic concentrations of nickel(II), cadmium(II), cobalt(II), and arsenic(III); the repair of oxidative DNA base modifications is disturbed by nickel(II) and cadmium(II). One reason for repair inhibition appears to be the displacement of zinc(II) and magnesium(II). Potentially sensitive targets are so-called zinc finger structures present in several DNA repair enzymes such as the mammalian XPA protein and the bacterial formamidopyrimidine-DNA glycosylase (Fpg protein); detailed studies revealed that each zinc finger protein exerts unique sensitivities toward toxic metal ions. Taken together, toxic metal ions may lower the genetic stability by inducing oxidative DNA damage and by decreasing the repair capacity towards DNA lesions induced by endogenous and exogenous mutagens, which may in turn increase the risk of tumor formation.