Nickel (II) enhances benzo[a]pyrene diol epoxide-induced mutagenesis through inhibition of nucleotide excision repair in human cells:: a possible mechanism for nickel (II)-induced carcinogenesis
Nickel (II) enhances benzo[a]pyrene diol epoxide-induced mutagenesis through inhibition of nucleotide excision repair in human cells:: a possible mechanism for nickel (II)-induced carcinogenesis
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DOI：
10.1093/carcin/bgh012
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发表时间：
2004-03-01
期刊：
影响因子：
4.7
通讯作者：
Tang, MS
中科院分区：
文献类型：
--
作者：
Hu, WW;Feng, ZH;Tang, MS
镍（II）是一种普遍存在的环境和工业污染物，是一种众所周知的人类致癌物，特别是在人类肺癌中。虽然镍本身是一种弱诱变剂，但它能够显着增强其他诱变剂和致癌物的遗传毒性，如多环芳烃（PAH）和紫外线。某些人群，特别是吸烟者，经常暴露于镍（II）和多环芳烃。为了了解镍（II）和多环芳烃在致突变和人类致癌作用中的相互作用，我们使用穿梭载体致突变试验来检测镍（II）对（+/-）抗7 β，8 α-二羟基-9 α，10 α-环氧-7，8，9，10-四羟基苯并[a]芘（BPDE）诱导的人类细胞致突变的影响。BPDE是香烟烟雾中主要致癌物苯并[a]芘（BP）的活化代谢物。将用BPDE修饰的穿梭载体pSP 189转染到有和没有镍（II）暴露的人细胞中。我们发现，镍（II）曝光显着提高BPDE诱导的突变频率，但没有改变BPDE诱导的突变谱中的supF基因的pSP 189质粒复制的核苷酸切除修复（NER）精通人类细胞。然而，镍（II）对BPDE诱导的突变频率的增强作用在NER缺陷的人XPA细胞中没有观察到。我们还发现，镍（II）暴露的人类细胞没有改变自发突变频率的supF基因在NER-proficient或NER-deficient人类细胞，表明镍（II）不影响复制保真度在人类细胞。使用含有荧光素酶报告基因的质粒和宿主细胞再活化试验，我们发现，镍（II）曝光大大抑制了修复的BPDE-DNA加合物在NER-proficient，但不是在NER-deficient细胞。总之，这些结果强烈表明，镍（II）可以大大提高多环芳烃的诱变性和遗传毒性，通过抑制在人类细胞中的NER途径，这可能是一个重要的机制，镍（II）诱导的人类致癌。
Nickel (II), a ubiquitous environmental and industrial contaminant, is a well-known human carcinogen, particularly in human lung cancer. Although by itself it is a weak mutagen, nickel (II) is able to significantly enhance the genotoxicity of other mutagens and carcinogens, such as polycyclic aromatic hydrocarbons (PAHs) and ultraviolet light. Certain human populations, especially cigarette smokers, are frequently exposed to both nickel (II) and PAHs. To understand the interplay of nickel (II) and PAHs in mutagenesis and human carcinogenesis, we used a shuttle vector mutagenicity assay to examine the effect of nickel (II) on (+/-) anti-7beta, 8alpha-dihydroxy-9alpha, 10alpha-epoxy-7,8,9,10-tetrahydroxybenzo[a]pyrene (BPDE)-induced mutagenesis in human cells. BPDE is an activated metabolite of benzo[a]pyrene (BP), a major carcinogen in cigarette smoke. The shuttle vector pSP189 modified with BPDE was transfected into human cells with and without nickel (II) exposure. We found that nickel (II) exposure significantly enhanced BPDE-induced mutation frequency, but did not change BPDE-induced mutational spectrum in the supF gene of pSP189 plasmids replicated in nucleotide excision repair (NER)-proficient human cells. However, the enhancing effect of nickel (II) on BPDE-induced mutation frequency was not observed in NER-deficient human XPA cells. We also found that nickel (II) exposure of human cells did not change the spontaneous mutation frequency of the supF gene in NER-proficient or NER-deficient human cells, indicating that nickel (II) did not affect the replication fidelity in human cells. Using a plasmid containing a luciferase reporter gene and a host cell reactivation assay, we have found that nickel (II) exposure greatly inhibited the repair of BPDE-DNA adducts in NER-proficient but not in NER-deficient cells. Together these results strongly suggest that nickel (II) can greatly enhance the mutagenicity and genotoxicity of PAHs by inhibiting the NER pathway in human cells, and this may constitute an important mechanism for nickel (II)-induced human carcinogenesis.