Shen Shengwen, Lee Jane, Sun Xuejun, Wang Hailin, Weinfeld Michael, Le X Chris
Department of Public Health Sciences, University of Alberta, Edmonton, Canada.
Environ Health Perspect. 2006 Dec;114(12):1832-7. doi: 10.1289/ehp.9284.
Arsenite (iAsIII) can promote mutagenicity and carcinogenicity of other carcinogens. Considerable attention has focused on interference with DNA repair by inorganic arsenic, especially the nucleotide excision repair (NER) pathway, whereas less is known about the effect of arsenic on the induction of DNA damage by other agents.
We examined how arsenic modulates DNA damage by other chemicals.
We used an NER-deficient cell line to dissect DNA damage induction from DNA repair and to examine the effects of iAsIII on the formation of benzo[a]pyrene diol epoxide (BPDE)-DNA adducts.
We found that pretreatment with iAsIII at subtoxic concentrations (10 microM) led to enhanced formation of BPDE-DNA adducts. Reduced glutathione levels, glutathione S-transferase activity and chromatin accessibility were also measured after iAsIII treatment, but none of these factors appeared to account for the enhanced formation of DNA adducts. However, we found that pretreatment with iAsIII increased the cellular uptake of BPDE in a dose-dependent manner.
Our results suggest that iAsIII enhanced the formation of BPDE-DNA adducts by increasing the cellular uptake of BPDE. Therefore, the ability of arsenic to increase the bioavailability of other carcinogens may contribute to arsenic co-carcinogenicity.
亚砷酸盐（iAsIII）可促进其他致癌物的致突变性和致癌性。相当多的注意力集中在无机砷对DNA修复的干扰上，尤其是核苷酸切除修复（NER）途径，而关于砷对其他试剂诱导DNA损伤的影响则知之甚少。
我们研究了砷如何调节其他化学物质引起的DNA损伤。
我们使用一种NER缺陷细胞系来区分DNA损伤诱导和DNA修复，并研究iAsIII对苯并[a]芘二醇环氧化物（BPDE）-DNA加合物形成的影响。
我们发现，用亚毒性浓度（10 microM）的iAsIII预处理会导致BPDE-DNA加合物的形成增加。在iAsIII处理后还测量了谷胱甘肽水平、谷胱甘肽S-转移酶活性和染色质可及性，但这些因素似乎都不能解释DNA加合物形成的增加。然而，我们发现用iAsIII预处理会以剂量依赖的方式增加细胞对BPDE的摄取。
我们的结果表明，iAsIII通过增加细胞对BPDE的摄取来增强BPDE-DNA加合物的形成。因此，砷增加其他致癌物生物利用度的能力可能有助于砷的协同致癌作用。
