Characterization of nonmutagenic Cr(III)-DNA interactions
Characterization of nonmutagenic Cr(III)-DNA interactions
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DOI：
10.1021/tx034007g
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发表时间：
2003-07-01
影响因子：
4.1
通讯作者：
Stearns, DM
中科院分区：
文献类型：
--
作者：
Blankert, SA;Coryell, VH;Stearns, DM
细胞或动物暴露于致癌的铬（VI）（Cr（VI））会产生Cr（III）-DNA加合物。这些病变与Cr（VI）诱导的肿瘤的相关性尚不清楚。各种铬（III）络合物已被用来模拟从铬（VI）代谢产生的产品，以获得机理的见解。本研究的目的是表征Cr（III）配合物与DNA的相互作用，以评估其作为这些目的的模型。比较了DNA与六水合氯化铬（CrCl_3）和二（L-Cysteinato）铬（III）二水合物（Cr（cys）（2）（-））的反应性以及与顺式二氨二氯铂（II）（cis-platin）的反应性。Cr（III）和Pt（II）都能引起超螺旋DNA的解旋，这可以通过凝胶电泳观察到迁移率的变化。与顺铂相比，氯化铬对DNA的扭曲程度要小得多，DNA的解旋程度仅为1- 2度，Cr（cys）（2）（-）与DNA的相互作用很弱。与体外研究一致，CrCl 3在CHO AA 8细胞中产生的Cr-DNA加合物水平与Cr（VI）相当，而Cr（cys）（2）（-）未产生显著的加合物。在次黄嘌呤-Gua-磷酸核糖基转移酶试验中，CrCl 3产生的病变没有致突变性。这些数据是一致的氯化铬产生一个nondistorting病变，也许与磷酸骨架。这些结果有两种可能的解释：要么Cr（VI）代谢形成的Cr（III）产物不是由CrCl 3和Cr（cys）（2）（-）复合物模拟的，要么Cr（III）不是Cr（VI）诱导的DNA损伤的活性物质。这项研究提供了Cr（III）-DNA加合物的第一个结构证据。在我们确定Cr（VI）诱导的癌症中它们的相关性之前，有必要对Cr（III）-DNA相互作用进行分子理解。
Exposure of cells or animals to carcinogenic chromium(VI) (Cr(VI)) produces Cr(III)-DNA adducts. The relevance of these lesions to Cr(VI)-induced tumors is unclear. Various Cr(III) complexes have been used to model the products resulting from Cr(VI) metabolism in order to gain mechanistic insights. The purpose of this study was to characterize interactions of Cr(III) complexes with DNA in order to evaluate their use as models for these purposes. The reactivity of DNA with chromic chloride hexahydrate (CrCl3) and sodium bis(L-CySteinato)chromium(III) dihydrate (Cr(cys)(2)(-))was compared to that with cis-diamminedichloroplatinum(II) (cis-platin). Both Cr(III) and Pt(II) cause unwinding of supercoiled DNA that can be visualized as a mobility shift by gel electrophoresis. Chromic chloride was much less distorting than cis-platin, unwinding DNA by only 1-2degrees, and Cr(cys)(2)(-) interacted with DNA only weakly. Consistent with in vitro studies, CrCl3 produced Cr-DNA adducts in CHO AA8 cells at levels equivalent to those obtained with Cr(VI), whereas Cr(cys)(2)(-) did not produce significant adducts. Lesions produced by CrCl3 were not mutagenic in the hypoxanthine-Gua-phosphoribosyltransferase assay. These data are consistent with CrCl3 producing a nondistorting lesion, perhaps by association with the phosphate backbone. There are two possible interpretations of these results: Either the Cr(III) products formed by Cr(VI) metabolism are not modeled by CrCl3 and Cr(cys)(2)(-) complexes, or Cr(III) is not an active species for Cr(VI)-induced DNA damage. This study provides the first structural evidence for Cr(III)-DNA adducts. A molecular understanding of Cr(III)-DNA interactions will be necessary before we can determine their relevance in Cr(VI)-induced cancers.