Evaluation of the noncovalent binding interactions between polycyclic aromatic hydrocarbon metabolites and human p53 cDNA.
Evaluation of the noncovalent binding interactions between polycyclic aromatic hydrocarbon metabolites and human p53 cDNA.
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DOI：
10.1016/j.scitotenv.2010.09.024
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发表时间：
2010-11
期刊：
影响因子：
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通讯作者：
Yin Wei;Yuan Lin;Ai-qian Zhang;Liang-Hong Guo;Jie Cao
中科院分区：
文献类型：
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作者：
Yin Wei;Yuan Lin;Ai-qian Zhang;Liang-Hong Guo;Jie Cao
活性多环芳烃（PAH）代谢产物，酶促形成，DNA的结合是PAH在体内致癌的关键步骤。采用荧光置换法和分子对接技术研究了11种PAH代谢产物与人p53互补DNA（p53 cDNA）的非共价结合作用。所有检测的代谢物主要通过嵌入而不是沟结合与p53 cDNA相互作用。解离常数范围为0.02 ~ 12.34μM。在测试的代谢产物中，1-羟基芘和3-羟基苯并[a]芘显示出最强的DNA结合亲和力，而2-萘酚是最弱的DNA嵌入剂。通过将PAH苯环与DNA碱基对堆叠以及代谢物上的氧化物或羟基与DNA碱基或骨架之间形成氢键来稳定代谢物的嵌入。代谢产物与DNA的结合表现出一定的序列选择性。3-羟基苯并[a]芘、苯并[a]芘-4，5-二氢环氧化物（BPE）和苯并[a]芘-r-7，t-8-二氢二醇-t-9，10-环氧化物（BPDE）的结合亲和力和氢键不同。PAH芳香环周围的功能基团在调节其与DNA的结合亲和力中起着至关重要的作用。虽然很难确定DNA非共价结合亲和力和致癌性之间的相关性的一些PAH代谢产物，本研究提高了我们的理解PAH代谢产物-DNA加合物的形成。
The binding of reactive polycyclic aromatic hydrocarbon (PAH) metabolites, formed enzymatically, to DNA is a crucial step in PAH carcinogenesis in vivo. We investigated the noncovalent binding interactions between 11 PAH metabolites and human p53 complementary DNA (p53 cDNA) using the fluorescence displacement method and molecular docking analysis. All of the examined metabolites predominantly interacted with p53 cDNA by intercalation instead of groove binding. The dissociation constants ranged from 0.02 to 12.34μM. Of the metabolites tested, 1-hydroxypyrene and 3-hydroxybenzo[a]pyrene showed the strongest binding affinities to DNA, while 2-naphthol was the weakest DNA intercalator. The intercalation of the metabolites was stabilized by stacking the PAH phenyl rings with the DNA base pairs and the formation of hydrogen bonds between the oxide or hydroxyl groups on the metabolites, and DNA bases or backbones. The binding of the metabolites to DNA showed some sequence selectivity. The binding affinities and hydrogen bonds for 3-hydroxybenzo[a]pyrene, benzo[a]pyrene-4,5-dihydroepoxide (BPE) and benzo[a]pyrene-r-7,t-8-dihydrodiol-t-9,10-epoxide (BPDE) differed. It seems that the functional groups on the periphery of the PAH aromatic ring play crucial roles in regulating its binding affinity with DNA. Although it was difficult to determine the correlation between DNA noncovalent binding affinity and carcinogenicity for some of the PAH metabolites, the present study improved our understanding of the formation of PAH metabolite-DNA adducts.