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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >The benzene metabolite p-benzoquinone forms adducts with DNA bases that are excised by a repair activity from human cells that differs from an ethenoadenine glycosylase.
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The benzene metabolite p-benzoquinone forms adducts with DNA bases that are excised by a repair activity from human cells that differs from an ethenoadenine glycosylase.

机译：苯代谢物对苯醌与DNA碱基形成加合物，该DNA碱基通过不同于人类腺嘌呤糖基化酶的人类细胞修复活性而被切除。

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摘要

Benzene is a ubitiquous human environment mental carcinogen. One of the major metabolites is hydroquinone, which is oxidized in vivo to give p-benzoquinone (p-BQ). Both metabolites are toxic to human cells. p-BQ reacts with DNA to form benzetheno adducts with deoxycytidine, deoxyadenosine, and deoxyguanosine. In this study we have synthesized the exocyclic compounds 3-hydroxy-3-N4-benzetheno-2'-deoxycytidine (p-BQ-dCyd) and 9-hydroxy-1,N6-benzetheno-2'-deoxyadenosine (p-BQ-dAdo), respectively, by reacting deoxycytidine and deoxyadenosine with p-BQ. These were converted to the phosphoamidites, which were then used to prepare site-specific oligonucleotides with either the p-BQ-dCyd or p-BQ-dAdo adduct (pbqC or pbqA in sequences) at two different defined positions. These oligonucleotides were efficiently nicked 5' to the adduct by partially purified HeLa cell extracts--the pbqC-containing oligomer more rapidly than the pbqA-containing oligomer. In contrast to the enzyme binding to derivatives produced by the vinyl chloride metabolite chloroacetaldehyde, the oligonucleotides up to 60-mer containing p-BQ adducts did not bind measurably to the same enzyme preparation in a gel retardation assay. Furthermore, there was no competition for the binding observed between oligonucleotides containing 1,N6-etheno A deoxyadenosine (1,N6-etheno-dAdo; epsilon A in sequences) and these oligomers containing either of the p-BQ adducts, even at 120-fold excess. When highly purified fast protein liquid chromatography (FPLC) enzyme fractions were obtained, there appeared to be two closely eluting nicking activities. One of these enzymes bound and cleaved the epsilon A-containing deoxyoligonucleotide. The other enzyme cleaved the pbqA- and pbqC-containing deoxyoligonucleotides. One additional unexpected fact was that bulk p-BQ-treated salmon sperm DNA did compete effectively with the epsilon A-containing oligonucleotide for protein binding. This raises the possibility that such DNA contains other, as-yet-uncharacterized adducts that are recognized by the same enzyme that recognizes the etheno adducts. In summary, we describe a previously undescribed human DNA repair activity, possibly a glycosylase, that excises from DNA pbqC and pbqA, exocyclic adducts resulting from reaction of deoxycytidine and deoxyadenosine with the benzene metabolite, p-BQ. This glycosylase activity is not identical to the one previously reported from this laboratory as excising the four etheno bases from DNA.
机译：苯是人类环境中的致富致癌物。主要代谢物之一是对苯二酚，对苯二酚在体内会被氧化生成对苯醌（p-BQ）。两种代谢物均对人体细胞有毒。 p-BQ与DNA反应以与脱氧胞苷，脱氧腺苷和脱氧鸟苷形成苯乙炔加合物。在这项研究中，我们合成了环外化合物3-羟基-3-N4-苯并噻吩-2'-脱氧胞苷（p-BQ-dCyd）和9-羟基-1，N6-苯并噻吩-2'-脱氧腺苷（p-BQ- dAdo），分别使脱氧胞苷和脱氧腺苷与p-BQ反应。将它们转化为亚磷酰胺，然后将其用于在两个不同的定义位置与p-BQ-dCyd或p-BQ-dAdo加合物（顺序为pbqC或pbqA）制备位点特异性寡核苷酸。这些寡核苷酸通过部分纯化的HeLa细胞提取物（含pbqC的寡聚物比含pbqA的寡聚物）更快地在加合物的5'处形成切口。与酶结合由氯乙烯代谢物氯乙醛产生的衍生物相反，在凝胶阻滞分析中，含有多达60个单体的p-BQ加合物的寡核苷酸不能与同一酶制剂可测量地结合。此外，在含有1，N6-乙炔A脱氧腺苷（1，N6-乙炔-dAdo；序列中的εA）的寡核苷酸与这些含任何p-BQ加合物的寡聚体之间，即使在120-倍数多余。当获得高度纯化的快速蛋白液相色谱（FPLC）酶馏分时，似乎有两个紧密洗脱的切刻活性。这些酶之一结合并裂解了包含εA的脱氧寡核苷酸。另一种酶裂解了含pbqA和pbqC的脱氧寡核苷酸。另一个意外的事实是，大量经p-BQ处理的鲑鱼精子DNA确实与含epsilon A的寡核苷酸有效竞争了蛋白质结合。这就增加了这种DNA包含其他尚未鉴定的加合物的可能性，这些加合物被识别乙炔加合物的同一酶识别。总而言之，我们描述了以前从未描述的人类DNA修复活性，可能是糖基化酶，它从DNA pbqC和pbqA中切除，这是脱氧胞苷和脱氧腺苷与苯代谢物p-BQ反应产生的环外加合物。这种糖基化酶的活性与该实验室先前报道的从DNA中切下的四个乙炔碱基的活性不同。

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