CONFORMATIONALLY PROMOTED DEGRADATION OF BPDE DNA ADDUCTS

抽象的。苯并[a]芘(BP)是一种多环芳烃环境污染物，它被代谢成一系列区域和立体异构体的BP二醇环氧化物(BPDE)，包括高效致癌物质(+)-抗BPDE。每个代谢物立体异构体可以是亲核的，在碱基的苄基位置偶联到外环氨基。除了酶和水解法去除DNA中的BPDE损伤外，据报道，寡聚和单体加合物还会发生化学分解，其机制和副产物尚不清楚。我们建议研究BPDE修饰的DNA通过均裂过程降解的假说，该过程由碱基-芘堆积促进构象。为了验证这一假设，我们将检查一系列单体BPDE-脱氧核苷酸加合物的构象和降解，这些加合物在碱基和BP立体化学上有所不同。具体地说，我们将检查这些物种，以寻找内部电荷转移相互作用先于降解的证据，第三，我们将调查在BPDE修饰的单链和双链DNA中发生这些过程。在初步研究中，我们研究了由类似于BPDE-脱氧核苷酸加合物的C-N键连接的芘和芳基单元的模型化合物的分解。这些研究表明，加合物在与构象性质相关的不同位置降解。进一步的研究将检查芳基大小、芳基电子、溶剂和降解副产物，以深入了解BPDE-脱氧核苷酸加合物的降解情况。这些研究有助于在两个重要领域了解BPO的致癌机制。首先，这项建议的一个主要目的是调查单体BPDE-脱氧核苷酸加合物的构象性质。这些研究有助于在两个重要领域了解BP的致癌机制。首先，这项建议的一个主要目的是调查单体BPDE-脱氧核苷酸加合物的构象性质作为核苷酸碱基和立体化学的函数。这些单位可能是加合物DNA构象性质的重要贡献者，因此可能在病变的错误生物处理中起重要作用。第二，BPDE-DNA加合物通过同源或异源降解途径可能导致侧翼残基的DNA损伤，这可能有助于肿瘤的发生过程。

ABSTRACT. Benzo[a]pyrene (BP), one of many polycyclic aromatic hydrocarbon environmental pollutants, is metabolized to an array of regio- and stereoisomeric BP diol epoxides (BPDE), including the highly potent carcinogen (+)- anti-BPDE. Each metabolite stereoisomer can be nucleophilicity coupled at the benzylic site to the exocyclic amino groups of nucleobases. In addition to enzymatic and hydroytic removal of BPDE lesions from DNA, it has been reported that oligomeric and monomeric adducts undergo chemical decomposition, through the mechanism and byproducts of this process are unknown. We propose to investigate the hypotheses that BPDE-modified DNA degrades via a homolytic process that is conformationally promoted by nucleobase-pyrene stacking. To test this hypothesis we will examine the conformations and degradations of a series of monomer BPDE-deoxynucleotide adducts that vary in nucleobase and BP stereochemistry. Specifically, we will examine these species for evidence that intralesion charge transfer interaction precede degradation, and third, we will investigate the occurrence of these processes in BPDE-modified single-stranded and duplex DNA. In preliminary studies, we investigated the decompositions of model compounds that support a pyrene and aryl unit tethered by a C-N linkage similar to that of BPDE-deoxynucleotide adducts. These studies suggested that adducts degrade at different that are correlated with conformational properties. Further investigations will examine the aryl size, aryl electronics, solvent and degradation byproducts to provide insight on the degradations on BPDE-deoxynucleotide adduct. These studies contribute to the understand of BPO carcinogenesis in two important areas. First, a major thrust of this proposal is to survey the conformational properties of monomer BPDE-deoxynucleotide adducts. These studies contribute to the understanding of BP carcinogenesis in two important areas. First, a major thrust of this proposal is to survey the conformational properties of monomer BPDE-Deoxynucleotide adducts as a function of nucleobase and stereochemistry. These units may be important contributors to the conformational properties of adducted DNA and thus may be consequential in the erroneous bioprocessing at lesions. Second, BPDE-DNA adduct degradation via homo or heterolytic pathways may induce DNA damage at flanking residues that may contribute to the tumorigenic process.