CONFORMATIONALLY PROMOTED DEGRADATION OF BPDE DNA ADDUCTS

摘要。苯并[a]芘（BP）是一种多环芳烃类环境污染物，在代谢过程中可生成一系列区域异构和立体异构的BP二醇环氧化物（BPDE），其中包括强致癌物（+）- anti-BPDE。每种代谢物立体异构体可在苄基位点亲核性偶联至核碱基的环外氨基。 除了从DNA中酶促和水解去除BPDE损伤之外，据报道，低聚物和单体加合物通过该过程的机制和副产物进行化学分解是未知的。我们建议调查的假设，BPDE修饰的DNA降解通过均裂过程，这是构象促进核碱基芘堆积。为了验证这一假设，我们将研究一系列单体BPDE-脱氧核苷酸加合物的构象和降解，这些加合物在核碱基和BP立体化学上各不相同。具体来说，我们将研究这些物种的证据，intralesion电荷转移相互作用之前的降解，第三，我们将调查这些过程中发生的BPDE修饰的单链和双链DNA。在初步研究中，我们研究了模型化合物的分解，支持芘和芳基单元栓系的C-N键类似的BPDE-脱氧核苷酸加合物。这些研究表明，加合物在不同的降解与构象特性。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，以提供对BPDE-脱氧核苷酸加合物的降解的见解。这些研究有助于了解BPO在两个重要领域的致癌作用。首先，这个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特性。这些研究有助于在两个重要领域了解BP致癌作用。首先，这个建议的主要目的是调查作为核碱基和立体化学的功能的单体BPDE-脱氧核苷酸加合物的构象特性。这些单位可能是重要的贡献者加合DNA的构象特性，因此可能是在病变的错误的生物加工的后果。第二，BPDE-DNA加合物通过同源或异源降解途径降解可能诱导侧翼残基的DNA损伤，这可能有助于肿瘤发生过程。

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.