CONFORMATIONALLY PROMOTED DEGRADATION OF BPDE DNA ADDUCTS

摘要。苯并[a]芘（BP）是一种多环芳香烃环境污染物，它被代谢成一系列区域和立体异构体的苯并[a]芘二醇环氧化物（BPDE），包括高致癌物(+)-抗BPDE。每一个代谢物立体异构体都可以在苯基位点亲核偶联到核碱基的外环氨基上。除了酶和水解去除DNA中的BPDE病变外，据报道，低聚物和单体加合物也会进行化学分解，但这一过程的机制和副产品尚不清楚。我们建议研究bpde修饰的DNA通过核碱基-芘堆叠促进构象的均溶过程降解的假设。为了验证这一假设，我们将研究一系列在核碱基和BP立体化学中变化的单体bpde脱氧核苷酸加合物的构象和降解。具体地说，我们将研究这些物种的证据，以证明内部电荷转移相互作用先于降解，第三，我们将研究这些过程在bpde修饰的单链和双链DNA中发生的情况。在初步研究中，我们研究了支持芘和芳基单元的模型化合物的分解，这些单元由类似于bpde脱氧核苷酸加合物的C-N键连接。这些研究表明，加合物的降解与构象性质有关。进一步的研究将考察芳基大小、芳基电子学、溶剂和降解副产物，以提供对bpde -脱氧核苷酸加合物降解的见解。这些研究有助于了解BPO在两个重要领域的致癌作用。首先，本提案的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的致癌作用。首先，本提案的主要目的是调查单体bpde -脱氧核苷酸加合物的构象性质，作为核碱基和立体化学的函数。这些单位可能是内合DNA构象特性的重要贡献者，因此可能是病变错误生物处理的结果。其次，BPDE-DNA加合物通过同质或异质途径降解可能导致DNA损伤，这可能有助于致瘤过程。

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.