CONFORMATIONALLY PROMOTED DEGRADATION OF BPDE DNA ADDUCTS

BPDE DNA 加合物的构象促进降解

• 批准号: 6346180
• 负责人: George Raymond NEGRETE
• 金额: $ 14.87万
• 依托单位: UNIVERSITY OF TEXAS SAN ANTONIO
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-08-01 至 2001-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6346180
• 关键词: DNA; adduct; benzopyrenediol epoxide; biotransformation; carbopolycyclic compound; chemical carcinogen; chemical carcinogenesis; chemical models; chemical structure function; conformation; high performance liquid chromatography; nuclear magnetic resonance spectroscopy; nucleic acid structure; nucleobase; nucleoside analog; nucleosides; organic chemicals; racemization; stereochemistry; stereoisomer

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.

抽象的。苯并[a]芘 (BP) 是多种多环芳烃环境污染物之一，可代谢为一系列区域和立体异构 BP 二醇环氧化物 (BPDE)，包括强效致癌物 (+)- 抗 BPDE。每种代谢物立体异构体可以在苄基位点处与核碱基的环外氨基进行亲核偶联。 据报道，除了酶法和水解法从 DNA 上去除 BPDE 损伤外，寡聚体和单体加合物还会发生化学分解，但这一过程的机制和副产物尚不清楚。我们建议研究以下假设：BPDE 修饰的 DNA 通过核碱基-芘堆积在构象上促进的均裂过程进行降解。为了检验这一假设，我们将检查一系列核碱基和 BP 立体化学各不相同的单体 BPDE-脱氧核苷酸加合物的构象和降解。具体来说，我们将检查这些物种，寻找损伤内电荷转移相互作用先于降解的证据，第三，我们将研究这些过程在 BPDE 修饰的单链和双链 DNA 中的发生情况。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，这些单元通过类似于 BPDE-脱氧核苷酸加合物的 C-N 键连接。这些研究表明加合物在与构象特性相关的不同条件下降解。进一步的研究将检查芳基尺寸、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。这些研究有助于了解两个重要领域的 BPO 致癌作用。首先，该提案的主要目的是调查单体 BPDE-脱氧核苷酸加合物的构象特性。这些研究有助于了解两个重要领域的 BP 致癌作用。首先，该提案的主要目的是调查单体 BPDE-脱氧核苷酸加合物的构象特性作为核碱基和立体化学的函数。这些单位可能对加合 DNA 的构象特性有重要贡献，因此可能对病变处的错误生物处理产生影响。其次，BPDE-DNA 加合物通过同源或异源途径降解可能会诱导侧翼残基发生 DNA 损伤，从而导致致瘤过程。