Molecular Structure of Chromium-DNA Adducts

铬-DNA 加合物的分子结构

• 批准号: 10358312
• 负责人: JOHN Bertram VINCENT
• 金额: $ 43.45万
• 依托单位: UNIVERSITY OF ALABAMA IN TUSCALOOSA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10358312
• 关键词: Amino Acids; Animals; Antioxidants; Area; Base Composition; Base Pairing; Base Sequence; Binding; Binding Sites; Biochemical; Biological; Carcinogens; Categories; Cell Culture Techniques; Cells; Chemistry; Chromates; Chromium; Complex; Cultured Cells; DNA; DNA Adducts; DNA Damage; DNA Sequence; Data; Exposure to; Goals; Human; Industrialization; Inhalation; Knowledge; Laboratories; Lead; Lesion; Location; Magnetism; Malignant Neoplasms; Mismatch Repair; Molecular; Molecular Structure; Mutagenesis; Mutagens; Mutation; Nature; Oligonucleotides; Oral; Oxidation-Reduction; Pathway interactions; Peptides; Polymers; Population; Process; Proteins; Role; Site; Structure; Sulfhydryl Compounds; System; Techniques; Testing; Work; adduct; ascorbate; base; calf thymus DNA; carcinogenesis; carcinogenicity; chemical property; chromium hexavalent ion; crosslink; design; experimental study; genotoxicity; insight; plasmid DNA; prevent; repaired; small molecule; tumorigenesis; virtual

Chromium(VI) complexes are potent mutagens and carcinogens when inhaled, while the potential of these complexes to generate similar effects when taken orally is an area of active debate. The exact mechanism(s) of action of this activity is unknown, but potential mechanisms can be grouped into two categories. The first is mechanisms associated with the redox chemistry during the reduction of Cr(VI) ultimately to Cr(III). In the 20 years, significant progress has been made in characterizing alterations to DNA results from these redox processes. The second mechanism is based on the generated Cr(III) binding to DNA to form binary and ternary complexes, which ultimately give may arise to the mutagenic and carcinogenic effects. Unfortunately, while these Cr‐DNA complexes have been studied intensely the last circa 15 years, virtually no data on the molecular level structure of these Cr(III)‐DNA complexes exists. Such knowledge is essential to understanding and determining the potential of these complexes to lead to deleterious effects. Because of the unique magnetic and chemical properties of Cr(III) complexes, characterization of Cr(III)‐biomolecules is not trivial, requiring special expertise. Additionally, previous studies have used plasmid DNA, DNA polymers, calf thymus DNA, or DNA isolated from cultured cells, which because of their size and complexity present numerous potential Cr‐binding sites with a wide range of binding constants. What is required to determine the preferential sites for Cr‐binding and to characterize the structure of these sites is the use of DNA oligomers significantly smaller in size whose base sequences can be carefully designed and which can readily be synthesized in appreciable quantities and whose Cr(III) complexes are readily amendable to characterization by spectroscopic and magnetic techniques. Our long term goal is to characterize the binding of chromium(III) to DNA at a molecular level and relate the structures to the genotoxicity and carcinogenicity of Cr(VI).

铬（VI）复合物是遗传时潜在的诱变剂和致癌物，而 这些复合物的潜力在口服是活跃的区域时产生类似效果的潜力 辩论。该活动的作用的确切机制尚不清楚，但潜在的机制 可以分为两类。第一个是与氧化还原相关的机制 CR（VI）最终将CR（III）降低期间的化学。在20年中，取得了重大进展 已经制作了这些氧化还原过程对DNA结果的改变。这 第二种机制基于生成的Cr（III）与DNA结合以形成二元和三元 最终可能给出的复合物可能引起诱变和致癌作用。 不幸的是，尽管这些CR -DNA复合物已诚实地研究了最后一个大约15 几乎没有关于这些Cr（III）-DNA复合物的分子水平结构的数据。 这种知识对于理解和确定这些复合物的潜力至关重要 导致有害影响。由于CR（III）具有独特的磁性和化学性能 复合物，Cr（III） - 生物分子的表征并不是微不足道的，需要特殊的专业知识。 此外，先前的研究使用了质粒DNA，DNA聚合物，小腿胸腺DNA或DNA 从培养的细胞中分离出来，由于它们的大小和复杂性，众多 具有广泛结合常数的潜在CR结合位点。确定需要什么 用于CR结合和表征这些站点结构的首选位点是使用 DNA低聚物的尺寸明显小得多，其基本序列可以仔细设计，并且 可以很容易地以可欣赏的数量合成，并且其Cr（iii）复合物是 可以通过光谱和磁技术进行表征来修正。我们的长期 目标是表征铬（III）与分子水平上的DNA的结合，并将 CR（VI）的遗传毒性和致癌性的结构。