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).

吸入六价铬络合物是强效诱变剂和致癌物，而 这些复合物口服时产生类似效果的潜力是一个活跃领域 辩论。该活动的确切作用机制尚不清楚，但潜在机制 可以分为两类。第一个是与氧化还原相关的机制 Cr(VI) 最终还原为 Cr(III) 过程中的化学反应。 20年来，取得了重大进展 已经对这些氧化还原过程导致的 DNA 变化进行了表征。这 第二种机制是基于生成的 Cr(III) 与 DNA 结合形成二元和三元 复合物，最终可能产生致突变和致癌作用。 不幸的是，虽然这些 Cr-DNA 复合物在过去大约 15 年中得到了深入研究 多年来，几乎没有关于这些 Cr(III)-DNA 复合物的分子水平结构的数据。 这些知识对于理解和确定这些复合体的潜力至关重要 导致有害影响。由于 Cr(III) 独特的磁性和化学性质 Cr(III)-生物分子的表征并非易事，需要特殊的专业知识。 此外，之前的研究使用了质粒 DNA、DNA 聚合物、小牛胸腺 DNA 或 DNA 从培养细胞中分离出来，由于其大小和复杂性，存在大量 潜在的 Cr 结合位点具有广泛的结合常数。需要什么来确定 Cr 结合的优先位点并表征这些位点的结构是使用 DNA寡聚体的尺寸明显更小，其碱基序列可以精心设计和 它可以很容易地大量合成，其 Cr(III) 配合物是 易于通过光谱和磁技术进行表征。我们的长期 目标是在分子水平上表征铬 (III) 与 DNA 的结合，并将 Cr(VI)的遗传毒性和致癌性的结构。