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）络合物是潜在的诱变剂和致癌物，当吸入时， 这些复合物在口服时产生类似效果的潜力是本发明的活性领域。 辩论该活性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 在Cr（VI）最终还原为Cr（III）的过程中，在过去的20年里， 在表征这些氧化还原过程导致的DNA改变方面已经取得了进展。的 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，最终可能会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年中得到了深入的研究， 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存在。 这些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）独特的磁性和化学性质， 由于Cr（III）-生物分子的复杂性，Cr（III）-生物分子的表征并不简单，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、小牛胸腺DNA或DNA聚合物。 从培养的细胞中分离，由于它们的大小和复杂性， 潜在的Cr结合位点，具有广泛的结合常数。需要确定什么 铬结合的优先位点和表征这些位点的结构是使用 DNA寡聚体的大小明显较小，其碱基序列可以仔细设计， 其可以容易地以可观的量合成，并且其Cr（III）络合物 易于通过光谱和磁性技术表征。我们的长期 目的是在分子水平上表征铬（III）与DNA的结合，并将其与 Cr（VI）的遗传毒性和致癌性。