PATHWAYS OF ACTIVATION AND DNA ADDUCTS OF CYCLOPENTA PAH

环五 PAH 的激活途径和 DNA 加合物

• 批准号: 3191816
• 负责人: Avram Gold
• 金额: $ 14.77万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 1988
• 资助国家: 美国
• 起止时间: 1988-07-15 至 1991-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3191816
• 关键词: DNA; adduct; benzanthracenes; benzopyrenes; bioassay; carbopolycyclic compound; chemical carcinogen; chemical carcinogenesis; chemical structure function; chemical synthesis; cyclopentane; diol; epoxides; halobiphenyl /halotriphenyl compound; high performance liquid chromatography; laboratory rat; liver metabolism; microsomes; mutagen testing; nucleic acid chemical synthesis; radiotracer; tissue /cell culture; tritium

This proposal concerns the metabolism, biological activity and DNA adduct formation of a series of PAH which may be activated via epoxidation of a cyclopenta ring fused to the molecular periphery: cyclopenta(cd)pyrene, I benz(j)aceanthrylene, II; benz(l)aceanthrylene, III; naphtho (2,1,8-hij)acephenanthrylene, IV; and dibenzo(b, mno)acephenanthrylene, V. The long-term goals of this study are to gain insight into the effects of molecular geometry and peripheral functionalization (e.g. vicinal hydroxy groups of diolepoxides) on mutagenic and carcinogenic activity. Such information will ultimately be important in the rational selection of DNA lesions to serve as models is the elucidation of mechanisms linking DNA adducts to genetic effects. Of the PAH proposed for study, preliminary results on the metabolism and biological activity of I - III demonstrate that these compounds transform C3H10T1/2 cells, form DNA adducts and that the most potent activity results from II which can be activated either by a cyclopenta epoxide or a bay region diolepoxide. Compound I should be activated by cyclopenta ring epoxidation and III must be activated by multiple pathways. Short terms goals will be (1) synthesis of IV, V and determination of mutagenicity and cell transforming activity; (2) identification of ultimate active metabolities of I - III and/or IV, V (contingent on cell transforming activity); (3) synthesis of standards for identification of DNA adducts of I - III and/or IV, V,; (4) identification and quantitation of DNA adducts of C3H1OT1/2 cells treated with the tographic properties of adducts and suitably prepared standards by 32-p-postlabeling techniques or by HPLC, utilizing 3H-labeled PAH for treatment of C3H10T1/2 cells. Conclusions should be possible regarding the importance of the bay region diolepoxide metabolites in cell transformation and their activity relative to cyclopenta epoxides, as well as the generality of the regioselectivity of activated PAH metabolites for addition to the exocyclic amino group of guanosine and the relevance of this lesion to the transformation of C3H10T1/2 cells.

该提案涉及新陈代谢、生物活性和 DNA加合物形成一系列可能被激活的PAH 通过与分子稠合的环戊环的环氧化 外围：环戊(cd)芘，I，苯并(j)苊，II； 苯并(l)苊，III；萘并(2,1,8-hij)苊菲，IV； 和二苯并(b，mno)苊菲，V.的长期目标 这项研究的目的是深入了解分子的影响 几何形状和外围功能化（例如邻羟基 二醇环氧化物基团）的致突变和致癌活性。 这些信息最终将在理性思考中发挥重要作用。 选择 DNA 损伤作为模型是为了阐明 将 DNA 加合物与遗传效应联系起来的机制。 拟议研究的 PAH 的初步结果 I - III 的代谢和生物活性表明 这些化合物转化 C3H10T1/2 细胞，形成 DNA 加合物 最有效的活性来自 II，可以是 由环戊环氧化物或湾区激活 二醇环氧化物。 化合物 I 应被环戊环活化 环氧化和 III 必须通过多种途径激活。 短的 术语目标将是 (1) IV、V 的合成并确定 致突变性和细胞转化活性； (2) 鉴定 I - III 和/或 IV、V 的最终活性代谢（取决于 细胞转化活性）； (3) 标准综合 I-III和/或IV、V的DNA加合物的鉴定； (4) C3H1OT1/2 DNA 加合物的鉴定和定量 用加合物的拓扑特性处理的细胞，并适当地 通过 32-p-后标记技术或通过 HPLC 制备标准品， 利用 3 H 标记的 PAH 处理 C3H10T1/2 细胞。 关于其重要性的结论应该是可能的 湾区二烯环氧丙烷代谢物在细胞转化中的作用 它们相对于环戊环氧化物的活性，以及 活化 PAH 代谢物区域选择性的一般性 用于添加鸟苷的环外氨基和 该损伤与 C3H10T1/2 细胞转化的相关性。