HALOHYDRIN INTERMEDIATES IN ACTIVATION OF BENZO[A]PYRENE

卤代醇中间体用于活化苯并[A]芘

• 批准号: 6308803
• 负责人: Thomas Meehan
• 金额: $ 0.99万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-03-01 至 2002-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6308803
• 关键词: biological products; biomedical resource; drug adverse effect; health care; spectrometry; structural biology

Tumor initiation by chemical carcinogens is thought to result from binding to DNA that leads to activation/deactivation of critical proto-oncogenes and suppressor genes. We havebeen studying the environmental pro-carcinogen benzo[a]pyrene (BaP) as a model for understanding molecular carcinogenesis. BaP is converted into a potent chemical carcinogen by cellular metabolism and this intermediate is 7R,8S-dihydroxy-9S,10R-epoxy-7,8,9,10-tetrahydroBP[(+)-anti-BPDE]. A (-)-anti-BPDE enantiomer is also made but this metabolite has 50-fold less biological activity. For the past two decades the initiation of tumors by BP has been viewed as a process in which epoxides directly alkylate DNA. However, we have recently discovered a new pathway in which chloride ions catalyze both adduct formation from BPDE and hydrolysis (passive detoxification) of the carcinogen. BPDE forms many adducts with DNA but the identity of the adduct that induces tumor initiation has not been determined. Conformational studies have focused on the major trans(+)-anti- and trans(-)-anti-BPDE-dGuo adducts but not on the minor dAdo and dCyd adducts have not been carried out, in part because of the poor synthetic reactions that are currently employed to make BPDE-DNA adducts. An important aspect of this proposal is the analysis of minor adducts since, in principle, even a single adduct could be biologically amplified. This research has three aims: (i) to study the mechanism of chloride-catalyzed adduct formation through in vitro model systems, (ii) to develop new synthetic schemes for making BPDE-deoxynucleoside adducts and use them to assemble oligodeoxynucleotides (ODNs) modified with the minor adducts for conformational studies, and (iii) to analyze the occurrence and properties of dCyd adducts in reaction profiles between BPDE and DNA. Aim (i) will be pursued by synthesizing halohydrins of BPDE and comparing adducts formed with this intermediate and from BPDE. We will also study the role of bromide and iodide in adduct formation. An important question concerning carcinogenesis mechanisms is whether chloride participates in the tumor initiation properties of all electrophilic chemical carcinogens or whether the reaction is confined to epoxides. Aim (ii) will be accomplished by substantially improving synthetic methods for making adducts. This will permit the synthesis and conformational study of ODNs modified with minor adducts. Aim (iii) will be accomplished by development of separation systems capable of resolving dCyd adducts from other components in BPDE-DNA reactions. The long term goal of this work is to determine the mechanism by which chemical carcinogens attack DNA, and to assess the relative biological activity of each of the BPDE-DNA adducts that are formed from the carcinogen. These investigations will provide necessary information concerning which BPDE adduct is responsible for the biological activity of this important and ubiquitous environmental contaminant.

化学致癌物的肿瘤开始被认为是由 与DNA结合，导致临界的激活/失活 原始基因和抑制基因。 我们正在研究 环境促癌苯并[a] pyrene（BAP）作为模型 了解分子癌变。 BAP转换为 细胞代谢有效的化学致癌物，这 中间是 7r，8s-dihydroxy-9s，10R-蛋白-7,8,9,10-四氢螺旋体[（+） - 抗BPDE]。 一个 （ - ） - 抗BPDE对映异构体也是制造的，但该代谢物具有50倍 较少的生物活性。 在过去的二十年中 BP肿瘤已被视为环氧化物直接的过程 烷基化DNA。 但是，我们最近在 哪个氯离子催化了BPDE的加合物形成 致癌物的水解（被动解毒）。 BPDE形式 许多具有DNA的加合物，但具有诱导的加合物的身份 尚未确定肿瘤的启动。 构象研究已有 专注于主要反式（+） - 抗和反式（ - ） - 抗BPDE-DGUO 加合物，但没有在次要的dado和DCYD加合物上 进行，部分原因是合成反应不良 目前被用来制作BPDE-DNA加合物。 一个重要方面 该建议是对次要加合物的分析，因为原则上 即使是单个加合物也可以在生物学上放大。 这项研究 有三个目标：（i）研究氯化物催化的机制 通过体外模型系统形成加合物形成，（ii）开发新的 用于制作BPDE-脱氧核苷加合物并使用的合成方案 组装用小调修饰的寡脱氧核苷酸（ODN） 构象研究的加合物，（iii）分析 DCYD加合物在反应曲线中的出现和特性 BPDE和DNA。 目的（i）将通过合成的卤水 BPDE和与此中间体形成的加合物的比较 bpde。 我们还将研究溴化物和碘化物在加合物中的作用 形成。 关于致癌机制的重要问题 是氯化物是否参与 所有亲电化学致癌物或反应是 局限于环氧化物。 目标（ii）将通过基本上实现 改进合成方法进行加合物。 这将允许 用次要修饰的ODN的合成和构象研究 加合物。 目的（iii）将通过开发分离来实现 能够从其他组件中解决其他组件中的DCYD加合物的系统 BPDE-DNA反应。 这项工作的长期目标是确定 化学致癌物攻击DNA并评估的机制 每个BPDE-DNA加合物的相对生物学活性 由致癌物形成。 这些调查将提供 有关BPDE累加负责的必要信息 这种重要且无处不在的环境的生物学活动 污染物。