MECHANISM OF BENZO(A)PYRENE CARCINOGENESIS

苯并(A)芘的致癌机制

• 批准号: 3252081
• 负责人: SUBODH KUMAR
• 金额: $ 11.52万
• 依托单位: BUFFALO STATE COLLEGE
• 依托单位国家: 美国
• 财政年份: 1987
• 资助国家: 美国
• 起止时间: 1987-05-01 至 1989-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3252081
• 关键词: benzopyrenes; bioassay; chemical carcinogenesis; chemical synthesis; chromatography; cyclic compound; epoxides; hydrocarbons; microsomes; mutagens

Polycyclic aromatic hydrocarbons (PAHs) are ubiquitous environmental contaminants, many of which are capable of inducing mutagenicity and carcinogenicity. For some time, PAHs have been known to require metabolic activation for producing their biological effects, but only recent evidence has implicated the bay-region diol epoxides as the ultimate mutagen/carcinogen of several PAHs. There is now growing evidence to indicate that metabolites other than (anti)-trans-7,8-dihydroxy-9,10-epoxy-7,8,9,10-tetrahydrobenzo(a)pyrene (anti-BPDE) may be involved in the carcinogenesis of benzo(a)pyrene(BP). While definite evidence for the structure of reactive metabolite(s) other than anti-BPDE is lacking, we propose 3-hydroxy-anti-BPDE as a most probable candidate based on the following reasons: (i) 3-Hydroxy-anti-BPDE should be a better electrophile than anti-BPDE due to electronic reasons, (ii) 3-Hydroxy-anti-BPDE is the suspected intermediate in the metabolic activation of 3-hydroxy-BP and anti-BPDE, and (iii) The analogous triol-epoxide has been identified as a reactive intermediate in the metabolic activation of chrysene. Our specific aims are: (1) to synthesize 3-hydroxy-BP-7,8-diol and their diastereomeric epoxides, 3-hydroxy-anti-BPDE and 3-hydroxy-syn-BPDE, (2) to compare the metabolic activation of BP-7,8-diol and 3-hydroxy-BP-7,8-diol to mutagenic products using Ames assay, (3) to assess the mutagenic activity of diastereomeric BPDEs and 3-hydroxy-anti-BPDEs using Ames assay, (4) to determine the extent to which BP is converted to 3-hydroxy-BP-7,8-diol by mouse liver microsomes, and (5) to assess the tumorigenic activity of 3-hydroxy-BP-7,8-diol and its diastereomeric epoxides. This assay will only be done if these compounds will show high mutagenic activity in Ames assay (see nos. 2 and 3). The long term goal is to understand the mechanism(s) involved in the mutagenesis/carcinogenesis of PAHs.

多环芳烃 (PAH) 是普遍存在的环境污染物 污染物，其中许多能够诱发致突变性和 致癌性。 一段时间以来，人们知道多环芳烃需要代谢 激活以产生其生物效应，但只有最近的证据 暗示湾区二醇环氧化物是最终的 多种 PAH 的诱变剂/致癌剂。 现在有越来越多的证据表明 表明除 (反)-反式-7,8-二羟基-9,10-环氧-7,8,9,10-四氢苯并(a)芘 (抗BPDE)可能参与苯并(a)芘(BP)的致癌作用。 虽然有明确的证据证明反应性代谢物的结构 由于缺乏抗 BPDE，我们建议 3-羟基抗 BPDE 作为最 可能的候选者基于以下原因： (i) 3-羟基-抗-BPDE 由于电子原因，应该是比抗 BPDE 更好的亲电试剂， (ii) 3-Hydroxy-anti-BPDE 是代谢过程中的可疑中间体 3-羟基-BP和抗-BPDE的激活，以及(iii)类似的 三醇环氧化物已被确定为反应中间体 屈的代谢活化。 我们的具体目标是：（1）合成3-羟基-BP-7,8-二醇及其 非对映体环氧化物，3-羟基-抗-BPDE 和 3-羟基-顺-BPDE，(2) 至 比较 BP-7,8-二醇和 3-羟基-BP-7,8-二醇的代谢活化 使用Ames试验对致突变产品进行评估，（3）评估致突变性 使用 Ames 测定法测定非对映异构体 BPDE 和 3-羟基抗 BPDE 的活性， (4) 确定BP转换为的程度 通过小鼠肝微粒体检测 3-羟基-BP-7,8-二醇，以及 (5) 评估 3-羟基-BP-7,8-二醇及其非对映异构体的致瘤活性 环氧化物。仅当这些化合物表现出高浓度时才会进行该测定 艾姆斯试验中的诱变活性（参见第 2 和第 3 项）。 长期目标是了解参与的机制 PAH 的诱变/致癌作用。