MECHANISM OF BENZO(A)PYRENE CARCINOGENESIS

苯并(A)芘的致癌机制

• 批准号: 3252086
• 负责人: SUBODH KUMAR
• 金额: $ 10.96万
• 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/3252086
• 关键词: benzopyrenediol epoxide; benzopyrenes; bioassay; chemical carcinogenesis; chemical synthesis; chromatography; hydrocarbons; laboratory rat; 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（PAHs）是环境中普遍存在的一类有机污染物 污染物，其中许多能够诱导致突变性， 致癌性 一段时间以来，人们已经知道多环芳烃需要代谢 激活产生其生物效应，但只有最近的证据 暗示海湾地区的二醇环氧化物是最终的 几种多环芳烃的诱变剂/致癌物。 越来越多的证据表明 表明除了 （反）-反式-7，8-二羟基-9，10-环氧-7，8，9，10-四氢苯并（a）芘 （抗BPDE）可能参与了苯并（a）芘（BP）的致癌作用。 虽然有明确的证据表明反应性代谢物的结构，但其他 比抗BPDE缺乏，我们建议3-羟基-抗BPDE作为最 可能的候选人基于以下原因：（i）3-羟基-抗-BPDE 由于电子原因， (ii)3-羟基-抗-BPDE是代谢中的疑似中间体 3-羟基-BP和抗-BPDE的活化，和（iii）类似物 三醇-环氧化物已被确定为在合成中的反应性中间体。 代谢活化的方法。 我们的具体目标是：（1）合成3-羟基-BP-7，8-二醇及其衍生物 非对映体环氧化物，3-羟基-反-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 采用艾姆斯试验对致突变性产品进行评价，（3）评价致突变性 使用艾姆斯分析的非对映体BPDE和3-羟基-抗-BPDE的活性， (4)以确定BP转换为 3-羟基-BP-7，8-二醇，以及（5）评估 3-羟基-BP-7，8-二醇的致瘤活性及其非对映体 环氧化物。仅当这些化合物显示高浓度时，才进行该测定。 艾姆斯试验中的诱变活性（参见编号第2和第3段）。 长期目标是了解参与的机制 多环芳烃的诱变/致癌作用。