MECHANISM OF BENZO(A)PYRENE CARCINOGENESIS

多环芳烃(PAHs)是一种普遍存在的环境污染物 污染物，其中许多能够诱发突变和 致癌性。一段时间以来，多环芳烃一直被认为需要代谢 激活产生其生物效应，但只有最近的证据 已经暗示海湾地区的二元醇环氧化物是最终的 几种多环芳烃的诱变剂/致癌物。现在有越来越多的证据表明 表明除 (anti)-trans-7，8-dihydroxy-9，10-epoxy-7，8，9，10-tetrahydrobenzo(a)pyrene (抗BPDE)可能参与了苯并(A)芘(BP)的致癌作用。 而反应代谢物结构的确凿证据(S)其他 由于抗BPDE缺乏，我们提出了以3-羟基-抗BPDE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更好的电泳剂， (Ii)3-羟基-抗BPDE可能是代谢的中间产物 激活3-羟基-BP和抗BPDE，以及(Iii)类似物 三醇-环氧化物已被确定为一种活性中间体，在 大黄素的代谢活化。 我们的具体目标是：(1)合成3-羟基-BP-7，8-二醇及其衍生物 非对映异构体环氧化物，3-羟基-反-BPDE和3-羟基-SYN-BPDE，(2)至 BP-7，8-二醇和3-羟基-BP-7，8-二醇代谢活性的比较 用Ames试验对诱变产物进行检测，(3)评价其致突变性 Ames法测定非对映异构体BPDEs和3-羟基抗BPDEs的活性 (4)确定BP转换到什么程度 3-羟基-BP-7，8-二醇对小鼠肝微粒体的影响 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。只有当这些化合物显示出很高的浓度时，才会进行这项测试 Ames试验中的诱变活性(见nos.2和3)。 长期目标是理解(S)参与其中的机制 多环芳烃的诱变/致癌作用。

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.