MUTAGENESIS/CARCINOGENESIS OF DIBENZ(A,C)ANTHRACENE

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-氧化物是最终的致癌物， 几种PAH。 最近，有人提出， 代谢成海湾区二醇-环氧化物，其中邻位二醇 锁定在准二轴构象应该是弱 致突变/致癌。 然而，这件事还没有解决。 二苯（a，c）蒽也可代谢到湾区 如上所述具有相似构象偏好的二醇-环氧化物， 比强致癌物二苯并（a，h）蒽更具致突变性。 而 最终诱变剂/致癌物结构的明确证据 的二苯并（a，c，）蒽缺乏，我们提出角芳烃氧化物作为 最可能的候选人基于两个假设： (1)这些芳烃氧化物不是环氧化物水解酶的良好底物， (2)它们不易于分子重排成酚。 的 拟议研究的目的是测试这些假设，并评估 二苯并（a，c，）蒽芳烃氧化物在代谢中的作用 母烃的活化。 本课题的具体研究目标是：（1）合成芳烃 二苯并（a，c）蒽的氧化物和其他衍生物，（2）评估 芳烃氧化物的内在致突变活性体外致突变性 测定，（3）检查芳烃氧化物的代谢活化和 二苯并（a，c，）-蒽的反式二氢二醇体外致突变性 （4）研究了二苯并（a，c，） 蒽通过环氧化物水解酶通过检查（a）内在致突变性 和（B）在环泊苷水解酶的存在下， 芳烃氧化物转化为相应的反式-二氢二醇 环氧化物水解酶，和（5）以确定自发的速率 二苯并[c]芳烃氧化物水解（Ko）和重排（K-NIH） （a，c）蒽转化为二氢二醇和酚。 拟议研究的长期目标是了解 涉及多核突变/致癌作用的机制 芳香烃.

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-expoxides as the ultimate carcinogens of several PAHs. More recently, it has been suggested that PAHs which are metabolized to bay-region diol-epoxides in which the vicinal diols are locked in quasi-diaxial conformation should be weakly mutagenic/carcinogenic. However, the matter is not yet settled. Dibenz(a,c) anthracene which can also be metabolized to bay-region diol-epoxides of similar conformational preferences as described above is more mutagenic than the potent carcinogen dibenz(a,h) anthracene. While definite evidence for the structures of the ultimate mutagens/carcinogens of dibenz(a,c,) anthracene is lacking, we propose angular arene oxides as the most probable candidates based on two hypotheses: (1) These arene oxides are not good substrates for epoxide hydrolase and (2) they are not susceptible to molecular rearrangement to phenols. The objective of the proposed research is to test these hypotheses and assesses the role of arene oxides of dibenz(a,c,) anthracene in the metabolic activation of the parent hydrocarbon. The specific aims of the proposed research are: (1) to synthesize arene oxides and other derivatives of dibenz(a,c,) anthracene, (2) to assess the intrinsic mutagenic activity of the arene oxides in vitro mutagenicity assays, (3) to examine the metabolic activation of the arene oxides and the trans dihydrodiols of dibenz(a,c,) - anthracene in vitro mutagenicity assays, (4) to study the hydration of the arene oxides of dibenz (a,c,) anthracene by epoxide hydrolase by examining (a) the intrinsic mutagenicity of the arene oxides in the presence of eposide hydrolase and (b) the conversion of arene oxides to respective trans-dihydrodiols in the presence of epoxide hydrolase, and (5) to determine the rate of spontaneous hydrolysis (Ko) and rearrangement (K-NIH) of various arene oxides of dibenz (a,c,) anthracene to dihydrodiols and phenols. The long-term goal of the proposed research is to understand the mechanism(s) involved in the mutagenesis/carcinogenesis of polynuclear aromatic hydrocarbons.