MUTAGENESIS/CARCINOGENESIS OF DIBENZ(A,C)ANTHRACENE

二苯(A,C)蒽的诱变/致癌作用

• 批准号: 3251485
• 负责人: SUBODH KUMAR
• 金额: $ 8.3万
• 依托单位: BUFFALO STATE COLLEGE
• 依托单位国家: 美国
• 财政年份: 1985
• 资助国家: 美国
• 起止时间: 1985-08-29 至 1988-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3251485
• 关键词: benzanthracenes; biotransformation; chemical carcinogen; chemical structure function; chemical synthesis; conformation; diol; environment related neoplasm /cancer; epoxide hydrolase; epoxides; hydrolase; mass spectrometry; mutagen testing; mutagens; nuclear magnetic resonance spectroscopy; oxygenous heterocyclic compound; toxin metabolism

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.

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 暗示海湾地区的二醇环氧化物是最终致癌物 多种多环芳烃。 最近，有人提出 PAHs 代谢为湾区二醇环氧化物，其中邻位二醇为 锁定在准双轴构象应该很弱 致突变/致癌。 然而，事情尚未解决。 二苯并(a,c)蒽也可代谢为湾区 具有与上述相似的构象偏好的二醇-环氧化物是 比强效致癌物二苯并(a,h)蒽更具致突变性。 尽管 最终诱变剂/致癌物结构的明确证据 缺少二苯(a,c,)蒽，我们建议角芳烃氧化物为 基于两个假设的最有可能的候选人： (1) 这些芳烃氧化物不是环氧化物水解酶的良好底物， (2)它们不易发生酚类分子重排。 这 拟议研究的目的是测试这些假设并评估 二苯并(a,c)蒽的芳烃氧化物在代谢中的作用 母体烃的活化。 本研究的具体目标是：（1）芳烃的合成 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 化验，（3）检查芳烃氧化物的代谢活化和 二苯并(a,c,)反式二氢二醇-蒽 体外致突变性 化验，（4）研究二苯（a，c，）芳烃氧化物的水合 通过环氧化物水解酶检测蒽的内在致突变性 在环氧乙烷水解酶存在下的芳烃氧化物和（b） 在存在下将芳烃氧化物转化为相应的反式二氢二醇 环氧化物水解酶，以及（5）确定自发的速率 二苯的各种芳烃氧化物的水解(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 参与多核细胞突变/致癌的机制 芳香烃。