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MUTAGENESIS/CARCINOGENESIS OF DIBENZ(A,C)ANTHRACENE

二苯(A,C)蒽的诱变/致癌作用

基本信息

批准号：
3251486
负责人：
SUBODH KUMAR
金额：
$ 9.88万
依托单位：
BUFFALO STATE COLLEGE
依托单位国家：
美国
项目类别：
财政年份：
1985
资助国家：
美国
起止时间：
1985-08-29 至 1989-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/3251486
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

项目摘要

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（PAHs）是一种普遍存在的环境物质