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:3251485
- 负责人:
- 金额:$ 8.3万
- 依托单位:
- 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 1988-07-31
- 项目状态:已结题
- 来源:
- 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,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
已经暗示湾区的二元醇环氧化物是
几种多环芳烃。最近,有人提出,多环芳烃是
代谢成湾区二醇-环氧化物,其中邻近的二醇是
锁定在准二轴构象中的应该是弱的
致突变性/致癌性。然而,这件事还没有解决。
二苯并(a,c)菲,也可代谢到湾区
具有上述相似构象偏好的二元醇-环氧化物是
比强致癌物质二苯并(a,h)菲更具诱变性。而当
最终诱变剂/致癌物结构的确凿证据
缺少二苯并(a,c)菲,我们建议角状芳烃氧化物为
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)它们对苯酚的分子重排不敏感。这个
拟议研究的目标是检验这些假设和评估
二苯并(a,c)菲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)合成芳烃
二苯并(a,c,)菲的氧化物和其他衍生物,(2)评估
芳香族氧化物的本征致突变性研究
测定,(3)检测芳烃氧化物的代谢活性和
二苯并(a,c,)-菲的反式二氢二醇的体外致突变作用
(4)研究二苯并[a,c]芳烃氧化物的水合反应。
用环氧化物水解酶检测(A)内源致突变性
在依波得水解酶存在下的芳烃氧化物和(B)
芳烃氧化物在存在下转化为相应的反式二氢二醇
环氧化物水解酶活性;(5)测定自发性
二苯并芳烃氧化物的水解(KO)和重排(K-NIH)
(a,c,)菲为二氢二酚和苯酚。
拟议研究的长期目标是了解
多核细胞诱变/致癌机制(S)
芳香烃。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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SUBODH KUMAR其他文献
SUBODH KUMAR的其他文献
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{{ truncateString('SUBODH KUMAR', 18)}}的其他基金
MUTAGENESIS/CARCINOGENESIS OF DIBENZ(A,C)ANTHRACENE
二苯(A,C)蒽的诱变/致癌作用
- 批准号:
3251481 - 财政年份:1985
- 资助金额:
$ 8.3万 - 项目类别:
MUTAGENESIS/CARCINOGENESIS OF DIBENZ(A,C)ANTHRACENE
二苯(A,C)蒽的诱变/致癌作用
- 批准号:
3251486 - 财政年份:1985
- 资助金额:
$ 8.3万 - 项目类别:
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