QUINONE METHIDE TOXICITY
醌甲基化物毒性
基本信息
- 批准号:2154846
- 负责人:
- 金额:$ 8.92万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:1992
- 资助国家:美国
- 起止时间:1992-06-01 至 1997-05-31
- 项目状态:已结题
- 来源:
- 关键词:adduct butylated hydroxytoluene chemical addition chemical reaction chemical synthesis cytochrome P450 cytotoxicity enzyme activity hepatotoxin high performance liquid chromatography laboratory mouse laboratory rat mass spectrometry nuclear magnetic resonance spectroscopy peroxidases phenols quinones respiratory toxin thin layer chromatography tissue /cell culture toxicant interaction toxin metabolism
项目摘要
Most xenobiotics must be metabolized to exert their toxic or carcinogenic
effects. Pan research has focused on the formation of reactive
electrophilic intermediates as mediators of these deleterious processes.
Two widely studied classes of reactive intermediates are quinones and
quinoneimines. A structurally related class of chemical intermediates,
quinone methides, has received surprisingly little attention. Phenolic
compounds with ortho or para alkyl groups are capable of forming quinone
methides. This includes a large number of chemicals present in foods and
medicines. It is our hypothesis that the toxicity of certain phenolic
compounds can be explained, in part, by their metabolism to reactive
quinone methides, which in turn covalently bind to cellular macromolecules.
Previous work has demonstrated that quinone methides are formed during
xenobiotic metabolism of a limited number of phenolic compounds, but data
showing a causal linkage between quinone methide formation and toxicity is
lacking. Butylated hydroxytoluene and eugenol are examples of phenolic
compounds for which the formation of reactive quinone methide intermediates
has been suggested to play a role in the hepatic and pulmonary toxicity of
these compounds. This proposal seeks to measure and quantify the amount of
quinone methides formed during the oxidative metabolism of butylated
hydroxytoluene, eugenol and related phenols and to link the formation of
these reactive intermediates to toxicity. seen in isolated liver cells or
tissue slices from liver or lung. Analogs of these compounds which cannot
form quinone methide metabolites will be used to assess the role of other
possible mechanisms of toxicity. In addition, stable quinone methides from
these compounds will be tested directly on cells and tissue slices for
their possible cytotoxic effects and mechanism of toxicity.
大多数外源性物质必须经过代谢才能发挥其毒性或致癌性
方面的影响. 潘的研究主要集中在反应性的形成
亲电中间体作为这些有害过程的介质。
两类广泛研究的反应性中间体是醌和
醌亚胺。 结构上相关的一类化学中间体,
醌甲基化物,令人惊讶地很少受到关注。 酚醛
具有邻或帕拉烷基的化合物能够形成醌
甲基化物 这包括食品中存在的大量化学物质,
药 我们假设某些酚类物质的毒性
化合物可以解释,部分原因是它们的代谢反应,
醌甲基化物,其又共价结合到细胞大分子。
以前的工作已经证明,醌甲基化物是在
有限数量的酚类化合物的异生物质代谢,但数据
显示醌甲基化物形成和毒性之间的因果关系,
缺乏 丁基化羟基甲苯和丁香酚是酚类化合物的实例。
形成反应性醌甲基化物中间体的化合物
已被认为在肝和肺毒性中起作用,
这些化合物。 这项建议旨在衡量和量化
醌甲基化物形成的氧化代谢过程中的丁基
羟基甲苯,丁香酚和相关酚,并连接形成
这些活性中间体的毒性。在分离的肝细胞中观察到,
肝脏或肺的组织切片。 这些化合物的类似物不能
形式醌甲基化物代谢物将被用来评估其他的作用
可能的毒性机制。 此外,稳定的醌甲基化物从
这些化合物将直接在细胞和组织切片上进行测试,
其可能的细胞毒性作用和毒性机制。
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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