权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

OXYGEN FREE RADICALS AND DIOXIN CARCINOGENESIS

氧自由基和二恶英致癌

基本信息

批准号：
2616275
负责人：
JOHN D. TESSARI
金额：
$ 7.02万
依托单位：
COLORADO STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
1998
资助国家：
美国
起止时间：
1998-02-09 至 2000-02-08
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/2616275
关键词：
DNA damage adduct catechols chemical carcinogen chemical carcinogenesis cytochrome P450 dioxins electron spin resonance spectroscopy enzyme activity estrogens free radical oxygen gas chromatography mass spectrometry liver cells liver neoplasms tissue /cell culture

项目摘要

The specific aims of this proposal are to explore a role for reactive oxygen species in the carcinogenesis of dioxin-like agents, and to determine whether cytochrome P450-catalyzed oxidative estrogen metabolism is in part responsible for the gender differences that these agents display with respect to their carcinogenic potencies. In order to accomplish these objectives, we are proposing to integrate the following laboratory analyses into the ongoing exposures studies of the National Toxicology Program, which are being performed in female animals, as well as perform a parallel series of experiments in male animals that we are currently exposing to the same polychlorinated biphenyl agents under separate auspices. The following experimental end-points will be measured in liver tissues: 1) microsomal CYP1/2 P450 activities by enzymatic substrate assays; 2) microsomal estrogen catechol metabolism by gas chromatography-electron capture detection; 3) production of oxygen free radicals by electron paramagnetic resonance/spin trap analyses; and 4) oxidative DNA damage by gas chromatography-mass spectrometry detection of oxidized DNA base adducts. The comparisons of male and female responses to dioxin-like agents will provide further elucidation of the biological pathways responsible for their carcinogenesis, and the comparisons of the P450-catalyzed metabolism of estrogen and concomitant production of oxygen free radicals will provide further evidence for a role of the Ah receptor in a mechanistic pathway of carcinogenesis. These data should prove useful in assessing the utility of the Toxic Equivalency Factor approach for predictive modelling of the carcinogenicity of dioxin-like mixtures, as well as in the identification of other possible risk factors for individuals exposed to dioxin-like contaminants.

本提案的具体目的是探讨反应性二恶英类物质致癌作用中的氧物种，确定细胞色素P450催化的氧化雌激素新陈代谢是部分负责性别差异，这些试剂显示关于它们的致癌效力。为了为达致这些目标，我们建议把根据对正在进行的接触研究的实验室分析，国家毒理学计划，正在女性中进行动物，以及在男性中进行一系列平行实验我们现在接触到的多氯化物联苯剂在单独的主持下。以下实验将在肝组织中测量终点：1）微粒体CYP 1/2 P450 活性（酶底物测定法）; 2）微粒体雌激素邻苯二酚代谢的气相色谱-电子捕获检测法; 3)电子顺磁产生氧自由基共振/自旋陷阱分析;和4）气体氧化DNA损伤氧化的DNA碱基加合物的色谱-质谱检测。男性和女性对二恶英类物质反应的比较将进一步阐明了导致它们的致癌作用，以及P450催化的雌激素代谢和伴随的无氧代谢自由基将提供进一步的证据表明，Ah受体的作用，一种致癌的机械途径。这些数据应该证明是有用的在评估毒性当量系数方法对以下方面的效用时，二恶英类混合物致癌性的预测模型，以及确定其他可能的风险因素，暴露于二恶英类污染物的个人。