OXYGEN FREE RADICALS AND DIOXIN CARCINOGENESIS

这项提议的具体目的是探索被动型 氧物种在二恶英类制剂致癌中的作用 确定细胞色素P450催化的氧化雌激素 新陈代谢是造成这些性别差异的部分原因 药物显示出它们的致癌能力。按顺序 为了实现这些目标，我们建议将 在对正在进行的暴露研究进行实验室分析后 国家毒理学计划，正在对女性进行 动物，以及在雄性动物身上进行一系列平行实验 我们目前暴露在相同的多氯化物质中的动物 联苯剂在单独的主持下。以下是试验性的 将在肝组织中测量终点：1)微粒体细胞色素P450/2 酶底物测定法；2)微粒体雌激素 儿茶酚代谢的气相色谱-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；4)气体对DNA的氧化损伤 氧化dna碱基加合物的色质联用检测。 男性和女性对二恶英类物质的反应将进行比较 对生物途径提供进一步的解释。 它们的致癌作用，以及P450催化的比较 雌激素的代谢与伴随的氧自由基的产生 自由基将提供进一步的证据，证明AH受体在 致癌的机械性途径。这些数据应该被证明是有用的 在评估毒性当量因子法对 二恶英类混合物致癌性的预测模型 以及在确定其他可能的风险因素方面 接触二恶英类污染物的个人。

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.