ENVIRONMENTAL TOXINS--PREDICTION OF FETAL METABOLISM

环境毒素--胎儿代谢的预测

• 批准号: 3252447
• 负责人: MONT R JUCHAU
• 金额: $ 8.15万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 1986
• 资助国家: 美国
• 起止时间: 1986-09-15 至 1989-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3252447
• 关键词: acetylaminofluorene; adrenal glands; benzopyrenes; biotransformation; chemical carcinogen; cytochrome P450; embryo /fetus cell /tissue; embryo /fetus pharmacology; embryo /fetus toxicology; environmental toxicology; gas chromatography mass spectrometry; high performance liquid chromatography; intestines; kidney; liver; lung; oxidoreductase; oxidoreductase inhibitor; scintillation counter; scintillation spectrometry; statistics /biometry; toxin metabolism; warfarin

Prediction of fetal/embryonic metabolism is an important consideration in determining the risk associated with exposure of the fetus/embryo to potentially toxic compounds. The objective of this proposal is to utilize chemical substrate probes for analysis of the FUNCTIONAL P-450 isozyme composition and the accompanying capacity of fetal hepatic and extrahepatic tissues to catalyze regioselective metabolism of environmental toxins and prototype chemical carcinogens. Two types of probe, both of which exhibit restricted isozyme specificity, will be used in these studies; a) enantiomeric warfarin which produces a range of hydroxylated products from the parent molecule, and b) a series of phenoxazone ethers which are oxidized to a common metabolite. As test substrates, benzo(Alpha)pyrene (BP) and 2-acetylaminofluorene (AAF) will be employed. The proposal is based on the hypothesis that patterns of biotransformation of the two classes of chemical probes (warfarin and the phenoxazone ethers) will be highly predictive for the specific biotransformation of test substrates (BP and AAF). The hypothesis will be tested by 1) determining the goodness of fit for correlations of analyzed metabolic pathways under a variety of conditions and after perturbation by a series of regulatory agents, 2) making predictions based on the goodness of fit, and finally, 3) testing the predictability by analyzing tissues of unknown isozymic composition with the chemical probes and determining the degree to which these analyses predict BP and AAF metabolite profiles within the same tissues. The long-range goal of these investigations is to enable the ascertainment of P-450-dependent biotransforming and bioactivating capacities of fetal/embryonic tissues and others for which isolation and purification of the isozymic forms is impractical.

胎儿/胚胎代谢的预测是重要的考虑因素 确定与胎儿/胚胎暴露有关的风险 潜在的有毒化合物。 该提议的目的是利用 化学底物探针用于分析功能性P-450同工酶 胎儿肝和肝外术的组成和伴随的能力 组织催化环境毒素和 原型化学致癌物。 两种类型的探针，两种探针都表现出来 这些研究将使用受限的同工酶特异性；一个） 对映体华法林产生一系列羟基化产品 母体分子，b）一系列苯氧唑醚是 氧化为普通代谢产物。 作为测试底物，苯并（alpha）pyrene （BP）和2-乙酰氨基氟烯（AAF）将采用。 该提议是 基于两个假设，即两者的生物转化模式 化学探针类（华法林和苯氧唑醚）将是 高度预测测试底物的特定生物转化（BP 和AAF）。 该假设将通过1）确定的好处进行检验 适合分析的代谢途径的相关性 条件和一系列调节剂的扰动后，2） 根据拟合的优点进行预测，最后3）测试 通过分析未知同学组成的组织的可预测性 使用化学探针并确定这些分析的程度 预测同一组织中的BP和AAF代谢物谱。 这 这些调查的远程目标是使确定 p-450依赖性生物转化和生物活化能力 胎儿/胚胎组织和其他组织的隔离和纯化 同学形式是不切实际的。