ENVIRONMENTAL TOXINS--PREDICTION OF FETAL METABOLISM

胎儿/胚胎代谢的预测是一个重要的考虑因素， 确定与胎儿/胚胎暴露于 潜在的有毒化合物。 本提案的目的是利用 用于分析功能性P-450同工酶的化学底物探针 胎儿肝、肝外膜的组成及伴行量 组织催化环境毒素的区域选择性代谢， 原型化学致癌物。 两种类型的探针，都表现出 限制性同工酶特异性，将用于这些研究; a） 对映体华法林，其产生一系列羟基化产物， 母体分子，和B）一系列吩恶嗪酮醚， 氧化成普通的代谢物 作为测试底物，苯并（α）芘 (BP)和2-乙酰氨基芴（AAF）。 该提案 基于这样的假设， 化学探针类（华法林和吩恶嗪醚）将被 高度预测测试底物（BP）的特异性生物转化 AAF）。 假设将通过以下方式进行检验：1）确定 适用于各种条件下分析的代谢途径的相关性 条件和一系列调节剂扰动后，2） 根据拟合优度进行预测，最后，3）测试 通过分析未知同工酶组成的组织的可预测性 并确定这些分析 预测BP和AAF在相同组织内的代谢产物谱。 的 这些调查的长期目标是确定 P-450依赖的生物转化和生物活化能力 胎儿/胚胎组织和其他需要分离和纯化的组织， 同工酶形式是不切实际的。

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.