NMR STUDIES OF CELLULAR METABOLISM

本项目旨在开发和应用体内和 研究新陈代谢的体外核磁共振波谱方法及其应用 受到化学毒素的干扰。最近在这一领域的努力已经 重点分析了含氟化合物的代谢和对环境的影响 使用含氟化合物来探测细胞功能。在过去 一年，重点抓好了几个重大项目：1.氟化 葡萄糖类似物在PET扫描应用中被广泛使用。一个 对这些制剂的运输和新陈代谢的理解是 对解释这类研究提供的信息至关重要。 2-氟-2-脱氧-D-葡萄糖的~(19)F核磁共振研究 以确定其运输和代谢特性。这些 结果证实了最近的一项提议，即在最初的 磷酸化，该化合物转化为相应的甘露糖 类似物，即2-氟-2-脱氧-D-甘露糖-6-磷酸，作为以下结果 与磷酸葡萄糖异构酶的相互作用。2.一秒钟 对大卫·汤普森教授进行了一系列研究，以提供 对烷基酚代谢的洞察。大量这样的人 化合物，特别是防腐剂BHT，存在于各种食物中。 还有药品。以前的工作已经证明，甲基苯二酚是 在某些细胞色素P450依赖的代谢过程中形成 这组化合物的代表。这些研究被处理了 在确定简单、不受阻碍的烷基酚是否也 通过这种对苯二酚的代谢代谢。的结构 用核磁共振方法对几种谷胱甘肽加合物进行了分析，测定了谷胱甘肽加合物的产率。 加合物形成的能力与亲本的能力有关 烷基酚对大鼠肝脏切片的毒性作用。3.有 最近对了解新陈代谢和潜在的 含硅化合物的毒性。我们一直在努力开发 新的核磁共振方法表征这一组的代谢物 化合物，并对几个化合物进行了初步系列研究 芳基硅烷。

This program is aimed at the development and application of in vivo and in vitro NMR spectroscopic methods for studying metabolism and its perturbation by chemical toxins. Recent efforts in this area have focused on analysis of the metabolism of fluorinated compounds and on the use of fluorinated compounds to probe cellular function. During the past year, efforts were focused on several major projects: 1. Fluorinated glucose analogs are widely used in PET scanning applications. An understanding of the transport and metabolism of these agents is essential for interpreting the information provided by such studies. Fluorine-19 NMR studies on 2-fluoro-2-deoxy-D-glucose were performed in order to characterize its transport and metabolic properties. These results confirmed a recent proposal that subsequent to its initial phopshorylation, the compound is converted into the corresponding mannose analog, i.e., 2-fluoro-2-deoxy-D-mannose-6-phosphate, as a consequent of the interaction with the enzyme phosphoglucose isomerase. 2. A second series of studies with Prof. David Thompson was undertaken to provide insight into the metabolism of p-alkylphenols. A large number of such compounds, particularly the preservative BHT, is present in various foods and medicines. Previous work has demonstrated that quinone methides are formed during cytochrome P450-dependent metabolism of some representatives of this group of compounds. These studies were addressed at determining whether simple, unhindered alkylphenols were also metabolized by this quinone methide metabolism. The structures of several glutathione adducts were analyzed using NMR methods, and the rate of adduct formation was found to correlate with the ability of the parent alkylphenols to elicit toxicity in rat liver slices. 3. There has recently been interest in understanding the metaboism and potential toxicity of silicon-containing compounds. We have been working to develop new NMR methods for characterizing the metabolites of this group of compounds, and have carried out an initial series of studies on several arylsilanes.