NMR STUDIES OF CELLULAR METABOLISM

该计划旨在开发和应用体内和

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.