NMR STUDIES OF CELLULAR METABOLISM

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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. Most of the group effort in this area involves analysis of the metabolism of fluorinated compounds or the use of fluorinated compounds to probe cellular function. During the past year, efforts were focused on several major projects: 1. A 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. Earlier work has demonstrated that quinone methides are formed during cytochrome P450-dependent metabolism of some representatives of this group of compounds. Previous studies on simple, unhindered alkylphenols have been extended to examine the effects of additional fluorine or other halogen substituents. Additionally, quinone methide metabolic transformation of 4-hydroxyphenylacetone, an analog of acetaminophen, has also been demonstrated, and a glutathione adduct characterized by NMR spectroscopy. 2. There has recently been interest in understanding the metabolism 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. 3. As a consequence of the widespread fluoridation of water and the occasional exposure of some populations to considerably higher fluoride levels, it is important to understand the biochemistry of this element. We have recently begun a series of fluorine-19 NMR studies in order to develop a more detailed understanding of fluoride metabolism. The metabolism of 2-fluoro-2-deoxy-D-glucose (2FDG), a radio-active analog of which is widely used in PET scanning studies, has also been investigated by NMR, and the enzymatic formation of 2FDG-6-phosphate and 2-fluoro-2-deoxy-D- mannose-6-phosphate demonstrated.