IN VIVO F-19 NMR STUDIES OF THE METABOLISM OF FLUROINATED ANESTHETICS

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The liver is the principal organ involved in the detoxification of a broad range of xenobiotics. During the past decade, it has become possible to monitor the metabolism of organs non-invasively in anesthetized animals and humans using surface coil NMR probes which can be placed directly over the tissue of interest. Using this technique, the metabolic transformations of xenobiotics can, in favorable cases, be directly observed, and perturbations of cellular energy metabolism and redox chemistry can also be studied. Using this technique, we have carried out studies of metabolism of several fluorinated inhalation anesthetics in order to obtain a better understanding of the basis for the toxic side effects which accompany the use of many of these compounds. These studies ave provided the first unequivocal identification of methoxydifluoroacetate as a metabolite of the anesthetic methoxyflurane. Additionally, we have adapted this technique to the study of transmethylation reactions based on direct observations by deuterium NMR of (methyl-2H3)methionine. It was found that excess methionine s metabolized largely via the initial transfer of the methyl group to glycine to yield N-methylglycine (sarcosine), which is subsequently processed in the mitochondrion. The activity of this glycine/sarcosine shuttle is subject to interference by a number of chemicals including the methionine analog ethionine, as well as sodium benzoate. Studies with deuterated D-methionine indicate that his analog is metabolized via initial oxidative deamination by D-amino acid oxidase, then transaminated to yield L-methionine which is the metabolized via glycine N-methyltransferase.