Back to Results

< Previous   Next >

Alcoholism is a tremendous health problem throughout the world. Ethanol is a unique drug that is consumed in large quantities for pharmacologic effect, reaching blood concentrations as high as 100mM. Ethanol is eliminated almost exclusively via oxidation to acetate in the liver, and nearly all of the ethanol-derived acetate is released into the blood where it travels to other organs, including the brain, for use as an energy source. Thus ethanol directly alters metabolism in the liver, and causes the production of large amounts of acetate which may serve as a substrate for brain, possibly contributing to intoxication and dependence. This dissertation describes two separate approaches to study the metabolic effects of ethanol. First, 1H NMR-based metabolomic analysis of endogenous metabolites revealed decreased lactate and alanine, and increased acetate and ketone bodies due to ethanol. These results provided new insights regarding the effect of ethanol on gluconeogenesis. In addition, we determined that ethyl glucuronide (EtG), a unique metabolite of ethanol, produces a characteristic NMR signal. EtG is formed within hours of ethanol dosing, and remains elevated during a 4 day binge exposure. The antioxidant BHT appears to reduce formation of EtG during a 4 day exposure to ethanol. Our second approach used 13C-enriched tracers along with 13C NMR to measure brain metabolism of ethanol-derived acetate. Our hypothesis was that cerebral metabolism of acetate released from the liver during ethanol oxidation perturbs cerebral metabolism, and thereby contributes to neuroadaptation associated with alcohol dependence and withdrawal. Using a single dose of [2-13C] ethanol intragastrically, we found carbons derived from ethanol are rapidly incorporated into brain amino acids glutamate, glutamine, and GABA. Next, we investigated whether a 10 day exposure to ethanol would increase cerebral utilization of acetate. We found that acetate metabolism was not increased, most likely because transport into brain astrocytes was not increased. We did find, however, that ethanol induced significant changes in metabolism of GABA, and we speculate that this may reflect neuroadaptations that produce tolerance to ethanol.