Mechanism and regulation of ethanol elimination in humans: intermolecular hydrogen transfer and oxidoreduction in vivo

Abstract

Ethanol metabolism was studied in four healthy volunteers by intravenous infusion of a mixture of [1,1-2H2]ethanol (1.0 mmol/kg) and [2,2,2-2H3]ethanol (1.0 mmol/kg) followed by blood sampling at 10-min intervals. The concentrations of ethanols labeled with 1, 2, 3, and 4 deuterium atoms were determined by gas chromatography/mass spectrometry of the 3,5-dinitrobenzoates. During the first 30 min mono- and tetradeuteriated molecules appeared rapidly, which indicates that a fraction of the ethanol was formed from acetaldehyde by exchange. This fraction was calculated to be 38-58% and the hydrogen incorporated during the reduction was mainly (63-82%) derived from C-1 of ethanol, indicating slow exchange of enzyme-bound NADH. After 30 min the elimination followed first-order kinetics with t1/2 of 18-31 min and with a small primary isotope effect (1.05-1.11). This indicates almost complete removal of ethanol from blood passing through the liver when the concentration is low (below 1 mM). The results indicate that as long as hepatic blood flow is not limiting, the rate of alcohol dehydrogenase-catalyzed elimination of a small dose of ethanol in vivo is limited by the dissociation of NADH from the enzyme and by the rates of oxidation of acetaldehyde and reoxidation of NADH.