It is now widely accepted that the various pharmacologic and addictive consequences of alcohol consumption are related to the tissue concentration of ethanol or its metabolic products. The oxidative metabolism of ethanol in liver is principally catalyzed by alcohol dehydrogenase and aldehyde dehydrogenase. Both of these enzymes exist in multiple molecular forms, and genetic models have been proposed to account for the multiplicity of isoenzymes. Alcohol dehydrogenase subunits are encoded at five different gene loci, and genetic polymorphism occurs at two alcohol dehydrogenase loci. Variant isoenzymes produced at the two polymorphic alcohol dehydrogenase loci account for the differences in enzyme electrophoretic patterns observed among individuals. Some of these variant isoenzymes exhibit widely different kinetic properties, and this may account for the 2- to 3-fold variation in alcohol elimination rate among individuals. Since the protein sequence of several of the alcohol dehydrogenase subunits has been determined and several of the alcohol dehydrogenase genes has been cloned, some of the structural changes which give rise to differences in catalytic and electrophoretic properties are now known. Genetic polymorphism also occurs at the aldehyde dehydrogenase gene locus which encodes the mitochondrial low Km for acetaldehyde aldehyde dehydrogenase isoenzyme. The variant isoenzyme exhibits little or no catalytic activity. Individuals with this "null" variant have higher than normal blood acetaldehyde levels and exhibit an alcohol-flush reaction which appears to be a deterrent to heavy drinking and alcoholism.(ABSTRACT TRUNCATED AT 250 WORDS)

Alcohol Oxidoreductases↗

PubMedDate not supplied

Progress toward a voluntary oral consumption model of alcoholism.

With the goal of obtaining a suitable animal model for voluntary oral consumption of ethanol, the investigators selectively bred lines of alcohol-preferring and alcohol-nonpreferring rats, with preference considered as a function of the concentration of ethanol ingested. Studies with these animals showed that drinking is voluntary and not contingent on caloric restriction; that they will work to obtain ethanol even when food and water are freely available, and in so doing, show psychological or behavioral tolerance; that the amount of ethanol voluntarily consumed approaches their apparent maximum capacity for ethanol elimination. This amount of ethanol was capable of altering brain neurotransmitter content, thus exerting a CNS pharmocologic effect. In addition, the rats will bar-press for intravenous administration of ethanol, and with prolonged, free-choice consumption, ethanol intake increases to as much as 12 g per kg body weight per day without producing behavioral deficits, suggesting the development of tolerance.

Acetaldehyde↗