- Email: [email protected]
Effect of ethanol on cellular membranes
Abstracts of the 1986 UAEM/IRIEM Research Symposium on Toxicology /Editor's. Note: The following 16 abstracts will be presented at the UAEM/IRIEM Research Symposium on Toxicology in San Francisco, February 13 and 14, 1986.]
Effect of Ethanol on Cellular M e m b r a n e s Dora B Goldstein, MD, Professor, Department of Pharmacology, Stanford University, Stanford, California Like other anesthetic agents, ethanol disorders lipid bilayers, causing a linear, concentration-related decrease in EPR order parameter or fluorescence polarization. The effect is small, even when compared to a trivial rise in temperature. In several respects, however, the sensitivity of an animal's membranes to ethanol agrees with the intensity of intoxication in the whole animal. For example, aliphatic alcohols disorder membranes and anesthetize mice with potencies related to their lipid solubilities. Furthermore, synaptosomal plasma membranes of genetically ethanol-sensitive mice are more strongly disordered by ethanol in vitro than are membranes of ethanol-resistant animals. Membranes of mice made tolerant by previous administration of ethanol are relatively resistant to disordering. Under some conditions, these membranes are more rigid than normal. The changes in membrane properties seen after chronic administration of ethanol may be viewed as adaptive mechanisms for maintaining a normal degree of membrane order despite the persistent presence of a disordering drug. They may be mediated by changes in the lipid composition of biomembranes, such as an increase in the content of cholesterol or of saturated fatty acyl chains. In vitro, the transfer of cholesterol and of palmitic acid into membranes is accelerated by ethanol, which suggests that physicochemical forces rather than physiological responses may mediate some of the adaptation to ethanol. We postulate that the primary action of ethanol is on hydrophobic regions of membrane lipids and proteins, and that the altered functions of membrane proteins account for the deranged working of the brain during intoxication.
Alcohol Tolerance Boris Tabakoff, PhD, Director, Division of Intramural Clinical and Biological Research, National Institute of Alcohol Abuse, Bethesda, Maryland Alcohol is consumed by two thirds of the adults in the United States, and 10% of the population drinks substantial amounts of alcohol daily., The consumption of alcohol alters an individual's response to a number of drags in addition to altering the individual's response to ethanol. The diminished response to alcohol after prior consumption of this drug indicates the development of tolerance. Alcohol tolerance is a multifaceted phenomenon that encompasses aspects of learning or conditioning as well as molecular changes in the structure of neurons in the CNS. Alcohol tolerance can also represent changes in the capacity of individuals to metabolize ethanol and other xenobiotic substances. The propensity of human beings or animals to develop alcohol 15:1 January 1986
tolerance has been shown to be, to a significant extent, genetically determined and to be selective for particular aspects of ethanol's Spectrum of effects. For instance, tolerance develops in animals to the sedative-hypnotic actions of ethanol, but not to the locomotor stimulatory effects of ethanol. Inbred strains of rats and mice have been shown to develop tolerance to the incoordinating effects of ethanol at different rates and to varying extents, and animals of certain strains (eg, Maudsley Reactive) may become sensitized to ethanol during periods of chronic exposure. The development of tolerance may contribute to continued increase in consumption of ethanol by certain individuals and to diminished effects of barbiturates and benzodiazepines in these persons. Current experiments in ethanol-tolerant animals cast doubt on whether cross-tolerance between ethanol and barbiturates and benzodiazepines can be explained at the level of CNS receptors for these substances.
G e n e t i c Variability of Enzymes of Alcohol Metabolism in H u m a n Beings Ting Kai Li, MD, Distinguished Professor of Medicine and Biochemistry, Department of Medicine, Indiana University, Indianapolis, Indiana Alcohol is eliminated from the body almost entirely by hepatic metabolism, first to acetaldehyde, then to acetate, and finally to carbon dioxide and water. The time course of elimination is best described by Michaelis-Menten kinetics, and rates of elimination following standard doses of ethanol vary as much as threefold among subjects. Studies comparing rates of elimination in identical and fraternal twins have shown that about half of the variability is attributable to genetic factors. The principal enzymes responsible for ethanol metabolism are alcohol dehydrogenase and aldehyde dehydrogenase. The reaction catalyzed by alcohol dehydrogenase is the rate-limiting step of the pathway. Human livers c o n t a i n m u l t i p l e i s o e n z y m i c forms of alcohol dehydrogenase, which are dimeric molecules arising from the random association of different subunits coded by three different structure genes. Genetic polymorphism at two of these gene loci has been described, and all known homo- and heterodimeric forms of the isoenzymes have been isolated and characterized. Notably some of them differ quite strikingly in reactivity toward ethanol. Thus a basis for the genetic variability in alcohol metabolic rate may be found in the kinetic properties of the alcohol dehydrogenase isoenzymes. The efficient oxidation of acetaldehyde by hepatic aldehyde dehydrogenase is essential for ethanol oxidation to continue over time, because the equilibrium of the alcohol dehydrogenase reaction favors the conversion of acetaldehyde to ethanol. Acetaldehyde is also a very toxic substance, whose removal makes possible the consumption of ethanol in the amounts that humans ingest. There are also multiple molecular
Annals of Emergency Medicine
91/149
Effect of Ethanol on Cellular M e m b r a n e s Dora B Goldstein, MD, Professor, Department of Pharmacology, Stanford University, Stanford, California Like other anesthetic agents, ethanol disorders lipid bilayers, causing a linear, concentration-related decrease in EPR order parameter or fluorescence polarization. The effect is small, even when compared to a trivial rise in temperature. In several respects, however, the sensitivity of an animal's membranes to ethanol agrees with the intensity of intoxication in the whole animal. For example, aliphatic alcohols disorder membranes and anesthetize mice with potencies related to their lipid solubilities. Furthermore, synaptosomal plasma membranes of genetically ethanol-sensitive mice are more strongly disordered by ethanol in vitro than are membranes of ethanol-resistant animals. Membranes of mice made tolerant by previous administration of ethanol are relatively resistant to disordering. Under some conditions, these membranes are more rigid than normal. The changes in membrane properties seen after chronic administration of ethanol may be viewed as adaptive mechanisms for maintaining a normal degree of membrane order despite the persistent presence of a disordering drug. They may be mediated by changes in the lipid composition of biomembranes, such as an increase in the content of cholesterol or of saturated fatty acyl chains. In vitro, the transfer of cholesterol and of palmitic acid into membranes is accelerated by ethanol, which suggests that physicochemical forces rather than physiological responses may mediate some of the adaptation to ethanol. We postulate that the primary action of ethanol is on hydrophobic regions of membrane lipids and proteins, and that the altered functions of membrane proteins account for the deranged working of the brain during intoxication.
Alcohol Tolerance Boris Tabakoff, PhD, Director, Division of Intramural Clinical and Biological Research, National Institute of Alcohol Abuse, Bethesda, Maryland Alcohol is consumed by two thirds of the adults in the United States, and 10% of the population drinks substantial amounts of alcohol daily., The consumption of alcohol alters an individual's response to a number of drags in addition to altering the individual's response to ethanol. The diminished response to alcohol after prior consumption of this drug indicates the development of tolerance. Alcohol tolerance is a multifaceted phenomenon that encompasses aspects of learning or conditioning as well as molecular changes in the structure of neurons in the CNS. Alcohol tolerance can also represent changes in the capacity of individuals to metabolize ethanol and other xenobiotic substances. The propensity of human beings or animals to develop alcohol 15:1 January 1986
tolerance has been shown to be, to a significant extent, genetically determined and to be selective for particular aspects of ethanol's Spectrum of effects. For instance, tolerance develops in animals to the sedative-hypnotic actions of ethanol, but not to the locomotor stimulatory effects of ethanol. Inbred strains of rats and mice have been shown to develop tolerance to the incoordinating effects of ethanol at different rates and to varying extents, and animals of certain strains (eg, Maudsley Reactive) may become sensitized to ethanol during periods of chronic exposure. The development of tolerance may contribute to continued increase in consumption of ethanol by certain individuals and to diminished effects of barbiturates and benzodiazepines in these persons. Current experiments in ethanol-tolerant animals cast doubt on whether cross-tolerance between ethanol and barbiturates and benzodiazepines can be explained at the level of CNS receptors for these substances.
G e n e t i c Variability of Enzymes of Alcohol Metabolism in H u m a n Beings Ting Kai Li, MD, Distinguished Professor of Medicine and Biochemistry, Department of Medicine, Indiana University, Indianapolis, Indiana Alcohol is eliminated from the body almost entirely by hepatic metabolism, first to acetaldehyde, then to acetate, and finally to carbon dioxide and water. The time course of elimination is best described by Michaelis-Menten kinetics, and rates of elimination following standard doses of ethanol vary as much as threefold among subjects. Studies comparing rates of elimination in identical and fraternal twins have shown that about half of the variability is attributable to genetic factors. The principal enzymes responsible for ethanol metabolism are alcohol dehydrogenase and aldehyde dehydrogenase. The reaction catalyzed by alcohol dehydrogenase is the rate-limiting step of the pathway. Human livers c o n t a i n m u l t i p l e i s o e n z y m i c forms of alcohol dehydrogenase, which are dimeric molecules arising from the random association of different subunits coded by three different structure genes. Genetic polymorphism at two of these gene loci has been described, and all known homo- and heterodimeric forms of the isoenzymes have been isolated and characterized. Notably some of them differ quite strikingly in reactivity toward ethanol. Thus a basis for the genetic variability in alcohol metabolic rate may be found in the kinetic properties of the alcohol dehydrogenase isoenzymes. The efficient oxidation of acetaldehyde by hepatic aldehyde dehydrogenase is essential for ethanol oxidation to continue over time, because the equilibrium of the alcohol dehydrogenase reaction favors the conversion of acetaldehyde to ethanol. Acetaldehyde is also a very toxic substance, whose removal makes possible the consumption of ethanol in the amounts that humans ingest. There are also multiple molecular
Annals of Emergency Medicine
91/149