Biochemical Pharmacology of Ethanol

A number of excellent symposia, reviews and monographs on the biology of ethanol have been published during the last decade. Al though it may appear that another such publication may be superflu ous, the subject of alcohol abuse is still open for further explora tion and the field of the biochemical pharmacology of ethanol is in its infancy. This is evidenced, for example, by the unavailability of any drugs that are designed specifically for the treatment of alcohol intoxication or alcohol addiction. The impetus for this publication was generated by a spontane ous enthusiasm following the symposium on BiochemicaZ Ph~acoZogy of EthanoZ that was organized at the annual meeting of the American Chemical Society, Division of Biological Chemistry in August 1973 in Chicago. It was the first symposium on such a topic ever in cluded in the program of that large society of American chemists. The original aim of the symposium was to acquaint the members of the society with some basic facts about the biological chemistry of ethanol. The symposium included seven papers and covered a rela tively narrow range of ethanol biochemistry. In view of the enthu siasm shown at the Chemical Society meeting, the panelists decided to publish the program and to amplify it by inclusion of additional topics which have remained relatively unexplored in earlier publica tions. In addition, reviews have been included which discuss old topics from a new perspective.

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Mammalian Liver Alcohol Dehydrogenases.- 1. Physical and Chemical Properties of Alcohol Dehydrogenases from Livers of Horse, Man and Rat.- a. Molecular Weight, Subunit Composition, Ultraviolet Absorption, Catalytic Sites Per Mole, Zn++ Content, Sulfhydryl Groups, End Groups, Residues Per Subunit, Heterogeneity.- b. The Role of Zinc.- c. X-ray Crystallography.- d. Coenzyme Binding.- e. Conformational Changes.- f. Ternary Complexes: Significance and Use.- g. Substrate Specificity.- h. Catalytic Mechanism.- 2. Structure-Function Relationship in Isoenzymes.- a. Alcohol Dehydrogenase from Horse Liver.- b. Alcohol Dehydrogenase from Human Liver.- c. Alcohol Dehydrogenase from Rat, Rhesus Monkey and Other Species.- d. Significance of Steroid Activity.- Summary.- References.- Microsomal Ethanol Oxidation: Activity in Vitro and in Vivo.- 1. In Vitro Activity.- a. Evidence of Mixed Function Oxidase Activity.- b. Hydrogen Peroxide Dependence of the Ethanol Oxidizing Reaction.- c. The Role of Catalase in MEOS.- d. Separation of Catalase from Microsomal Components.- 2. In Vivo Activity.- 3. Conclusion.- Summary.- References.- Pathways of Ethanol Metabolism in Perfused Rat Liver.- 1. Alcohol Dehydrogenase Pathway.- a. Hydrogen Shuttle Mechanisms.- b. Rate-Limiting Step for the Alcohol Dehydrogenase Reaction.- c. Quantitation of Alcohol Dehydrogenase-Dependent Ethanol Oxidation.- 2. Quantitation of Catalase-Dependent Ethanol Oxidation.- a. Activation of Ethanol Utilization by Hydrogen Peroxide-Generating Substrates.- 3. Microsomal Ethanol Oxidizing System (MEOS).- 4. Adaptive Increase in Ethanol Utilization Following Chronic Ethanol Pretreatment.- Summary.- References.- Rate-Limiting Steps in Ethanol Metabolism and Approaches to Changing These Rates Biochemically.- 1. Metabolism of Ethanol.- 2. Liver Alcohol Dehydrogenase.- 3. Acetaldehyde Dehydrogenase.- 4. Transport and Oxidation of Reducing Equivalents.- 5. Lipogenesis.- 6. Inhibition of Ethanol Metabolism.- 7. Acceleration of Ethanol Metabolism.- Summary.- References.- Metabolic Correlates of Ethanol, Acetaldehyde, Acetate and Methanol in Humans and Animals.- A. Biological Properties of Ethanol.- 1. Ethanol Acts both as a Narcotic and as an Aberrant Nutrient.- 2. Competition for Coenzymes.- 3. Competitive Inhibitions of Enzyme Catalyzed Reactions.- a. Accumulation of Methanol in Ethanol-Drinking Subjects.- b. Biogenic Amine Condensation Products.- c. Shift in the Metabolism of Biogenic Amines.- B. Effects of Ethanol oN Liver Metabolism.- 1. Inhibition of Carbon Dioxide Formation.- 2. Suppression of Respiratory Quotient.- 3. Ethanol Inhibits its Own Intermediary Metabolism.- 4. Effects of Ethanol on the Metabolism of Glucose in the Liver.- C. Comparison of the Effects of Ethanol on Liver and BRAIN Metabolism.- 1. Diverse Effects of Ethanol on Brain and Liver Monoamine Oxidase.- D. Blood Concentrations of Ethanol, Acetaldehyde, Acetate and Methanol During Acute and Chronic Administration of Alcoholic Beverages in Humans and Animals.- 1. Subjects.- 2. Blood Ethanol Levels.- 3. Acetaldehyde.- a. Methodological Considerations.- b. Nonenzymatic Formation of Acetaldehyde.- 4. Acetaldehyde: Human Investigations.- a. Chronic Studies.- b. Acute Studies.- 5. Acetaldehyde: Animal Studies.- a. Methodology.- b. Sex, Strain and Alcohol Preference.- c. Acetaldehyde in Brain.- 6. Acetate.- 7. Methanol Accumulation.- Summary.- References.- Alcohol and Aldehyde Metabolism in Brain.- A. Attempts to Demonstrate Ethanol Metabolism in Brain.- 1. Oxygen Consumption and Carbon Dioxide Production.- 2. Conversion of Ethanol to Amino Acids in Brain.- 3. Histochemical Techniques.- B. Enzymes Which May Metabolize Ethanol in Brain.- 1. Catalase.- 2. Alcohol Dehydrogenase.- 3. Ethanol Metabolism and Redox Changes in Brain.- C. Aldehyde metabolism in Brain - Oxidation and Reduction.- 1. Substrate Specificity and Reaction Mechanism of Aldehyde Dehydrogenase - Oxidation.- 2. Activation and Inhibition of Aldehyde Dehydrogenase, Activity.- 3. Subcellular Distribution and Isozymes of Aldehyde Dehydrogenase.- 4. Reduction of Aldehydes to Alcohols in Brain.- 5. Characteristics of Aldehyde Reductase in Brain.- Summary.- References.- Effects of Ethanol on Brain Metabolism.- Effects on Intermediary Metabolism.- 1. Effects on Glycolysis.- 2. Energy-Rich Phosphates.- 3. Oxygen Consumption.- 4. Carbon Dioxide Production.- 5. Tricarboxylic Acid Cycle Inhibition.- 6. Lipid Metabolism.- 7. Amino Acid and Protein Metabolism.- Summary.- References.- Effects of Ethanol on Protein Synthesis.- A. Cardiac Protein Synthesis, Ethanol and Nutrition.- 1. Amino Acid Availability and Cardiac Protein Synthesis.- 2. Effects of Ethanol or Metabolites on the Heart.- a. Ethanol and Cardiac Metabolic Effects.- b. Ethanol and Cardiac Protein Synthesis.- B. Hepatic Protein Synthesis.- a. Albumin Synthesizing Mechanism.- b. Factors Influencing Hepatic Albumin Production.- c. Clinical Liver Disease.- d. Amino Acids and Nutritional Effects on Albumin Synthesis.- Summary.- References.- The Effects of Aliphatic Alcohols on the Biophysical and Biochemical Correlates of Membrane Function.- 1. Interactions of Alcohols with Membranes.- a. Membrane Protection.- b. Membrane Expansion.- c. Membrane Disordering.- d. Lipid Disorganization.- 2. Alcohols and the Electrical Properties of Membranes and Related Biochemical Events.- 3.Alcohols and the Active Transport of Cations and the Na-K ATPase.- 4. Alcohols and Calcium and Magnesium Metabolism.- 5. Concluding Remarks.- Summary.- References.- Interactions of Ethanol with Cyclic Amp.- 1. Acute Effects of Ethanol on the Cyclic AMP System.- a. Effects of Ethanol on Adenylate Cyclase.- b. Effects of Ethanol on Phosphodiesterases.- c. Effect of Ethanol on ATP Levels and ATPase Activity.- d. Effects of Ethanol on Cyclic AMP Levels.- 2. Changes of the Cyclic AMP System after Chronic Ethanol Administration.- a. Changes in the Central Nervous System.- b. Changes in the Peripheral Organs.- 3. Possible Role of Cyclic AMP in Ethanol Effects.- a. Ethanol-Induced Fatty Liver.- b. Implication of Cyclic AMP System in the Central Effects of Ethanol.- 4. Conclusions.- Summary.- References.- Alcohol, Aldehydes and Biogenic Amines.- 1. Biogenic Amine Catabolism and the Effects of Ethanol and Acetaldehyde.- 2. Effects of Ethanol and Acetaldehyde on Biogenic Amine Turnover and Steady-State Levels in Brain.- 3. Effects of Ethanol on the Uptake of Transmitters by Brain Tissue In Vitro.- 4. The Effect of Ethanol on the Urinary Excretion of the Biogenic Amines and their Metabolites.- Summary.- References.- Formation of Aberrant Neurotransmitters and Its Implication for Alcohol Addiction and Intoxication.- 1. Storage and Release of False Neurotransmitters.- 2. False Neurotransmitters and Alcoholism.- 3. Formation and Inhibition of Tetrahydroisoquinoline Derivatives.- 4. Newer Concepts Related to the Involvement of Biogenic Amines in Alcoholism.- Summary.- References.- Interaction of Biogenic Amines with Ethanol.- 1. Effects of Ethanol on Monamine Metabolism.- 2. Aberrant Neurotransmitters: Hypothetical Role in Alcoholism.- 3. Serotonergic Regulation of Respiratory Depression Induced by Ethanol.- 4. Discussion and Critique.- Summary.- References.- Some Endocrine Aspects of Alcoholism.- 1. The Adrenal Cortex.- 2. Aldosterone.- 3. Cortisol.- 4. Sex Hormone Metabolism.- 5. Insulin.- 6. Miscellaneous.- Summary.- References.- Marihuana VS. Alcohol: A Pharmacologic Comparison.- 1. Drug Classification.- 2. Behavior.- 3. Pharmacology.- 4. Toxicity.- 5. Therapeutic Effects.- Summary.- References.- Induction of Physical Dependence on Alcohol in Rodents.- 1. Experimental Conditions Necessary for Induction of Physical Dependence.- 2. Objective Criteria of Physical Dependence (Physical signs induced by withdrawal).- a. Quantification.- 3. Methods for Induction of Physical Dependence.- a. Criteria.- b. Supplementary Measures.- c. Liquid Diet Procedures.- d. Changes in Behavior.- e. Inhalation of Ethanol.- f. Gastric Intubation.- g. Intravascular Catheterization.- Conclusion.- Summary.- References.- Induction of Physical Dependence Upon Alcohol in Nonhuman Primates.- 1. The Concept of Physical Dependence.- 2. Measurement of Physical Dependence.- 3. Infusion Procedures.- 4. Intubation Procedures.- 5. Nonvolitional Oral Intake.- 6. Miscellaneous Procedures.- 7. Discussion.- Summary.- References.- Genetic Determinants of Alcohol Addiction.- 1. Biological Variation.- 2. Family Studies.- 3. Twin Studies.- 4. Adoption Studies.- 5. Genetic Marker Studies.- 6. Comment.- Summary.- References.- List of Contributors.