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Alcohol Metabolism, Alcohol Intolerance, and Alcoholism Biochemical and Pharmacogenetic Approaches

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Alcohol Metabolism, Alcohol Intolerance, and Alcoholism Biochemical and Pharmacogenetic Approaches D. P. Agarwal H. W. Goedde Alcohol Metabolism, Alcohol Intolerance, and Alcoholism Biochemical and Pharmacogenetic Approaches With 46 Figures, some in color, and 27 Tables Springer-Verlag Berlin Heidelberg New York London Paris Tokyo Hong Kong Professor Dr. Dharam P. Agarwal Professor Dr, H. Werner Goedde Institute of Human Genetics, University of Hamburg Butenfeld 32,0-2000 Hamburg 54 Federal Republic of Germany ISBN-13: 978-3-642-74906-3 e-ISBN-13: 978-3-642-74904-9 001: 10.1007/978-3-642-74904-9 Library of Congress Cataloging-in-Publication Data Agarwal, Dharam P. Alcohol metabolism, alcohol intolerance. and alcoholism: biochemical and pharmacogenetic approaches / Dharam P. Agarwal. H. Werner Goedde. p. em. Includes bibJio2.raohical references. ISBN-13: 978-3-642-74906-3 1. Alcohol-Physiological effect. 2. Alcohol-Metabolism. 3. Alcohol intolerance. 4. Alcoholism-Genetic aspects. 5. Brain-Effect of drugs on. I. Goedde, H. W. (H. Werner) 1I. Title. [DNLM: 1. Alcohol. Ethyl­ metabolism. 2. Alcohol. Ethylpharmacology. 3. Alcoholism-genetics. WM 274 A261a] QP80l.A3A34 1990 616.86'107-dc20 DNLMIDLC 89-26087 This work is subject to copyright. All rights arc reserved. whether the whole or part of the material is concerned. specifically the rights of translation, reprinting. reuse of illustrations, recitation, broadcasting, reproduction on microfilms or in other ways. and storage in data banks. Duplication of this publication or parts thereof is only permitted under the provisions of the German Copyright Law of September 9. 1965. in its version of June 24.1985, and a copyright fee must always be paid. Violations fall underthe prosecution act of the German Copyright Law. © Springer-Verlag Berlin Heidelberg 1990 Softcover reprint of the hardcover 1st edition 1990 The use of general descriptive names. registered names. trademarks, etc. in this publication does not imply. even in the absence of a specific statement. that such names are exempt from the relevant protective laws and regulations and therefore free for general use. Product Liability: The publisher can give no guarantee for information about drug dosage and application thereof contained in this book. In every individual case the respective user must check its accuracy by consulting other pharmaceutical literature. Typesetting and printing: Meininger. Neustadt Binding: Schaffer. GrUnsladt 2127/3145-543210 - Printed on acid-free paper Preface Alcohol abuse, alcohol intolerance, alcohol dependence and other alcohol-related disabilities are some of the most challenging public health problems facing our modern-day society. The biochemical, pharmacogenetic and pathological disturbances observed in humans after acute and chronic intake of alcohol are exceedingly complex and many social, biological and environmental factors may influence their outcome. Evidence gathered over the past decade supports the notion that genetically controlled biological factors regulate alcohol drinking habits as well as the quantity of alcohol consumed in certain racial and ethnic groups and thus may represent important determinants of alcoholism. Many recent investigations have shown that genetic variations in alcohol and acetaldehyde metabolism may indeed be responsible for individual and racial differences in acute reactions to ethanol, alcohol drinking habits and vulnerability to alcohol-related organ damage. Our own studies have demonstrated that in Asian popu­ lations a high percentage of people have a very high prevalence of an abnormal form of the enzyme aldehyde dehydrogenase that does not adequately metabolize acetaldehyde arising from the ingested ethanol. This inherited abnormality of acetaldehyde metabolism leads to facial flushing and other cardiovascular symptoms of alcohol sensitivity after drinking alcohol. Epidemiological studies indicate that this genetically determined enzyme variation acts as a deterrent for alcohol abuse and alcoholism in Oriental populations of Mon­ goloid origin. The purpose of this comprehensive monograph is to review the available knowledge concerning the pharmacogenetic basis of al­ cohol sensitivity and its physiological implications as well as to synthesize the bulk of existing knowledge regarding metabolic fea­ tures and biomedical disturbances related to alcoholism. Much of the current literature on metabolic and pathogenetic aspects of alcohol abuse has been concerned with animal studies elucidating the possible basic mechanisms involved since, for obivous technical or ethical reasons, many such studies cannot be conducted in hu­ mans. However, most of the animal reports on the subject are of no direct value to basic science researchers, clinicians, biochemists VI Preface and geneticists. In the present volume, studies reported mainly for humans have been dealt with to provide an effective update of the whole area of alcohol research for specialists and non-specialists in the field. Readers will find an objective and critical evaluation of the literature concerning alcohol metabolism and its enzymes as well as regarding various metabolic, pathological, psychopharma­ cological, genetic and environmental aspects of alcohol-related dis­ abilities. Different chapters of the book cover a broad array of disciplines and approaches to alcohol metabolism, alcohol intolerance and alcoholism. Chapter 1 gives an overview of historical and epide­ miological aspects of alcohol use and abuse as well as the current problems and perspectives related to alcoholism. Chapters 2 and 3 deal with the biochemistry and molecular genetics of enzymes in­ volved in alcohol metabolism, including the enzyme polymorphisms and their role in acute reactions to alcohol. Two chapters (4 and 5) are devoted to biochemical and neuropsychopharmacological ef­ fects of alcohol, bridging basic research findings to clinical obser­ vations, and thus deal with the aetiology of alcoholism. In Chap. 6, major emphasis is placed on the role of genetic factors in alcoholism. The experimental details, including materials and biochemical methodology for electrophoretic procedures, subcellular fraction­ ation of isozymes, enzyme purification, immunochemical determi­ nations and molecular genetic analyses are summarized in Chap. 7. Finally, a comprehensive bibliography on alcohol metabolism, al­ cohol sensitivity and alcoholism is included in References. We would like to thank Dr. R. Eckey for help during the pre­ paration of the manuscript. We also wish to thank Dr. J. Wieczorek, Springer-Verlag, Heidelberg, for his keen interest in the publication of this book. Hamburg, October 1989 Dharam P. Agarwal H. Werner Goedde Contents 1 Introduction ......................................... 1 2 Alcohol Metabolism: Biochemistry and Genetic Variations . 6 2.1 Absorption, Body Distribution, and Elimination of Ethanol ......................... 6 2.1.1 Absorption ......................................... 6 2.1.2 Tissue Distribution .................................. 8 2.1.3 Excretion and Elimination ......................... 9 2.2 Biochemical Pathways of Ethanol Degradation ..... 11 2.2.1 Microsomal Ethanol-Oxidizing System .............. 12 2.2.2 Catalase ............................................. 12 2.2.3 Alcohol Dehydrogenase (ADH) .................... 13 2.2.4 Aldehyde Dehydrogenase (ALDH) ................. 23 3 Alcohol-Metabolizing Enzymes and Acute Reactions to Alcohol 52 3.1 Ethanol- and Acetaldehyde-Mediated Acute Response to Alcohol ................................. 52 3.2 Ethnic Differences in Acute Response to Alcohol ... 53 3.2.1 Familial Resemblances in Flushing Response ........ 55 3.3 Mechanism of Alcohol Sensitivity .................... 55 3.3.1 Relationship to Ethanol- and Acetaldehyde-Oxidizing Capacity .............................................. 55 3.3.2 Alcohol Absorption Rate ............................ 56 3.3.3 Alcohol Metabolism and Clearance Rate ............ 57 3.3.4 Variation in ADH .................................... 57 3.3.5 Variation in ALDH .................................. 58 VIII Contents 3.3.6 Prostaglandin- and Histamine-Mediated Flushing Reactions to Alcohol ................................. 59 3.4 Racial-Ethnic Patterns of Alcohol Abuse and Alcoholism ....... 60 3.4.1 Drinking Patterns and Ethnic Background........... 60 3.4.2 Correlations Between Flushing Response, ALDH I Isozyme Abnormality, Alcohol Use, and Alcoholism ......................... 60 3.4.3 Aldehyde Dehydrogenase I Isozyme Abnormality and Alcoholism ....................................... 63 3.4.4 Gene-Culture Coevolution of Alcohol Usage ........ 65 3.4.5 Implications.. .. .. .. 65 4 Biochemical Aspects of Alcoholism .................. 67 4.1 Alcohol-Related Metabolic Derangements........... 67 4.1.1 Organ Dysfunction 67 4.2 Metabolic Changes 70 4.2.1 Lipid Metabolism .................................... 71 4.2.2 Protein Metabolism .................................. 73 4.2.3 Carbohydrate Metabolism ..... 73 4.2.4 Endocrine Effects of Alcohol ........................ 74 4.2.5 Carcinogenetic and Mutagenic Effects of Ethanol. 75 4.3 Changes in Alcohol-Metabolizing Enzymes in Alcohol-Related Disorders........................... 76 4.3.1 Alcohol Dehydrogenase.............................. 76 4.3.2 Microsomal Ethanol-Oxidizing System ............... 77 4.3.3 Aldehyde Dehydrogenase ............................ 77 4.4 Biochemical Markers of Alcohol Abuse and Alcoholism ....... 87 4.4.1 Conventional Markers................................ 88 4.4.2 Test Combinations ................................... 92 4.4.3
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