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

192 Pages·1990·5.59 MB·English

by  Professor Dr. Dharam P. Agarwal

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
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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 Coming Markers ..................................... 93
5 Neuropsychopharmacology of Alcoholism ........... 96
5.1 Alcohol Effects in the CNS ........................... 96
5.1.1 Electrophysiological Actions of Ethanol ............. 96
Contents IX
5.1.2 Neuropsychological Impairments in Alcoholics 97
5.2 Addiction, Tolerance, and Dependence.............. 98
5.2.1 Biochemical Basis of Addiction to Ethanol........... 98
5.2.2 Biogenic Amine-Aldehyde Condensation
Products .............................................. 99
5.2.3 Membrane Actions ................................... 100
5.2.4 Alcohol and Neurotransmitters ...................... 101
5.2.5 Neuropeptide Effects on Tolerance .................. 102
5.2.6 Role of Prostaglandins in Alcoholism ................ 103
5.3 Metabolic Factors .................................... 104
5.3.1 Alcohol Metabolism in the Brain ..................... 104
5.3.2 Acetaldehyde Metabolism in the Brain. . . . . . . . .. . . . .. 104
5.3.3 Metabolism of Biogenic Aldehydes .................. 105
6 Genetic Factors in Alcoholism ....................... 107
6.1 Ethnic and Cultural Variables ........................ 107
6.2 Familial and Nonfamilial Alcoholism. . . . . . . . . . . . . . . .. 108
6.3 Genetic Contributions. . . .. . . . . . . .. . . . . . . . . .. . . . . . . . .. 108
6.3.1 Family Studies ........................................ 109
6.3.2 Adoption Studies. . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . .. 110
6.3.3 Twin Studies ......................................... 112
6.3.4 What Is Inherited .................................... 114
6.3.5 Mode of Inheritance. . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . .. 114
6.4 Genetic and Environmental Interactions
in Alcoholism ........................................ 115
6.5 Biological Mediators of Alcoholism .................. 116
6.5.1 Biomedical Markers of Alcoholism. . . . . . . . . . . . .. . . . .. 117
6.5.2 Characterization of High-Risk and Low-Risk
Individuals ........................................... 117
6.5.3 Some Baseline Metabolic Differences Presaging
Alcoholism ........................................... 119
6.5.4 Neurophysiological and Neuropsychological
Differences ........................................... 120
6.5.5 Metabolic Variables .................................. 121
6.5.6 Genetic and Serological Markers of Alcoholism ...... 122
6.5.7 Altered Alcohol Metabolism ......................... 124
6.5.8 Adenylate Cyclase .................................... 125
x Contents
7 Experimental Section 126
7.1 Subjects and Materials ............................... 126
7.1.1 Patients. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . .. 126
7.1.2 Healthy Subjects ..................................... 127
7.1.3 Biopsy Material ...................................... 127
7.1.4 Autopsy Material .... . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 127
7.1.5 Blood Samples ....................................... 127
7.1.6 Hair Root Follicles ................................... 127
7.2 Methods .............................................. 128
7.2.1 Alcohol Sensitivity Questionnaire .................... 128
7.2.2 Alcohol Dehydrogenase......................... ... .. 128
7.2.3 Aldehyde Dehydrogenase ............................ 130
7.2.4 Protein Determination ............................... 141
7.2.5 Separation of Erythrocytes Based on Cell Age ....... 141
7.2.6 Densitometry ......................................... 141
7.2.7 Cloning and Sequencing of ALDH I-cDNA .......... 142
7.2.8 Chromosomal Localization of ALDH I Isozyme ..... 142
7.2.9 Genotyping of ALDH I Alleles ...................... 144
References ................................................... 145
Subject Index ................................................ 179
1 Introduction
In this introductory chapter a brief overview of the epidemiology of alcohol abuse
and the state of current research concerning biochemical and pharmacogenetic
approaches to alcohol metabolism and alcoholism is given.
Alcohol (ethanol, ethyl alcohol) is the most widespread psychoactive drug and
has been known in almost all civilizations since ancient times (Keller 1979).
Primitive alcoholic beverages served as foods, medicines, and euphoriants. Tra
ditionally, excessive drinking has been viewed simply as a sin (e.g., Christian
Puritanism, Islam) or a bad habit. Not until the last quarter of the nineteenth
century did the medical profession come to consider these "bad habits" as a kind
of disease. The ill effects of alcohol on the fetus had already been appreciated by
the ancient Greeks, who instituted laws prohibiting the use of alcohol by newly
wed couples to prevent conception during intoxication. Following the events
observed during the "Gin Epidemic" in England (1720-1750), medical literature
in the nineteenth century warned against the damaging effects of parental drinking
on the fetus (Maykut 1979). In America, alcoholism was first considered to be an
addictive disorder in the 1930s and 1940s.
While in the past researchers paid more attention to the social, cultural, and
medical aspects of alcohol use and abuse, in recent years there has been a growing
recognition that biological factors may be equally important in the development
of alcoholism. In particular, much progress has been made in the elucidation of
biochemical and pharmacogenetic variables which may be important determinants
of alcohol intolerance, alcohol-related tissue and organ damage, alcohol tolerance,
and alcohol dependence. From such studies we have acquired not only a greater
understanding of the causes of the disease alcoholism but also new concepts for
specific preventive strategies and therapeutic measures. Alcoholism is now gen
erally accepted as one of the most serious addictive diseases prevalent in our
society. The economic, medical, and social consequences are far-reaching. Not
only do the industrialized countries have to deal with these consequences, but,
increasingly, more and more third world countries are facing similar problems.
Alcohol-related problems are serious, widespread, and complex. They include
neuropsychiatric and physical disorders, and deterioration of social functioning
accompanied by family breakdown. Also, many physiological and psychological
impairments are associated with reduced performance and increased incidence of
traffic and industrial accidents. It is now well accepted that chronic alcohol drink
ing produces a variety of physiological and physical changes in humans. The liver
is among the most severely damaged of the organs physiologically altered as a