Alcoholism: A Molecular Perspective

358 Pages·1991·13.34 MB·English

by  Charles S. Lieber (auth.)

Alcoholism
A Molecular Perspective
NATO ASI Series
Advanced Science Institutes Series
A series presenting the results of activities sponsored by the NATO Science Committee,
which aims at the dissemination of advanced scientific and technological knowledge,
with a view to strengthening links between scientific communities.
The series is published by an international board of publishers in conjunction with the
NATO Scientific Affairs Division
A Life Sciences Plenum Publishing Corporation
B Physics New York and London
C Mathematical and Physical Sciences Kluwer Academic Publishers
D Behavioral and Social Sciences Dordrecht. Boston. and London
E Applied Sciences
F Computer and Systems Sciences Springer-Verlag
G Ecological Sciences Berlin. Heidelberg, New York, London,
H Cell Biology Paris, Tokyo, Hong Kong, and Barcelona
I Global Environmental Change
Recent Volumes in this Series
Volume 202-Molecular Aspects of Monooxygenases and Bioactivation
of Toxic Compounds
edited by Emel Aring, John B. Schenkman, and Ernest Hodgson
Volume 203-From Pigments to Perception: Advances in Understanding
Visual Processes
edited by Arne Valberg and Barry B. Lee
Volume 204-Role of Melatonin and Pineal Peptides in Neuroimmunomodulation
edited by Franco Fraschini and Russel J. Reiter
Volume 205-Developmental Patterning of the Vertebrate Limb
edited by J. Richard Hinchliffe, Juan M. Hurle,
and Dennis Summerbell
Volume 206-Alcoholism: A Molecular Perspective
edited by T. Norman Palmer
Volume 207-Bioorganic Chemistry in Healthcare and Technology
edited by U. K. Pandit and F. C. Alderweireldt
Volume 208-Vascular Endothelium: Physiological Basis of Clinical Problems
edited by John D. Catravas, Allan D. Callow,
C. Norman Gillis, and Una S. Ryan
Series A: Ufe Sciences
Alcoholism
A Molecular Perspective
Edited by
T. Norman Palmer
The University of Western Australia
Nedlands, Perth, Australia
Plenum Press
New York and London
Published in cooperation with NATO Scientific Affairs Division
Proceedings of a NATO Advanced Study Institute on the
Molecular Pathology of Alcoholism,
held August 26-September 6, 1990,
in " Ciocco, Italy
Library of Congress Cataloging-in-Publication Data
NATO Advanced Study Institute on th~ Molecular Pathology of Alcohol,sm
(1990 II Ciocca. Italy)
Alcoholism a molecular perspective / edited by T. Norman Palmer.
p. cm. -- (NATO AS! series. Series A. L,fe sciences; v.
206)
"Proceedings of a NATO Advanced Study Institute on the Molecular
Pathology of Alcoholism held August 26-September 6. 1990. in II
Ciocca. Italy"--T.p. verso.
"Publ,shed in cooperation with NATO Scientific Affairs Division."
Includes bibliographical references and index.
ISBN-13: 978-1-4684-5948-7 e-ISBN-13: 978-1-4684-5946-3
001: 10.1007/978-1-4684-5946-3
1. Alcoholism--Molecular aspects--Congresses. 2. Alcohol-
-Mechanism of act;on--Congresses. 1. Palmer, T. Norman. II. North
ATianT'c TreaTY Organization. Sc,entific Affairs Division.
III. Title. IV. Series.
[DNLM; 1. Alcohol. Ethyl--metabol ism--congresses. 2. Alcohol ism-
-genetics--congresses. 3. Alcoholism--metabolism--congresses. WM
274 N281a 1990]
RC564.7.N38 1990
616.86'107--dc20
DNLM/DLC
for Library of Congress 91-21253
CIP
ISBN-13: 978-1-4684-5948-7
@ 1991 Plenum Press, New York
A Division of Plenum Publishing Corporation
233 Spring Street, New York, N.Y. 10013
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No part of this book may be reproduced, stored in a retrieval system, or transmitted
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PREFACE
This book contains selected proceedings from the NATO Advanced Study Institute
(AS I) "The Molecular Pathology of Alcoholism" held at the Hotel Il Ciocco in Tuscany
during 26th August -6th September 1990. Alcoholism remains one of the most challenging
problems in medical care, with far-reaching medical, social and economic consequences. For
example in the U.S., estimates indicate that 18 million people have a serious drinking
problem and that the total cost to the economy of alcohol abuse is $117 billion. Treatment
of alcohol dependence and other alcohol-related disorders accounts for almost 15% of the
total health bill of the United States.
Despite the scale of the medical problem, biomedical research on alcoholism
remains something of a 'Cinderella science'. Research funding from government and other
bodies is relatively poor and the number of medical scientists working in the field remains
small. The Organizing Committee for this NATO ASI, comprising Charles Lieber (New
York), Timothy Peters (London), Mario Dianzani (Torino), Emanuele Albano (Torino) and
Norman Palmer (perth, Director), were therefore particularly grateful to the NATO Scientific
Affairs Division for their active support of this AS I, the first dealing with a topic related to
alcohol abuse. We moreover hope that this support will continue. The theme of the ASI
was an in depth discussion of the molecular events initiated by alcohol abuse that culminate
in onset of alcohol-related disease. The last few years have seen major advances in our
knowledge of the molecular pathology of alcoholism in a number of key areas. These
include the molecular genetics and enzymology of the alcohol metabolising enzymes, the
role of genetic factors in alcoholism, the interaction of alcohol with the central nervous
system, and the role of acetaldehyde, acetaldehyde-protein adducts and free radicals in the
pathogenesis of alcohol-related disease. The scale of these advances in knowledge may herald
new advances in diagnosis and therapy.
I would like to express my appreciation to Charles Lieber, Timothy Peters, Mario
Dianzani and Emanuele Albano for their invaluable help in the organisation of the AS!. My
particular thanks go to Bobbie Ward and Bruno Giannasi for their enthusiastic assistance in
the practical management of the Institute. Aside from the NATO Scientific Affairs Division,
the ASI was generously supported in a variety of ways by The Greek Ministry of Industry,
Energy and Technology, The Scientific and Technical Research Council of Turkey, The
National Council for Scientific Investigation and Technology of Portugal, The Brewer's
Society (London), SA Sanofi Labaz (Bruxelles), Du Pont (U.K.), the Ram Brewery
(London), Scottia Pharmaceuticals and the Dow Chemical Company (Midland, Michigan).
Finally I would like to thank Jenny Gillet and especially Raelene Bacon for their enormous
assistance in the preparation of this book.
March 1991 Norman Palmer
v
CONTENTS
Pathways of ethanol metabolism and related pathology 1
Charles S . Lieber
Regulation of rates of ethanol metabolism and liver
[NAD+]/[NADH] ratio 27
Michael J. Hardman, Rachel A. Page, Mark S. Wiseman and
Kathryn E. Crow
Free radical pathology in alcohol-induced liver injury 35
Mario Umberto Dianzani
Free radical mediated reactions and ethanol toxicity:
Some considerations on the methodological approaches 45
Emanuele Albano, Magnus Ingelman-Sundberg, A. Tomasi and
G. Poli
The molecular pathology of alcoholic liver disease: An overview 57
Samuel W. French
Acetaldehyde adducts and excessive alcohol consumption 71
Onni Niemela
Studies of a chemical measure of acetaldehyde adduct formation 77
Charles M. Peterson
Ethanol-induced phosphorylation of cytokeratins in primary
cultured hepatocytes 89
Samuel W. French, H. Kawahara and M. Cadrin
Cloning and characterization of new alcohol dehydrogenase and
aldehyde dehydrogenase isozymes 95
Akira Yoshida, L. Hsu and M. Yasunami
Physiological role of aldehyde dehydrogenase (EC 1.2.1.3) 101
Regina Pietruszko, Gloria Kurys and Wojciech Ambroziak
The alcohol dehydrogenase system in the rat: Comparison with the
human enzyme 107
M. Dolors Boleda, Pere Julia, Alberto Moreno, Nards Saubi and
Xavier Pares
vii
Changes in the inducibility of a hepatic aldehyde dehydrogenase 115
P. Pappas, V. Vasiliou, M. Karageorgou and M. Marselos
Class III alcohol dehydrogenases: Evidence for their identity with the
glutathione-dependent fonnaldehyde dehydrogenases 121
Martti Koivusalo and Lasse Uotila
Genetic polymorphisms of alcohol metabolizing enzymes and their
significance for alcohol-related problems 127
Akira Yoshida
Biochemical and genetic studies in ALDH1-deficient subjects 139
Roberta Ward, Andrew Macpherson, Margaret Warren-Perry,
Vibha Dave, Lily Hsu, Akira Yoshida and Timothy J. Peters
Etiology of subgroups in chronic alcoholism and different
mechanisms in transmitter systems 145
Otto M. Lesch, H. Walter, W. Bonte, J. Grunberger, M. Musalek
and R. Sprung
Genetic linkage analysis: Simple solutions for complex traits? 161
Luis A. Giuffra
The changing view of ethanol's actions: From generalities to specifics 167
Boris Tabak9ff and Paula L. Hoffman
The neurochemistry of ethanol tolerance 175
Boris Tabakoff and Paula L. Hoffman
The role of calcium channels in ethanol dependence 183
Hilary J. Little and John M. Littleton
Structural changes in the hippocampal fonnation and frontal cortex after
long-tenn alcohol consumption and withdrawal in the rat 197
A. Cadete-Leite
Effect of ethanol on the rat medial septum nucleus: An in vivo study 211
Paul Verbanck, J. Scuvee, I. Giesbers, C. Kornreich and A. Dresse
Liver tryptophan pyrrolase, brain 5-hydroxytryptamine and alcohol
preference 217
Abdulla A.-B. Badawy
Alcohol abuse and fuel homeostasis 223
T. Nonnan Palmer, Elisabeth B. Cook and Paul G. Drake
Chronic alcoholism, malnutrition and folate deficiency 237
Charles H. Halsted
Alcohol and protein turnover 253
Victor R. Preedy, Tahir Siddiq, Elisabeth Cook, Darcey Black,
T. Nonnan Palmer and Timothy J. Peters
viii
Role of thiamine deficiency in the pathogenesis of alcoholic peripheral
neuropathy and the Wernicke-Korsakoff syndrome: An update 269
Roger F. Butterworth, Monique D'Amour, Julie Bruneau,
Maryse Heroux and Suzanne Brissette
Alcohol and'cancer: A critical review 275
Helmut K. Seitz and Ulrich A. Simanowski
Metabolism of ethanol and higher alcohols present in alcoholic drinks
and their corresponding aldehydes in subcellular components of rat
esophageal mucosa, and relevance for esophageal cancer in man 297
Valda M. Craddock
Activation by human gastric mucosa of alimentary procarcinogens 303
Romilda Cardin, M. Zordan, F. Farinati, R. Naccarato and
A.G. Levis
Effect of ethanol on gastrointestinal cell proliferation 309
Ulrich A. Simanowski, Burkhard Kommerell and Helmut K. Seitz
Chronic alcoholic skeletal myopathy: An overview 317
Timothy J. Peters and Victor R. Preedy
Effects of ethanol on the immune system 325
Thomas R. Jerrells
Workshop: Future Directions in Biomedical Research on Alcoholism
Introductory remarks 331
Jean-Pierre von Wartburg
Biologic disorders in alcoholism as a basis for a public health approach:
Policy implications 334
Charles S. Lieber
What can we expect from animal models in alcoholism research?
Limitations and relevance to the human condition 339
Ting-KaiLi
Alcoholism research: Crystal ball or wishful thinking 348
YediIsrael
Alcohol and cancer: Where do we stand and where should we go? 350
Helmut K. Seitz
Chronic alcoholism: Subtypes useful for therapy and research 353
Otto M. Lesch
Index 357
ix
PA TRW AYS OF ETHANOL METABOLISM AND RELATED PATHOLOGY
Charles S. Lieber
Bronx VA Medical Center and Mount Sinai School of Medicine
130 West Kingsbridge Road
Bronx, New York 10468 USA
METABOLIC AND PATHOLOGIC EFFECTS ASSOCIATED WITH ALCOHOL
DEHYDROOENASE-MEDIA TED ETHANOL METABOLISM
In ADH-mediated oxidation of ethanol, hydrogen is transferred from the substrate to
the cofactor nicotinamide adenine dinucleotide (NAD), converting it to the reduced form
(NADH) (Fig. 1). As a net result, ethanol oxidation by ADH generates an excess of
reducing equivalents as free NADH in hepatic cytosol, primarily because the metabolic
systems involved in NADH removal are not able to fully offset the accumulation of
NADH. The acetaldehyde produced in this reaction is converted to acetate by aldehyde
dehydrogenase, which is also associated with reduction ofNAD to NADH. The large
amounts of reducing equivalents produced overwhelm the hepatocyte's ability to maintain
redox homeostasis and a number of metabolic disorders ensue, including changes in protein,
carbohydrate ( hypoglycemia) and uric acid metabolism (Lieber, 1982). This redox
mechanism also affects lipids: 1) ethanol oxidation provides reducing equivalents and two
carbon units for lipid synthesis, 2) the more reduced redox state inhibits the oxidation of
fatty acids and diverts them into esterification which is further enhanced by the increased
concentration of sn-glycerol-3-phosphate, 3) ethanol affects the amount of fatty acids
transported from the adipose tissue into the liver (Lieber et al., 1959; Lieber and Schmid,
1961; Lieber, 1982). A characteristic feature of liver injury in the alcoholic is the
predominance of steatosis and other lesions in the perivenular (also called centrilobular)
zone or zone 3 of the hepatic acinus. The mechanism for this zonal selectivity of the toxic
effects involves several distinct and not mutually exclusive mechanisms: one hypothesis
postulates that ethanol can produce hypoxic damage of perivenular hepatocytes whereas
another postulates that relative hypoxic conditions normally prevailing in the perivenular
zone enhance the metabolic toxicity of ethanol. Furthermore, the selective presence and
induction of enzymes of alcohol metabolism in the perivenular zone is also contributory.
The hypoxia hypothesis originated from the observation that liver slices from rats fed
alcohol chronically consume more oxygen than those of controls (Videla and Israel, 1970).
It was then postulated that the increased consumption of oxygen would increase the gradient
of oxygen tensions along the sinusoids to the extent of producing anoxic injury of
perivenular hepatocytes (Israel et aI., 1975). Indeed both in human alcoholics (Kessler et al.,
1954) and in animals fed alcohol chronically (Sato et al., 1983; lauhonen et al., 1982),
decreases in either hepatic venous oxygen saturation (Kessler et aI., 1954) or P0 (Jauhonen
2
et al., 1982) and in tissue oxygen tensions (Sato et aI., 1983) have been found during the
Alcoholism: A Molecular Perspective 1
Edited by T.N. Palmer, Plenum Press, New York, 1991
M~/ ~NAD
'"°"'''7 ··· ..~ ;;; .....: ~.~~~.". ... ·0""" ,"0"'''
/ ~~~ AMIND ACDIS .. AMINO ACIDS
~~~
ACETALDEHYDE ? \
/ 0 0 M"ot_'on UREA
GSSG_~SH~AICETALDEHYDE ------ --------:_ __ -_------ ----_ACETATE
H,O ~o, ~
H,O ~
HACP CATALASE iii
~ H,o, ,,fJ _
011 ','
CYT. P .• SOIl E 1 H -
(MEOS) H ,---,
'ilJ2 fDH 1\ \.; t C.,~.• . •:
AO\ ~H-:r,!J, :;;';~;"
mo,,,
VITAMINS ETHANOL} NA
--..>-_ _ - I "-Cl GLYCEROPHOSPHATE
Fe» NAD",, t FAnYLIVER2
GLUTAMATE-. ? -~\r -~--
XANTHINE FERRITIN ADH
OX,DASE '(J""E' =%
t c=:::-'
~ XANTHINE ~
DEHYDROGENASE H HYDROXYPROLINE - -,
ACETATE~CETALDEHYDE;. ~
• --. •
ATP "PROCOLLAGEN-- ----.. HYPERLIPEMIA
HYPOGL YCEMIA~ --PYRUVATE LACTATE ~COLLAGEN
-------- ; PROPEP;;;;ES '---HYDROXYPROLINE
HYPERURICEMIA-HYPERLACTACIDEMIA
Fig. 1. Oxidation of ethanol in hepatocyte. Many disturbances in intennediary metabolism
and toxic effects can be linked to 1). alcohol dehydrogenase (ADH) mediated generation of
NADH 2). the induction of microsomal enzymes, especially P450IIEI and 3). acetaldehyde,
the product of ethanol oxidation. NAD, nicotinamide adenine dinucleotide; NADH, reduced
NAD; GSH, reduced glutathione; GSSG, oxidized glutathione. The broken lines indicate
pathways that are depressed by ethanol, whereas repeated arrows reflect stimulation or
activation. The symbol -[ denotes interference or binding. (From Lieber, 1990a).
withdrawal state. However, the changes in hepatic oxygenation found during the withdrawal
state disappeared (Jauhonen et aI., 1982; Shaw et aI., 1977) or decreased (Sato et al., 1983)
when alcohol was present in the blood. Acute ethanol administration increased splanchnic
oxygen consumption in naive baboons, but the consequences of this effect on oxygenation
in the perivenular zone were offset by increased blood flow resulting in unchanged hepatic
venous oxygen tension (Jauhonen et al., 1982). Indeed, ethanol in fact induces an increase
in portal hepatic blood flow (Stein et aI., 1963; Shaw et al., 1977; lauhonen et aI., 1982;
Carmichael et al., 1987). In baboons fed alcohol chronically, defective O2 utilization rather
than lack of O2 blood supply characterized liver injury produced by high concentration of
ethanol (Lieber et al., 1989). We postulated that the low oxygen tensions nonnally
prevailing in peri venular zones could exaggerate the redox shift produced by ethanol
(Jauhonen et al., 1982). To study the magnitude of such a shift in the baboon, the effects of
ethanol on the lactate!pyruvate ratio in hepatic venous blood (an approximation of that in
perivenular hepatocytes) were compared with the ratio in total liver. Ethanol increased the
lactate!pyruvate ratio and decreased pyruvate more in hepatic venous blood than in total
2