Metabolic Changes Induced by Alcohol

225 Pages·1971·9.63 MB·English

by  N. C. R. Räihä

Metabolic Changes
Induced by Alcohol
Edited by
G. A. Martini and Ch. Bode
With 122 Figures
Sp ringer-Verlag Berlin . Heidelberg . New York 1971
ISBN-13: 978-3-540-05296-8 e-ISBN-13: 978-3-642-65131-1
DOl: 10.1007/978-3-642-65131-1
This work is subject to copyright. All rights are reserved, whether the whole or part of the material is concerned,
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Under § 54 of the German Copyright Law where copies are made for other than private use, a fee is payable to the
publisher, the amount of the fee to be determined by agreement with the publisher.
© by Springer-Verlag Berlin' Heidelberg 1971. Library of Congress Catalog Card Number 77-142386.
Foreword
In nearly all parts of the world, the consumption of alcohol is increasing,
and the morbidity and mortality of diseases induced by alcohol are rising
correspondingly. It has been stated that alcohol is consumed because it pro
duces intoxication. This effect is due to its toxicological influence on the
central nervous system with the resulting functional disturbances. For many
years, the concept that alcoholic liver disease was of nutritional origin
and only indirectly related to alcohol consumption and metabolism was accepted.
Opinion has changed gradually in recent years and tends now to regard alcohol
itself through its combustion, as responsible for many metabolic disorders.
Interest in this problem has increased during the past decade, and numerous
papers bearing on this subject have appeared. It seems that the oxidation of
alcohol in the liver interferes in many ways with the intermediary metabolism
of lipids, carbohydrates and proteins, including enzymes and hormones, and
exerts damaging influence on the liver, the musculature, the heart, the brain
and the kidneys. The "Workshop Symposium" brought together a limited number
of the scientists involved in the new development, biochemists, physiologists,
pharmacologists, pathologists and clinicians from eight European countries
and from the United States and allowed a very lively and informal exchange.
The symposium was honored by the presence of Sir Hans Krebs, whose vast
experience stimulated the discussion. It is a great pleasure to dedicate
this volume to Sir Hans on the occasion of his 70th birthday on August 25th.
We hope that this record will be of interest to many workers in different
.
fields •
The editors wish to thank Dr. Reinicke and Dr. Wolf of the Deutsche Laevosan
Gesellschaft, Mannheim, without whose generous support the symposium would
not have been possible.
The Marburger Universitatsbund e.V. kindly gave financial help for the trans
lation of the manuscripts.
Marburg, August 25th, 1970 G.A. Martini
Contents
METABOLISM OF ALCOHOL AND ALCOHOL DEHYDROGENASE
1) RAIHA, N.R.C. and P.H. PIKKARAINEN, Helsink~
The Development of Alcohol Dehydrogenase and its Isoenzymes •••• 1
Discussion: Papenberg; Raiha •••••••.•••••••••••••••••••••••••• 6
2) v.WARTBURG, J.P., Bern:
Heterogeneity and Polymorphism of Human Liver Alcohol Dehydro-
genase ..•....................•................................ 8
Discussion: Karlson; v.Wartburg; Papenberg; Scholz; Krebs;
Lieber; Lundquist; Lelbach •••••••••••.•••••••••••• 12
3) FORSANDER, O.A., Helsinki:
Extrahepatic Oxidation of Alcohol and Alcohol Metabolites ••••• 14
Discussion: Lieber; Forsander; Krebs; Raiha ••••••••••••••••••• 22
4) GOEBELL, H. and Ch. BODE, Marburg/L:
Influence of Ethanol and Protein Deficiency on the Activity of
Alcohol Dehydrogenase in Rat Liver •••.••.•••••.•.•••••.••••••• 23
Discussion: Karlson; Goebell; Raiha; Papenberg; Bode;
Schimassek; Haberich •••••••••.•.••••••••••••••••••• 29
5) WINKLER,K., F. LUNDQUIST and N. TYGSTRUP:
Ethanol Metabolism in Cirrhosis of the Liver •••••••••••••••••• 31
Discussion: Martini; Winkler; Rubin; Salaspuro; Lundquist;
v • Wartburg ••..••..•.•••••••••••••••••••••••••••••• 36
6) BLOMSTRAND,R., Stockholm:
Studies on the Inhibitory Effect on Ethanol Oxidation in Man
after Administration of 4-methylpyrazole •••.•..•.•.••••••••••• 38
Discussion: Carulli; Blomstrand ••...•.•••.•••••••••••••••••••• 51
7) PAPENBERG, J., Heidelberg:
Ethanol Metabolism of the Isolated Perfuced Rat Liver. 1.
Effect of Ethanol Oxidation on Substrate Levels. 2. Effects
of Fructose and Pyrazole on Ethanol Oxidation ••••••••••••••••• 53
Discussion: Tygstrup; Papenberg; Lundquist; Scholz; Krebs;
Bode; Blomstrand •••••••.•.•••.••••.•••••••.••••••• 60
8) LELBACH, K., Bonn:
Experimental Hepatocellular Necrosis Induced by Ethanol after
Partial Inhibition of Liver Alcohol Dehydrogenase ••••••••••••• 62
Discussion: Sjovall; Lelbach; Forsander; Bode; Lieber;Martini •• 69
ETHANOL INDUCED ULTRASTRUCTURAL ALTERATIONS IN THE LIVER
9) RUBIN, E., New York:
Correlation of Biochemical and Functional Hepatic Changes with
Ethanol Induced Ultrastructural Alterations ••••••••••••••••••• 70
Discussion: Raiha; Rubin; Papenberg; Carulli •.•••••.••.••••••• 74
VI
10) GOTTLIEB,L.S., O.A.ISERI and H.D. FAHIMI, Boston:
Ultrastructural and Cytochemical Studies of Alcoholic Hyalin
and Megamitochondria •..••••.•.•••.•.•.•••.•••.••••..••••••.•.. 76
Discussion:Papenberg; Gottlieb; Martini; Rubin; v.Wartburg •••• 84
EFFECT OF ETHANOL ON MICROSOMAL FUNCTIONS
11) LIEBER,C.S., New York:
Effect of Ethanol on the Activity of Microsomal Enzymes ••••••• 85
Discussion: Raiha; Lieber; Bode; Sjovall; Lelbach •••••••••••••• 91
12) CARULLI,N. and F.MANENTI, Modena:
Microsomal Oxidation of Ethanol and the Drug Metabolizing
System. Studies in Animals and Man ••..••••••••••••••••••.•.••• 93
Discussion: Rubin ••..••••••••••••.•••••••.•••••••••••••••••••• 100
13) SCHOLZ,R., W.HANSEN and R.G. THURMAN ,Mlinchen:
Interaction between Ethanol Oxidation and Drug Metabolism ••••• 101
Discussion: Rubin; Scholz; Lieber ••••••••••••••••••••••••••••• 107
EFFECT OF ETHANOL ON METABOLITES AND COENZYMES OF THE ENERGY PRODUCING
METABOLISM
14) LUNDQUIST ,F. , H. THIEDEN and N.GRUNNET, Copenhagen:
Ethanol as an Energy Producing Substrate in the Liver •••••••••• 108
Discussion: Papenberg; Lundquist; v.Wartburg ••.••••••••••••••• 114
15) HEIM,F., C.-J.ESTLER and H.P.T. AMMON, Erlangen:
The Influence of Ethanol on Metabolites and Coenzymes of the
Energy prodl'cing Metabolism in Liver and Brain ••..••••••••••••• 115
Discussion: Papenberg; Estler; Bode ••..•.•••••.••••••••••••••• 124
16) SALASPURO, M.P., Helsinki:
Influence of Ethanol on the Metabolism of the Protein-
deficient Fatty Liver •......•.••••••.•••••.•..•••••••••.••.•.• 126
Discussion: Winkler; Salaspuro; Tygstrup; Goebell ••••••••••••• 132
17) BODE,Ch., CHRISTIANE BODE, H.GOEBELL, H.KONO and G.A. MARTINI,
Marburg/Lahn:
On the Independence of the Ethanol-Induced Triglyceride Accu
mulation in the Liver from Metabolic Changes Due to the Oxi
dation of Ethanol in the Liver •••••••••••••••••••••••••••••••• 133
Discussion: Lieber; Bode: Rubin; Estler •.••••••••••••••••••••• 141
18) TYGSTRUP,N., K. WINKLER and F.LUNDQUIST, Copenhagen:
Ethanol Metabolism in Man, Studied by Liver Vein Catheteriza
tion(Effect of Ethanol on Glycerol Metabolism) ••.••••••••••••• 143
Discussion: Lundquist .••..•....•.•.••..••••.•••••.•.•••.•...•. 151
EFFECTS OF ETHANOL ON CARBOHYDRATE METABOLISM
19) KREBS, H.A., Oxford:
Effects of Ethanol on Gluconeogenesis ••••.••••.•••.••••••••••• 152
Discussion: Bode; Krebs; Estler; Schimassek; Papenberg; Lund
quist; Scholz; Raiha •.••••••••••••••••••• 155
0 ••••••••
20) SCHIMASSEK, H., G. HOFER and A.K. WALLI, Heidelberg:
The Effect of Alcohol on the Embden-Meyerhof-Parnas-Pathway
in the Liver ••..•.••••••.••••••.••••••••••.•••••.•••••••.••.•• 157
VII
21) SCHOLZ,R., R.G. THURMAN and J.R. WILLIAMSON, MUnchen:
Effect of Ethanol Oxidation on Gluconeogenesis from Alanine •••• 166
Discussion: Lundquist; Scholz; Bode ••••••••••••••••••••.••••••• 174
22) HAKIM, J., P.BOIVIN and R. FAUVERT, Clichy:
Some Effects of Ethanol on Gluconeogenesis, Glycogenesis and
Glycogenolysis ................................•................ 176
Discussion: Bode; Hakim ........•............................... 187
EFFECT OF ETHANOL ON HORMONE METABOLISM
23) CRONHOLM, T., I. MAKINO and J.SJOVALL, Stockholm:
Effect of Ethanol on Steroid Metabolism ••••.••••••••••••••••••• 188
Discussion: Gerdes; Sjovall; v.Wartburg; Littmann; Lelbach;
Krebs; Rubin ••••••••••••..••••••••••••••••••••••••• 197
24) MERRY,J. and V. MARKS, Epsom:
Ethanol and Cortisol Release in Man •••••••••••••••••••••••••••• 199
Discussion: Gerdes; Merry; Carulli; Bode; Littmann; Lieber;
S j ovall ............................................ 206
25) ESTLER,C.-J. and H.P.T. Ammon, Erlangen:
The Influence of Antilipolytic Agents (Ko 592 and B-Pyridyl
carbinol) on Alcohol-Induced Deposition of Fat in the Liver •••• 207
Discussion: See page 216.
26) LIEBER, C.s.,New York:
Origin and Pathogenesis of Fatty Acid Accumulation in the Liver
During Prolonged Ethanol Consumption •..•••••••••••••••••••••••• 212
Discussion: Bode; Lieber; Rubin; Estler; v. Wartburg; Lundquist;
Hakim •••••••••••••••••••••••••••••••••••••••••••••• 216
List of Participants
BLOMSTRAND, R. Department of Clinical Chemistry, Serafimerlasarettet,
Hantverkargatan 2, Stockholm K, Sweden.
BODE,Christiane Medizinische Universitatsklinik Marburg, 355 Marburg/Lahn,
Germany.
BODE, Ch. Medizinische Universit~tsklinik Marburg, 355 Marburg/Lahn,
Germany.
CARULLI,N. Instituto di Clinica Medica Generale e Terapia Medica,
Universita di Modena, Via del Pozzo, Italy.
ESTLER,C.-J. Pharmakologisches Institut der Universitat Erlangen
Nlirnberg, 8520 Erlangen, Universitatsstrasse 22,Germany.
FORSANDER,O. Research Laboratories State Alcohol Monopoly, Alko,
Box 10350, Helsinki 10, Finland.
GERDES ,H. Medizinische Universitatsklinik Marburg, 355 Marburg/Lahn,
Germany.
GOEBELL,H. Medizinische Universitatsklinik Marburg, 355 Marburg/Lahn,
Germany.
GOTTLIEB, L.S. Mallory Institute of Pathology, Boston City Hospital,
Boston, Mass. 02118, U.S.A.
HABERICH,F.J. Institut flir Angewandte Physiologie der Universitat
Marburg, 355 Marburg/Lahn, Germany.
HAKIM,J. Unite de Recherches de Physio-Pathologie Hepatique,
Hopital Beaujon, 100, Bd. du General Leclerc,
92 - Clichy, France.
HEIM,F. Pharmakologisches Institut der Universitat Erlangen
Nlirnberg, 8520 Erlangen, Universitatsstr.asse 22,Germany.
HOFER, G. Institut flir Biochemie I der Universitat Heidelberg,
69 Heidelberg, Akademiestr. 5, Germany.
KARLSON,P. Physiologisch-chemisches Institut, Lehrstuhl I,
Vorklinische Forschungseinheit Lahnberge, 355 Marburg/Lahn,
Germany.
KREBS,H.A. Metabolic Research Laboratory,Nuffield Department of
Clinical Medicine, Radcliffe Infirmary, Oxford,
England.
LELBACH,W.K. Medizinische Universitatsklinik flir Innere- und Nerven
krankheiten, 53 Bonn, Venusberg, Germany.
LIEBER,C.S. Mount Sinai School of Medicine of the City University
of New York, Section of Liver Disease & Nutrition,
Veterans Admin. Hosp., 130 West Kingsbridge Road,
Bronx, N.Y. 10468, U.S.A.
LITTMANN,K.P. Medizinische Universitatsklinik Marburg, 355 Marburg/Lahn,
Germany.
LUNDQUIST ,F. Department of Biochemistry, University of Copenhagen,
Copenhagen, Juliane Maries Vej 30, Denmark.
MANENTI,F. Instituto di Clinica Medica Generale e Terapie Medica,
Universita di Modena, Via del Pozzo, Italy.
x
MARTINI,G.A. Medizinische Universitatsklinik Marburg, 355 Marburg/Lahn,
Germany.
MERRY, J. Epsom & West Park Group Hospital Management Committee,
West Park Hospital, Epsom, Surrey, England.
PAPENBERG, J. Medizinische Universitatsklinik (Ludolf-Krehl-Klinik)
69 Heidelberg, Bergheimer Strasse 58, Germany.
RAIHA,N.C.R. Research Laboratories State Alcohol Monopoly, Alko,
Box 10350, Helsinki 10, Finland.
RUBIN, E. Mount Sinai School of Medicine of The City University
of New York,5th Avenue and 100th Street,New York,
N.Y. 10029, U.S.A.
SALASPURO,M. Huovitie 3, E. 32, Helsinki 40, Finlan~.
SCHIMASSEK,H. Institut fUr Biochemie I der Universitat Heidel
berg, 69 Heidelberg, Akademiestr. 5, Germany.
SCHOLZ,R. Institut fUr Physiologische Chemie und Physika
lische Biochemie der Universitat MUnchen,8 MUnch en
15, Goethestr. 33, Germany.
SJ5VALL,J. Karolinska Institutet, Kemiska Institutionen,
Stockholm, Sweden.
TYGSTRUP,N. Rigshospitalet, Medicinsk Afdeling A, Blegdams
vej 9, 2100 K¢benhavn, Denmark.
WALLI, A.K. Institut fUr Biochemie I der Universitat Heidel
berg, 69 Heidelberg, Akademiestr. 5, Germany.
v.WARTBURG, J.P. Universitat Bern, Medizinisch-chemisches Institut,
3000 Bern, BUhlstrasse 28, Switzerland.
The Development of Alcohol Dehydrogenase
and its Isoenzymes
N.C.R. Raiha and P.H. Pikkarainen
During recent years ethanol has become a frequently used drug in obstetric ma
nagement of premature uterine contractions leading to abortion or premature
birth, due to its inhibitory effect on the release of oxytocin (LUUKKAINEN,
VAISTO, and JARVINEN, 1967). Since ethanol easily crosses the placental mem
branes and its oxidation has a marked effect on metabolic functions of the
liver, we decided to study alcohol dehydrogenase (ADH) and alcohol oxidizing
capacity in the developing mammalian liver. No previous information on this
was available and w.e thought that it would be of general interest to have in
formation concerning the capability of the fetus and the newborn to metabolize
ethanol, since it was used so freely by the obstetricians during human preg
nancy.
First we studied the development of ADH-activity in rat liver (RAlHA, KOSKINEN,
and PIKKARAINEN, 1967). The enzyme activity was measured by the method of
Bonnichsen and Brink in the supernatant of a Triton X-100 treated liver homo
genate and the results were expressed as Units per g wet weight of liver or per
mg soluble protein. Figure 1 shows the development of ADH-activity in rat liver.
1200
I.
~1000
OJ •
0; • f
,~.., 800 •• • • •
" •••
~ I • •
•
l":-! 600 • • • • ••
-O--J • :·1 -I: •
~ 400 • II •
:c:E:> II •• •
•
200 • ,
• •
• ,
0 I f---L-
-6 -4 -2 2 4 6 8 10 12 14 16 18 20 22 24 26
Fetal 81rth Postnatal Adult
AGE IN DAYS
Fig. 1. Development of ADH activity in the
foetal and postnatal rat liver
The enzyme is first detectable in the fetal liver on about the 18th day of
gestation and from this age on there is a fairly linear increase of activity,
2
reaching adult activity on the 18th postnatal day. When expressed per mg
soluble protein the increase is similar. Figure 2 shows the development of the
ethanol oxidizing capacity of liver slices. A close correlation to the increa
sing ADH-activity was found. In order to see whether the measured ADH-activity
-
"::'20
a.
•
.~
•
~o 15 • •• • f
.0 •
'"
-S 10 • •• 0 •
'"
E ••
••
.. • • • •
•
• • •
,
• , , , , , , , , ,
-6 -4 -2 2 4 6 8 10 12 14 16 18 20 22 24 26 I~
Fl2tal Birth Postnatal Adult
AGE IN DAYS
Fig. 2. Development of ethanol-oxidizing capacity
in the foetal and postnatal rat liver
was "inducible" by ethanol during development we administered ethanol to preg
nant mothers and to the postnatal rats at different ages. As seen in Table 1
there was no effect on enzyme activity.
Table 1. Effect of ethanol administration on alcohol dehydrogenase
activity in newborn and postnatal rat liver
Expt. Age of rats when No. of ADH activity
no. killed for assay observations (milliunits/g
(days) wet wt. of liver
1 Ethanol 0 8 416 + 85
Control 0 5 438 "+ 91
2 Ethanol 1 4 589 "+ 74
Control 1 3 594"+ 44
3 Ethanol 8 2 757 -
Control 8 2 754
4 Ethanol 12 4 967 + 47
Control 12 2 975 -
Pregnant rats received 10 % ethanol as the only fluid intake during the latter
half of gestation, and in addition, 375 mg of ethanol (30 %, v/v)/100 g body
wt. by stomach tube daily during the 4 last days of pregnancy. Control rats
received water ad lib. and 0.9 % NaCl by stomach tube during the 4 last days
of gestation. The offspring were studied at birth. Postnatally the litters,
two in each experiment, were divided so that one half received intraperitoneal
injections of 200 mg of ethanol (20 %, v/v)/100 g body wt. daily, the other
half receiving 0.9 % NaCl. Newborn rats were studied 24 hr, and older offspring
72 hr after the first injection. The results are expressed as means ~ S.D.
Each determination represents five pooled livers.
Corticosteroid administration and/or adrenalectomy at birth also had no effect
on the development of ADH-activity. When some properties of ADH were compared