Metabolic Aspects of Alcoholism

308 Pages·1976·11.39 MB·English

by  C. S. Lieber (auth.)

Metabolic Aspects of Alcoholism
Metabolic Aspects
of
Alcoholism
Edited by
CHARLES S. LIEBER
Chief, Section of Liver Disease, Nutrition and Alcoholism,
Veterans Administration Hospital New York
and Professor of Medicine and Pathology
Mount Sinai School of Medicirre (CUNY) New York
MTP
Published by
MTP Press limited
St. Leonard's House
St. Leonardgate
LANCASTER
Copyright © 1977 MTP Press Limited
Softcover reprint of the hardcover 1st edition 1977
No part of this book may be
reproduced in any form without
permission from the publishers,
except for the quotation of
brief passages for the purpose
of review.
ISBN-13: 978-94-011-6155-8 e-ISBN-13: 978-94-011-6153-4
DOI: 10.1007/978-94-011-6153-4
at the Spottiswoode Ballantyne Press
by William Clowes & Sons limited,
London, Colchester and Beccles
Contents
Ust of Contributors vii
Introduction ix
C. S. Lieber
1. Metabolism of Ethanol 1
C. S. Lieber
2. Metabolic Effects of Alcohol on the Uver 31
C. S. Lieber and L. M. DeCarli
3. Metabolic Effects of Alcohol on the Intestine 81
E. Baraona and J. Lindenbaum
4. The Effect of Alcohol on the Heart 117
R. J. Bing and H. Tillmanns
5. Alcohol and Skeletal Disease 135
P. D. Saville
6. Metabolic Aspects of Alcoholism in the Brain 149
E. P. Noble and S. Tewari
7. The Effect of Alcohol on Striated and Smooth Muscle 187
S. A. Geller and E. Rubin
8. Metabolic Effects of Alcohol on the Blood and Bone 215
Marrow
J. Lindenbaum
9. Metabolic Effects of Alcohol on the Endocrine System 249
G. G. Gordon and A. L. Southren
Index 303
I-ist of Contributors
ENRIQUE BARAONA ERNEST P. NOBLE-
Assistant Professor of Medicine, Professor of Medicine,
Mount Sinai School of Medicine (CUNY), University of California, Irvine,
eronx Veterans Administration Hospital, Department of Psychiatry and Human
Bronx, New York 10468, U.S.A. Behavior,
California College of Medicine,
RICHARD J. BING Irvine, California 92717, U.S.A.
Professor of Medicine,
University of Southern California, EMANUEL RUBIN
Huntington Memorial Hospital, Professor and Chairman,
Pasadena, California 91105, U.S.A. Department of Pathology,
Mount Sinai School of Medicine (CUNY),
LEONORE M. DeCARLI New York, New York 10029, U.S.A.
Research Assistant,
Bronx Veterans Administration Hospital, PAUL D. SAVILLE
Bronx, New York 10468, U.S.A. Professor of Medicine,
Chairman, Division of Rheumatology,
STEPHEN A. GELLER Department of Medicine,
Associate Professor of Pathology, West Virginia University,
Mount Sinai School of Medicine (CUNY) Morgantown, West Virginia 26506,
New York, New York 10029, U.S.A. U.S.A.
A. LOUIS SOUTHREN
GARY G. GORDON Professor of Medicine,
Professor of Medicine, Chief, Endocrine Section, Department of
Endocrine Section, Department of Medicine,
Medicine, New York Medical College,
New York Medical College, Flower and Fifth Avenue Hospitals,
Flower and Fifth Avenue Hospitals, New York, New York 10029, U.S.A.
New York, New York 10029, U.S.A.
SUJATA TEWARI
CHARLES S. LIEBER
Assistant Professor-in-Residence,
Professor of Medicine and Pathology,
University of California, Irvine,
Mount Sinai School of Medicine (CUNY), Department of Psychiatry and Human
Chief, Section of Liver Disease, Behavior, California College of Medicine,
Nutrition and Alcoholism
Irvine, California 92717, U.S.A.
Bronx Veterans Administration Hospital,
Bronx, New York 10468, U.S.A.
HARALD TILLMANNS
Research Fellow,
JOHN LINDENBAUM
University of Southern California,
Professor of Medicine,
Los Angeles, California 90007, U.S.A.
Columbia University,
College of Physicians and Surgeons,
Chief, Hematology,
Harlem Hospital Center
New York, New York 10032, U.S.A.
* Presently Director, National Institute on Alcohol Abuse and Alcoholism, Rockville,
Maryland 20852, U.S.A.
Introduction
In the first annual report on Alcohol and. Health to Congress (December,
1971), the then HEW Secretary Elliot L. Richardson called alcohol 'the most
abused drug in the United States'. The report revealed that nine million
Americans are alcohol abusers and that alcoholic individuals represent almost
10 % of the nation's work force. With spreading alcoholism, the incidence of
physical damage due to alcohol has greatly increased. A question which is
often raised is 'in which way does an alcoholic differ from a non-alcoholic?'
Inquiries have focused on psychological make-up, behavioural differences and
socioeconomic factors. More recently, however, physical differences have
been delineated. Prior to the development of various disease entities, chronic
ethanol exposure results in profound biochemical and morphological changes.
Consequently an alcoholic does not respond normally to alcohol, or other
drugs or even other toxic agents. Some of these persistent biochemical and
morphological changes are the consequences of the injurious effects of
ethanol, whereas others may represent the possible adaptive responses to the
profound changes in intermediary metabolism which are a direct and im
mediate consequence of the oxidation of ethanol itself. Differentiation
between the effects of ethanol directly linked to its oxidation, and the adaptive
and injurious effects of ethanol are not simple, and overlap is common. In
general, however, metabolic effects are associated with the presence of
relatively low ethanol concentrations, whereas injurious effects occur with
high ethanol concentrations and/or after prolonged intake. High ethanol con
centrations also produce so-called pharmacological effects. The adaptive phase
is an intermediate stage which follows repeated administration of moderate to
large doses of ethanol. The liver, the main site of ethanol oxidation, displays
the broadest spectrum of metabolic response to ethanol. Other tissues however
can also be severely affected, including brain, gut, heart, endocrine systems,
bone, blood and muscle.
1
Metabolism of Ethanol
C. S. LIEBER
1.1 PATHWAYS OF ETHANOL OXIDATION
1.1.1 The alcohol dehydrogenase pathway (ADH) 2
1.1.2 Microsomal ethanol-oxidizing system (MEOS) 6
1.1.3 Catalase 9
1.2 PATHWAYS OF ACETALDEHYDE METABOLISM 10
1.3 ALTERATION IN THE METABOLISM OF ETHANOL AND
ACETALDEHYDE AFTER CHRONIC ETHANOL CONSUMPTION 11
1.3.1 Accelerated ethanol metabolism after chronic ethanol consumption 11
1.3.1.1 Increase in ethanol metabolism related to the ADH pathway 11
1.3.1.2 Non-ADH-related acceleration of ethanol metabolism 12
1.3.1.3 Energy cost related to stimulated microsomal function 15
1.3.2 Effect of chronic ethanol consumption on acetaldehyde metabolism 16
1.3.2.1 Mitochondrial acetaldehyde oxidation 16
1.3.2.2 Clinical implications of deranged acetaldehyde metabolism 17
References 21
1.1 PATHWAYS OF ETHANOL OXIDATION
Ethanol can be synthesized endogenously in trace amounts! including
bacterial fermentation in the gut2; it is however primarily an exogenous com
pound that is readily absorbed from the gastrointestinal tract. Only 2-10 % of
that absorbed is eliminated through the kidneys and lungs; the rest must be
oxidized in the body, principally in the liver. The rate of disappearance of
ethanol from the blood is indeed remarkably decreased or halted by hepatec
tomy or procedures damaging the liver3. Moreover, the predominant role of
the liver for ethanol metabolism was shown directly in individuals with por
tacaval shunts undergoing hepatic vein catheterization4• Extrahepatic
metabolism of ethanol, although it occurs, is small5,6. This relative organ
specificity of ethanol for the liver probably explains why, despite_the existence
of intracellular mechanisms responsible for redox homeostasis, ethanol oxida
tion produces striking metabolic imbalances in the liver. These effects are
1
METABOLIC ASPECTS OF ALCOHOLISM
Table 1.1 Charaeteristics of ethanol metaboUsm
1. Large caloric load, sometimes in excess of all other nutrients
2. Almost no renal or pulmonary excretion
3. No storage mechanism in the body
4. Oxidation predominantly in the liver
5. No feedback control of rates of ethanol oxidation
aggravated by the lack of feedback mechanism to adjust the rate of ethanol ox
idation to the metabolic state of the hepatocyte, and the inability of ethanol,
unlike other major sources of calories, to be stored or metabolized to a marked
degree in peripheral tissues (Table 1.1). The hepatocyte contains three main
pathways for ethanol metabolism, each located in a different subcellular com
partment: the alc~hol dehydrogenase pathway of the cytosol or the soluble
fraction of the cell, the microsomal ethanol oxidizing system located in the en
doplasmic reticulum and catalase located in the peroxisomes.
1.1.1 The alcohol dehydrogenase pathway (ADH)
The main pathway for ethanol disposition involves alcohol dehydrogenase
(ADH), an enzyme of the cell sap (cytosol) that catalyses the conversion of
ethanol to acetaldehyde. The enzyme has a broad substrate specificity, which
includes dehydrogenation of steroids 7 and omega oxidation of fatty acids8•
These compounds may represent the 'physiological' substrates for ADH,
A. CH3CH20H + NAD+--. CH3CHO + NADH + H+
ADH
B. CH3CH20H + NADPH + H+ + 02 • CH3CHO + NADP+ + 2H20
ME os
r
C. NADPH + ~ + 02 • NADP+ + H202
I
+ NADPH
Oxidase
L
H202 + CH3CH20H----+2H20 + CH3CHO
Catalase
r
D. HYPOXANTHINE+H20 + 02 • XANTHINE + H2<>.:!
+I Xanthine
Oxidase
.....- --H202 + CH3CH20H .2H20 + CH3CHO
Catalase
Figure 1.1 Ethanol oxidation by A, alcohol dehydrogenase (AD H), nicotinamide adenine
dinucleotide (NAD), nicotinamide adenine dinucleotide, reduced form (NADH); B, the hepatic
microsomal ethanol-oxidizing system (MEOS), nicotinamide adenine dinucleotide phosphate
(NADP); C, a combination ofNADPH oxidase and catalase; or D, xanthine oxidase and catalase
2
METABOLISM OF ETHANOL
Table 1.2 Hepatic metabolite concentrations in rats chronically fed ethanol (E) and
in their pair-fed controls (C) 90 min after acute intragastric administration of ethanol
(3 g/kg) or during moderate starvation (7 and 4 pairs, respectively). The metabolite
concentrations are given as means ± SD and npressed in nmol/I fresh weight (from
Domsehke et ",.133)
90 min after 3 g/kg ethanol 16-hour starvation
E C E C
Lactate 1153 ± 303 1369 ± 260 871 ± 192 955 ± 266
Pyruvate 60± 9 43 ± 9 54 ± 8 52 ± 13
Malate 1015 ± 77 1066 ± 101 565 ± 66 494 ± 56
P-Hydroxybutyrate 440 ± 93 720 ± 189 1509 ± 409 1403 ± 251
Acetoacetate 46 ± 17 29 ± 10 268 ± 105 217 ± 41
Glutamate 5163 ± 928 4781 ± 1308 2152 ± 771 1636 ± 346
Ammonia 882 ± 181 712 ± 130 812 ± 297 827 ± 131
a-Oxoglutarate 38 ± 8 23 ± 4 33 ± 9 22 ± 3
although the small amount of endogenous ethanol could also play such a role.
Hydrogen is transferred from ethanol to the cofactor nicotinamide adenine
dinucleotide (NAD), which is converted to its reduced form (NADH) (Figure
lolA). As a net result, ethanol oxidation generates an excess of reducing
equivalents in the liver, primarily as NADH. The altered redox state of the
cytosol can be calculated from the measurement of the lactate and pyruvate in
control rats given ethanol (Tables 1.2 and 1.3). These results are similar to
those obtained by Veech et al.9 The altered redox state in turn is responsible
for a variety of metabolic abnormalities, which will be discussed in a subse
quent chapter. Some of these, such as hyperlactacidaemia, are linked to the
utilization of the excess NADH in the cytosol (Figure 1.2). The H can also be
transferred to NADP and the increased NADPH can be utilized for synthetic
pathways in the cytosol and microsomal functions, as illustrated in Figure 1.2
and discussed in more detail subsequently.
Some of the excess hydrogen equivalents can also be transferred from the
Table 1.3 Cytoplasmic and mitochondrial ratios of free pyridine nucleotides in rat
livers calculated from values given in Table 1.2. The values compUed are the means
± SD of the ratios calculated for each individual animal (from Domsehke et al.133)
90 min after 3 g/kg ethanol 16-hour starvation
E C E C
Cytoplasm
(NAD)/
(NADH) 485 ± 96 292 ± 70 574 ± 143 537 ± 122
(NADP)/
(NADPH) 0.00198 ± 0.00036 0.00138 ± 0.00031 0.00327 ± 0.00078 0.00358 ± 0.00102
Mitochondria
(NAD)/
(NADH) 2.25 ± 0.79 0.82 ± 0.27 3.60 ± 0.79 3.21 ± 0.84
(NADP)/
(NADPH) 2.560 ± 0.540 1.490 ± 0.530 5.060 ± 1. 720 4.010 ± 1.090
3
METABOLIC ASPECTS OF ALCOHOLISM
mmn
G1UCOSl ~ ETHANOL iIYP!@IIICOIi,I]
Figure 1.2 Metabolism of ethanol in the hepatocyte. Pathways which are decreased after
ethanol abuse are represented by dashed lines. ADH, alcohol dehydrogenase: MEOS,
microsomal ethanol-oxidizing system; NAD, nicotinamide adenine dinucleotide; NADH,
nicotinamide adenine dinucleotide, reduced form; NADP, nicotinamide adenine dinucleotide
phosphate; NADPH, nicotinamide adenine dinucleotide phosphate, reduced form
cytosol into the mitochondria. Since the mitochondrial membrane is normally
impermeable to NADH, it is generally believed that the reducing equivalents
of NADH are transferred to the mitochondrial respiratory chain via shuttle
mechanisms. Thus, NADH reduces the oxidized partner of the shuttle pair
(i.e. oxaloacetate) in the presence of the cytoplasmic enzyme, thereby
regenerating NAD. The reduced component (i.e. malate) now traverses the
mitochondrial membrane where it reacts with the mitochondrial enzyme and
NAD (or FAD in the case of a-glycerophosphate) to generate NADH or FADH
plus the oxidized partner. FADH and NADH are oxidized by the respiratory
chain and the oxidized partner enters the cytoplasm where it is available for
another round of the shuttle cycle. The altered redox state of the mitochondria
can be calculated from changes of the j:l-hydroxybutyrate and acetoacetate in
control rats given ethanol (Tables 1.2 and 1.3). Several 'shuttle' mechanisms
have been proposed, three of which are illustrated in Figure 1.2, namely the
malate cycle10 (quantitatively probably the most important one), the fatty
acid elongation cyclell,12, and the a-glycerophosphate cycle13. Whereas the
latter shuttle seems to play an important role in some tissues, i.e. insect flight
muscle, its significance in the liver has been questioned because the activity
of hepatic a-glycerophosphate dehydrogenase is low, except in special
4