Alcohol Metabolism

NIH Public Access
Author Manuscript
Clin Liver Dis. Author manuscript; available in PMC 2013 November 01.

NIH-PA Author Manuscript

Published in final edited form as:
Clin Liver Dis. 2012 November ; 16(4): 667–685. doi:10.1016/j.cld.2012.08.002.

ALCOHOL METABOLISM
Arthur I Cederbaum, PhD
Department of Pharmacology and Systems Therapeutics Mount Sinai School of Medicine One
Gustave L Levy Place New York, New York 10029 [email protected] 212-241-9352
(Ph) 212-996-7214 (Fax)

Keywords
Alcohol dehydrogenase; Cytochrome P4502E1; Acetaldehyde metabolism; Hepatic redox state;
Alcohol absorption, distribution and elimination; Isoforms of alcohol dehydrogenase; Metabolic
Adaptation to alcohol

NIH-PA Author Manuscript

The goal of this Review is to describe the pathways responsible for the metabolism of
alcohol (ethanol) and understand the factors which regulate this oxidation. Understanding
pathways of alcohol oxidation is important because it allows us to:
1.

Learn how the body disposes of alcohol and its metabolites.

2.

Discern some of the factors which influence this process.

3.

Learn how alcohol influences the metabolism of nutrients and drugs.

4.

May learn how alcohol damages various organs.

5.

May help to identify individuals who are at increased or decreased risk for alcohol
toxicity.

Some suggested causes for alcohol toxicity are linked to changes produced by the
metabolism of ethanol such as redox state changes in the NAD+/NADH ratio, acetaldehyde
formation, oxidative stress, and mitochondrial function are shown in LIST 1 and will be
discussed below. General reviews on alcohol metabolism can be found in (1–9).

NIH-PA Author Manuscript

Distribution of Alcohol in the Body
The equilibrium concentration of alcohol in a tissue depends on the relative water content of
that tissue. Equilibration of alcohol within a tissue depends on the water content, rate of
blood flow and the tissue mass Ethanol is practically insoluble in fats and oils, although like
water, it can pass through biological membranes. Ethanol distributes from the blood into all
tissues and fluids in proportion to their relative content of water. The concentration of
ethanol in a tissue is dependent on the relative water content of the tissue, and reaches
equilibrium quickly with the concentration of ethanol in the plasma. There is no plasma
protein binding of alcohol.

© 2012 Elsevier Inc. All rights reserved
Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our
customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of
the resulting proof before it is published in its final citable form. Please note that during the production process errors may be
discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
DISCLOSURES: None to report.

Cederbaum

Page 2

NIH-PA Author Manuscript

The same dose of alcohol per unit of body weight can produce very different blood alcohol
concentrations in different individuals because of the large variations in proportions of fat
and water in their bodies, and the low lipid: water partition coefficient of ethanol. Women
generally have a smaller volume of distribution for alcohol than men because of their higher
percentage of body fat. Women will have higher peak blood alcohol levels than men when
given the same dose of alcohol as g per kg body weight but no differences occur when given
the same dose per liter of body water. First pass metabolism of alcohol by the stomach,
which may be greater in males, may also contribute to the higher blood alcohol levels found
in women (10,11).
The breath analyzer test for estimating blood alcohol concentrations is dependent on the
diffusion of ethanol from pulmonary arterial blood into the alveolar air. The ethanol vapor in
breath is in equilibrium with the ethanol dissolved in the water of the blood at a blood :
breath partition coefficient of about 2100:1. An excellent recent review which summarizes
many of these pharmacokinetic interactions can be found in (12).

Factors Affecting Alcohol Absorption

NIH-PA Author Manuscript

LIST 2 describes some factors which affect the absorption of alcohol. Absorption of alcohol
from the duodenum and jejunum is more rapid than from the stomach, hence the rate of
gastric emptying is an important determinant of the rate of absorption of orally administered
alcohol.

NIH-PA Author Manuscript

1.

Alcohol crosses biological membranes by passive diffusion, down its concentration
gradient. Therefore, the higher the concentration of alcohol, the greater is the
resulting concentration gradient, and the more rapid is the absorption.

2.

Rapid removal of alcohol from the site of absorption by an efficient blood flow will
help maintain the concentration gradient and thereby promote absorption.

3.

Alcohol has irritant properties and high concentrations can cause superficial
erosions, hemorrhages and paralysis of the stomach smooth muscle. This will
decrease alcohol absorption,

4.

Peak blood alcohol levels are higher if ethanol is ingested as a single dose rather
than several smaller doses, probably because alcohol concentration gradient will be
higher in the former case.

5.

In general, there is little difference in the rate of absorption of the same dose of
alcohol administered in the form of different alcoholic beverage i.e., blood ethanol
concentration is not significantly influenced by the type of alcoholic beverage
consumed.

6.

The presence of food in the stomach retards gastric emptying and thus will reduce
the absorption of alcohol, the “don't drink on an empty stomach” concept. Meals
high in either fat, or carbohydrate or protein are equally effective in retarding
gastric emptying. The major factor governing the absorption rate of alcohol is
whether the drink is taken on an empty stomach or together with or after a meal
(13–15).

The blood alcohol concentration is determined by the amount of alcohol consumed, by the
presence or absence of food in the stomach, factors which affect gastric emptying and the
rate of alcohol oxidation.

Clin Liver Dis. Author manuscript; available in PMC 2013 November 01.

Cederbaum

Page 3

First Pass Metabolism of Alcohol in the Stomach
NIH-PA Author Manuscript

Some of the alcohol which is ingested orally does not enter the systemic circulation but may
be oxidized in the stomach by ADH isoforms such as σADH and class I and class III ADH.
This first pass metabolism could modulate alcohol toxicity since its efficiency determines
the bioavailability of alcohol. Ethanol is rapidly passed into the duodenum from the stomach
in the fasted state. This will minimize first pass metabolism and thereby play a role in the
higher blood alcohol concentrations observed in the fasted versus the fed state.
First pass metabolism has been reported to be low in alcoholics, especially in alcoholic
women because of decreased ADH activity. This may be important in the increased
sensitivity to alcohol and the higher blood alcohol concentrations in women than in men
after an equivalent oral dose of ethanol. Several drugs, including H2 receptor blockers such
as cimetidine or ranitidine, or aspirin inhibit stomach ADH activity. This will decrease first
pass metabolism by the stomach, and hence, increase blood alcohol concentrations.
The overall significance of first pass metabolism by the stomach is controversial. The speed
of gastric emptying modulates gastric and hepatic first pass metabolism of alcohol.
Considering the greater levels of alcohol metabolizing enzymes in the liver compared to the
stomach, it seems likely that liver plays the major role in alcohol metabolism (16–18).

NIH-PA Author Manuscript

Alcohol Metabolism-General Principles (1–9)
LIST 3 describes some general principles of alcohol metabolism.
The major enzyme system(s) responsible for the oxidation of ethanol, alcohol
dehydrogenase, and to a lesser extent, the cytochrome P450-dependent ethanol-oxidizing
system, are present to the largest extent in the liver. Liver damage lowers the rate of alcohol
oxidation and hence, elimination from the body. Ethanol is a nutrient and has caloric value
(about 7 kcal per gram; carbohydrates and protein produce 4 kcal per gram, while fat
produces 9 kcal). However, unlike carbohydrates (glycogen in liver and muscle) and fat
(triglycerides in adipose tissues and liver) which can be stored and utilized in time of need
e.g. fasting, alcohol is not stored and remains in body water until eliminated. Whereas
metabolism of the major nutrients is under hormonal control, e.g insulin/glucagon, leptin,
catecholamine, thyroid hormones, generally, there is little hormonal regulation to pace the
rate of alcohol elimination. In view of these considerations, there is a major burden on the
liver to oxidize alcohol in order to remove this agent from the body.

NIH-PA Author Manuscript

Animals with small body weight metabolize alcohol at faster rates than larger animals e.g.
the rate of alcohol elimination in mice is 5 times greater than the rate in humans. These rates
of alcohol metabolism correlate with the basal metabolic rate for that species, indicating that
the capacity to oxidize ethanol parallels the capacity to oxidize the typical nutrients.
However, it is important to note that alcohol-derived calories are produced at the expense of
the metabolism of normal nutrients since alcohol will be oxidized preferentially over other
nutrients (19–23).

Kinetics of Alcohol Elimination In-vivo (12–14)
Alcohol elimination was originally believed to be a zero-order process, meaning that alcohol
was removed from the body at a constant rate, independent of the concentration of alcohol.
Since the Km of most ADH isozymes for ethanol is low (about 1 mM), ADH is saturated at
low concentrations of alcohol, hence, the overall elimination process proceeds at maximal
velocity and is independent of the alcohol concentration. However, linearity is not observed
at low alcohol concentration since ADH is no longer saturated with ethanol. Alcohol

Clin Liver Dis. Author manuscript; available in PMC 2013 November 01.

Cederbaum

Page 4

NIH-PA Author Manuscript

elimination now follows Michaelis-Menten kinetics; the rate of change in the concentration
of alcohol depends on the concentration of alcohol and the kinetic constants Km and Vmax
(23,24).
In addition, because the metabolism of alcohol by CYP2E1 and some ADH isozymes, such
as ADH4 involves a high Km for alcohol system, a concentration-dependent rate of ethanol
elimination can be observed, with higher rates of alcohol elimination at higher blood alcohol
concentrations. Because of this concentration dependence, it is not possible to estimate one
single rate of alcohol metabolism. Concentration-dependent metabolism of alcohol has been
observed in some, but not all studies on alcohol elimination (25,26).
Although rates vary widely, the “average” metabolic capacity to remove alcohol is about
170 to 240 g per day for a person with a body weight of 70 kg. This would be equivalent to
an average metabolic rate of about 7 g/hr which translates to about one drink per hr. Since
alcoholics may consume 200 to 300 g of ethanol per day, equivalent to 1400 to 2100 kcal,
consumption of normal nutrients is usually significantly decreased (typically, 2000–3000
kcal consumed per day in the absence of alcohol).

Factors Modifying the Alcohol Elimination Rate
NIH-PA Author Manuscript

There is a 3–4 fold variability in the rate of alcohol elimination by humans because of
various genetic and environmental factors described below.
Sex
There is a faster rate of alcohol elimination by women when rates are corrected for lean
body mass. Since women have smaller body size and therefore smaller lean body mass,
ethanol elimination per unit lean body mass is higher in women. Men and women generally
have similar alcohol elimination rates when results are expressed as g per hr or g per liter
liver volume. Because of first pass metabolism by the stomach, it is possible that a given
oral dose of alcohol may produce a higher blood ethanol concentration in females than
males (11,15).
Age
Very young animals have low alcohol elimination rates because ADH (and CYP2E1) are not
fully expressed. Fetal liver eliminates alcohol very poorly which may have consequences for
fetal alcohol syndrome. There may be a small decline in alcohol elimination with aging,
perhaps due to decreased liver mass, or body water content.

NIH-PA Author Manuscript

Race
Alcohol elimination is reported to be somewhat higher in subjects expressing the beta3 class
I ADH isoforms compared with individuals who only express the beta 1 isoform (see ADH
alleles discussed below). Some studies, but not all, suggest an increased rate of alcohol
elimination by native Americans compared to Caucasians. Rates of alcohol elimination by
Chinese are similar to those of Caucasians. Liver mass may explain ethnic and gender
differences in alcohol elimination rates. More research on possible population differences in
alcohol elimination is required (27,28).
Food
Alcohol metabolism is higher in the fed nutritional state as compared to the fasted state
because ADH levels are higher, and the ability of substrate shuttle mechanisms (see below)
to transport reducing equivalents into the mitochondria is elevated. Food may also increase
liver blood flow. The sugar fructose increases alcohol metabolism by providing substrates
Clin Liver Dis. Author manuscript; available in PMC 2013 November 01.

Cederbaum

Page 5

NIH-PA Author Manuscript

which help to convert NADH to NAD+, and by enhancing mitochondrial oxygen uptake.The
increase in the alcohol elimination rate by food was similar for meals of different
compositions as there was no difference between carbohydrate, fat and protein on alcohol
metabolic rate (29–31).
Biological Rhythms
The rate of alcohol elimination varies with the time of day, being maximal at the end of the
daily dark period. This may be related to a body temperature cycle.
Exercise
unclear literature, most studies report a small increase in alcohol elimination rate, perhaps
due to increased body temperature or catecholamine release.
Alcoholism
Heavy drinking increases alcohol metabolic rate ( see below). Advanced liver disease will
decrease the rate of ethanol metabolism.
Drugs

NIH-PA Author Manuscript

Agents which inhibit ADH (pyrazoles, isobutyramide) or compete with ethanol for ADH
(methanol, ethylene glycol) or which inhibit the mitochondrial respiratory chain will
decrease the alcohol elimination rate. Antabuse (disulfiram) by inhibiting the elimination of
acetaldehyde slows alcohol metabolism.
Scheme for Alcohol Metabolism—Fig 1 summarizes the basic overall metabolism of
alcohol.

NIH-PA Author Manuscript

Step 1

catalyzed by the enzyme alcohol dehydrogenase, which is present largely in
the liver, and consists of a family of isoforms. A vitamin-related cofactor,
nicotinamide adenine dinucleotide ( NAD) (derived from the vitamin niacin)
is required to accept reducing equivalents (hydrogen atoms and electrons)
from the alcohol. As a result, the ethanol is oxidized to the product
acetaldehyde and the vitamin cofactor, NAD+ is reduced to the product
NADH + H+ (note two hydrogens are removed from alcohol). The ADH
reaction is reversible.

Step 2

is catalyzed by the enzyme aldehyde dehydrogenase. Acetaldehyde is
oxidized to acetate; NAD+ is the cofactor, and is reduced to NADH. The
ALDH reaction is essentially irreversible. Much of the acetaldehyde produced
from the oxidation of alcohol is oxidized in the liver to acetate; circulating
levels of acetaldehyde are low under normal conditions.

Step 3

Much of the acetate produced by the oxidation of acetaldehyde leaves the
liver and circulates to peripheral tissues where it is activated to a key Acetyl
CoA. Acetyl CoA is also the key metabolite produced form all major
nutrients- carbohydrate, fat and excess protein. Thus, carbon atoms from
alcohol wind up as the same products produced from the oxidation of
carbohydrate, fat, and protein, including CO2, fatty acids, ketone bodies, and
cholesterol; which products are formed depends on the energy state and the
nutritional and hormonal conditions.

Clin Liver Dis. Author manuscript; available in PMC 2013 November 01.

Cederbaum

Page 6

ALCOHOL DEHYDROGENASE (4,32–34)
NIH-PA Author Manuscript

ADH is a zinc-containing enzyme, consisting of two subunits of 40 kDa each. It functions to
oxidize endogenous alcohol produced by microorganisms in the gut, to oxidize exogenous
ethanol and other alcohols consumed in the diet, and to oxidize substrates involved in steroid
and bile acid metabolism. The enzyme has broad substrate specificity, oxidizing many
primary or secondary alcohols. ADH is localized in the cytosolic fraction of the cell. ADH is
found in highest amount in the liver, followed by GI tract, kidneys, nasal mucosa, testes, and
uterus.

NIH-PA Author Manuscript

Multiple forms of ADH exist in human liver and their properties are reviewed in TABLE 1.
CLASS 1 ADH contains three genes, ADH1, ADH2 and ADH3 which code for the
following subunits α(ADHIA), β1, β2 and β3(ADHIB),and γ1 and γ2(ADH1C). These
different subunits and polymorphic forms can combine to produce a variety of homo-or
hetero-dimers e.g., αα, β1β1, αβ2. The forms are found primarily in the liver. The class I
ADH forms are mainly responsible for the oxidation of alcohol. In a new classification, the
family members have been classified into five distinct classes, designated ADH1 – ADH5,
on the basis of the structural and kinetic characteristics. Human ADH genes that encode the
subunit polypeptides α, β1, β2, β3, γ1, γ2, π, χ and (or named σ) are designated ADH1A
(old ADH1), ADH1B*1 (old ADH2*1), ADH1B*2 (old ADH2*2), ADH1B*3 (old
ADH2*3), ADH1C*1 (old ADH3*1), ADH1C*2 (old ADH3*2), ADH2(old ADH4),
ADH3(old ADH5) and ADH4 (old ADH7), respectively. The ADH5 (old ADH6)-encoding
polypeptide has not been given a Greek letter.
CLASS II ADH
The ADH4 gene codes for the π subunit, which produces ππ homodimers in the liver and to
a lesser extent in kidney and lung. The high Km for alcohol may make this enzyme more
important in metabolism of high concentrations of alcohol.
CLASS III ADH
The ADH5 gene codes for the χ subunit which produces χχ homodimers. This isoform has
a very high Km for alcohol (>2 M).
CLASS V ADH
The mRNA product produced by the ADH6 gene is present in liver and stomach, but the
protein has not been characterized.

NIH-PA Author Manuscript

CLASS IV ADH
The ADH7 gene encodes the sigma subunit which is very efficient in oxidizing retinol to
retinal. This form is present in the stomach.
The class I ADH isoforms play the most important role in alcohol oxidation (33–37). ADH
is present in low levels in fetal liver and the fetus eliminates ethanol very slowly because of
this late maturation of ADH genes. The ability to form many isoforms, with varying kinetic
properties, probably contributes to the large variability in the capacity for metabolizing
alcohol that human populations exhibit. The strong sensitivity of the Class I ADH to
pyrazole inhibition explains the powerful inhibition of alcohol metabolism by these agents.
Control of ADH activity is complex and involves:
a)

dissociation of the product NADH is rate limiting step

b)

subject to product inhibition by NADH and acetaldehyde

Clin Liver Dis. Author manuscript; available in PMC 2013 November 01.

Cederbaum

Page 7

c)

subject to substrate inhibition by high concentrations of ethanol

NIH-PA Author Manuscript

Alcohol oxidation is generally limited by the maximum capacity of ADH. The amount of
ADH in the liver is greater in the fed than the fasted state which plays a major role in the
increased rate of alcohol oxidation in the fed state (38,39). Inhibitors of ADH inhibit ethanol
oxidation in direct proportion to their potency as inhibitors of ADH. Hormonal effects on
ADH are complex; some stimulation is found after treatment with growth hormone,
epinephrine or estrogens. Thyroid hormones and androgens inhibit ADH activity.

NIH-PA Author Manuscript

The polymorphic forms of ADH (Class I ADH1B, ADH1C) vary to some extent in different
racial groups as shown in TABLE 2. To date, there are no clear associations between the
various ADH isozymes and the development of alcoholic liver disease, or the susceptibility
to alcohol actions, or the propensity to consume ethanol. Studies which have investigated the
association between alcoholism and alcohol-induced liver damage with the ADH2, ADH3,
CYP2E1 and ALDH2 polymorphisms are not conclusive. A large meta-analysis (36),
showed that carriers of the ADH2*1 and ADH3*2 alleles, the less active ethanol
metabolizing alcohol dehydrogenases, and the highly active ALDH2*1allele had an
increased risk of alcoholism. This likely reflects low accumulation of acetaldehyde in these
individuals. In liver disease, ALDH2*1 is a protective factor as it removes toxic
acetaldehyde. Neither the ADH2 nor the ADH3 polymorphism were implicated in the
development of liver disease. Allelic variants of CYP2E1 were not involved in determining
the risk of alcoholism or in alcoholic liver disease. Further research in this area is required,
as is research on what other substrates the various ADH isoforms oxidize.

Hepatic Redox State (40–42)
Because the ADH and ALDH2 reactions reduce NAD+ to NADH, the cellular NAD+/
NADH redox ratio is lowered as a consequence of ethanol metabolism. This has profound
effects on other liver metabolic pathways which require NAD+ or are inhibited by NADH.
Since the ADH reactions occur in the cytosol, the cytosolic NAD+/NADH redox ratio will
be lowered. This ratio is reflected by the pyruvate/lactate ratio because of the reaction.

NIH-PA Author Manuscript

Since the ALDH reaction occurs largely in the mitochondria, the mitochondrial NAD+/
NADH redox ratio will be lowered. This reaction is reflected by the beta hydroxybutyrate/
acetoacetate ratio because of the reaction.

Important reactions inhibited because of this decreased NAD+/ NADH redox ratio are
1.

Glycolysis

2.

Citric Acid Cycle (ketogenesis favored)

3.

Pyruvate Dehydrogenase

4.

Fatty Acid Oxidation

5.

Gluconeogenesis

Clin Liver Dis. Author manuscript; available in PMC 2013 November 01.

Cederbaum

Page 8

Reoxidation of NADH Generated by the ADH Reaction
NIH-PA Author Manuscript

To maintain effective rates of alcohol oxidation by ADH, it is important to regenerate NAD
+ from the NADH produced by the ADH reaction. Under certain conditions, the rate of
oxidation of alcohol can be limited by the reoxidation of NADH. The major system for
reoxidizing NADH is the mitochondrial electron transfer system. By coupling NADH
reoxidation to this system, energy will be produced from alcohol metabolism (7 kcal per g
ethanol). Fig 2 shows the typical mitochondrial respiratory chain found in all tissues except
the red blood cell. Note the 4 complexes which make up the chain. As electrons or reducing
equivalents pass through complexes I, III and IV, an energized electrochemical and pH
gradient is developed which is used to synthesize ATP via complex V, the ATP synthase
( 43,44).

Substrate Shuttles

NIH-PA Author Manuscript

Because intact mitochondria are not permeable to NADH, it is necessary to transfer the
reducing equivalents of NADH present in the cytosol into the mitochondria by substrate
shuttle mechanisms. The two major substrate shuttles are the -glycerophosphate shuttle
and the malate-aspartate shuttle (Fig 3). The malate-aspartate shuttle plays the major role in
transferring reducing equivalents into the mitochondria (45–48). The rate of alcohol
oxidation can be limited by the transfer of reducing equivalents into mitochondria or by the
actual capacity of the respiratory chain to oxidize these reducing equivalents. Shuttle
capacity may become limiting under fasting metabolic states as the levels of shuttle
components decrease. This may contribute to the lower rates of alcohol oxidation (in
addition to lower ADH content) in the fasting metabolic state. Agents or conditions which
enhance reoxidation of NADH by the respiratory chain can increase the rate of alcohol
metabolism e.g. uncoupling agents can accelerate ethanol oxidation in the fed metabolic
state (38,39).

Catalase-Dependent Oxidation of Alcohol

NIH-PA Author Manuscript

Catalase, a heme containing enzyme, is found in the peroxisomal fraction of the cell. This is
an important antioxidant enzyme since it normally catalyzes the removal of H2O2 (reaction
b above) but it can also oxidize alcohol as shown in reaction (a) above. This pathway is
limited by the rather low rates of H2O2 generation produced under physiological cellular
conditions (less than 4 umol/g liver/hr, only 2% that of alcohol oxidation) and appears to
have an insignificant role in alcohol oxidation by the liver.
A number of the central nervous system effects of ethanol are mediated by acetaldehyde.
Because circulating acetaldehyde levels are very low, the metabolism of alcohol to
acetaldehyde by the brain has been a major research area in alcohol research. Catalase is
present throughout the brain, in the peroxisomes. Inhibitors of catalase were reported to
depress oxidation of alcohol to acetaldehyde by the brain. Acetaldehyde derived from
catalase-dependent oxidation of alcohol in the brain has been suggested to play a role in the
development of tolerance to alcohol, to voluntary ethanol consumption and to the positive

Clin Liver Dis. Author manuscript; available in PMC 2013 November 01.

Cederbaum

Page 9

reinforcing actions of ethanol, perhaps via interaction with catecholamines to produce
various condensation products (49–51).

NIH-PA Author Manuscript

Microsomal (Cytochrome P450) Oxidation of Ethanol

Cytochrome P450s are a family of heme enzymes which are involved in the oxidation of
steroids, fatty acids, and numerous xenobiotics ingested from the environment. Highest
levels of cytochrome P450 are in the liver, where they are present mainly in the endoplasmic
reticulum (microsomal fraction). Some P450's are also found in mitochondria. P450
functions in conjunction with other microsomal enzymes such as NADPH-cytochrome P450
reductase and cytochrome b5 (52–54).There are many isoforms of P450; over 100 gene
families have been identified. The P450s arranged in families based on sequence
homologies. CYP2E1 is a P450 which has the highest activity for oxidizing alcohol to
acetaldehyde. Besides ethanol, CYP2E1 can oxidize many other compounds including
acetone, benzene, and other alcohols. A clear physiological function for CYP2E1 has not
been identified. Some of the significant properties of CYP2E1 are listed in LIST 4 (55–58).

NIH-PA Author Manuscript

The Km of CYP2E1 for alcohol is 10 mM ,10-fold higher than the Km of ADH for ethanol
but still within the range of alcohol concentrations seen in social drinking. At low alcohol
concentrations, CYP2E1 may account for about 10% of the total alcohol oxidizing capacity
of the liver. However in view of its higher Km, the relevance of CYP2E1 in ethanol
oxidation increases as blood alcohol concentrations increase. Alcohol oxidation increases at
higher ethanol concentrations, and much of this increase is due to CYP2E1 metabolism of
alcohol Many P450s are induced by their substrates; this helps to remove the xenobiotic
from the body. CYP2E1 levels are increased by chronic ethanol administration by a
mechanism largely involving protection of the enzyme against proteolysis by the
macromolecular proteasome complex. CYP2E1 is also induced in diabetics, in the fasted
nutritional state and by certain drugs. Because of its inducibility, CYP2E1 may play an
important role in alcohol metabolism after chronic ethanol consumption, i.e. in alcoholics.
As many as 13 different CYP2E1 polymorphisms have been identified. Some of these may
be important as risk factors for carcinogenicity of tobacco or certain toxins; however, there
is no evidence linking any of these polymorphisms to the frequency of alcohol liver damage.

Alcohol-Drug Interactions
NIH-PA Author Manuscript

Since ethanol and certain drugs compete for metabolism by CYP2E1, active drinkers will
often display an enhanced sensitivity to certain drugs as alcohol will inhibit the metabolism
of the drug and thereby prolong its half-life. Conversely, since CYP2E1 is induced after
chronic alcohol consumption, metabolism of drugs which are also substrates for CYP2E1
will be increased. This will decrease the half-life of the drug, and thus decrease the
effectiveness of the drug when ethanol is not present. CYP2E1 is very active in oxidizing
many chemicals to reactive intermediates, e.g. carbon tetrachloride, benzene, nitrosamines,
acetaminophen, halothane. Toxicity of these agents is enhanced in alcoholics (55,57–59).
The CYP2E1 catalytic turnover cycle results in the production of large amounts of reactive
oxygen intermediates such as the superoxide radical and hydrogen peroxide. This may be
important in mechanisms of alcoholic liver injury involving oxidative stress (60). Regulation
of CYP2E1 is complex involving transcription, translational and protein turnover
mechanisms.

Clin Liver Dis. Author manuscript; available in PMC 2013 November 01.

Cederbaum

Page 10

Metabolic Adaptation (Tolerance)
NIH-PA Author Manuscript

Besides CNS adaptation, alcoholics (in the absence of liver disease) often display an
increased rate of blood ethanol clearance. This is metabolic tolerance or adaptation.
Suggested mechanisms for this metabolic tolerance are shown in LIST 5 (55,61–63).

NIH-PA Author Manuscript

1.

Class I ADH is not inducible. Further work with the many human isoforms is
needed.

2.

Substrate shuttle capacity and transport of reducing equivalents into the
mitochondria is not altered by chronic alcohol consumption.

3.

A major theory to explain metabolic adaptation – the “Hypermetabolic state
hypothesis “ – postulates that changes in thyroid hormone levels increases (Na+ +
K+)-activated ATPase, with the subsequent increase of ADP levels. This increases
the state 3 mitochondrial oxygen consumption, therefore, increasing NADH
reoxidation. Increased oxygen consumption may cause hypoxia, especially to
hepatocytes of zone 3 of the liver acinus, the region where alcohol toxicity
originates (centrilobular hypoxia hypothesis).

4.

CYP2E1 levels are enhanced after alcohol treatment Since CYP2E1 is the most
active P450 for oxidizing alcohol, this may play an important role in metabolic
tolerance.

5.

Ethanol, perhaps via increasing endotoxin levels, may activate non-parenchymal
cells such as Kupffer cells to release mediators (cytokines and prostaglandins)
which stimulate oxygen consumption, thereby NADH reoxidation, by parenchymal
cells.

The so-called swift increase in alcohol metabolism (SIAM) refers to an increased rate of
ethanol metabolism within a few hours after alcohol administration in vivo or in vitro.
Mechanisms responsible for SIAM are quite complex and appear to involve three major
pathways, the mitochondria, the peroxisome and endotoxin activation of Kupffer cells (64).

Zonal Metabolism of Alcohol in the Hepatic Acinus (65–67)
Liver injury after chronic alcohol treatment originates in the perivenous zone of the hepatic
lobule. Possible factors to explain this include:
1.

NIH-PA Author Manuscript

Oxygenation is low in this zone since there is an oxygen gradient across the liver
lobule and less oxygen reaches the hepatocytes in the perivenous zone. This is
exacerbated after chronic alcohol administration which increases hepatic oxygen
uptake, so even less oxygen reaches perivenous hepatocytes

2. & 3-ADH and ALDH2, and rates of alcohol and acetaldehyde metabolism are evenly
distributed across the liver lobule. However, because of the lower oxygen
tension, there is a more pronounced reduction of the hepatic redox state
produced by ethanol in the perivenous zone
4.

CYP2E1 is largely in the perivenous zone which explains why toxicity of drugs
metabolized by CYP2E1 to reactive metabolites, e.g. CCl4, or acetaminophen
occurs in the perivenous zone.

5.

Level of antioxidants, such as glutathione are lower in the perivenous zone.

Clin Liver Dis. Author manuscript; available in PMC 2013 November 01.

Cederbaum

Page 11

Other Pathways of Alcohol Metabolism
1. Conjugation reactions

NIH-PA Author Manuscript

Ethanol can react with glucuronic acid to form ethylglucuronide. Such soluble conjugates
are readily excreted. Cofactor availability and the poor affinity for alcohol by most
conjugation enzymes limit these pathways. Ethyl glucuronide (68) is a non-volatile, watersoluble direct metabolite of ethanol. It can be detected in body fluids, tissue, sweat and hair
for an extended time after alcohol has been eliminated from the body. These led to the
suggestion that ethyl glucuronide may be a marker for alcohol consumption or for the
detection of relapse of alcoholics. Ethyl glucuronide is not detectable in abstinent patients,
non-drinkers or teetotalers and is thus specific for alcohol consumption.
3. Fatty Acyl Synthases

NIH-PA Author Manuscript

Fatty acid ethyl ester synthases catalyze the reaction between ethanol and a fatty acid to
produce a fatty acyl ester. These synthases are present in most tissues, especially the liver
and pancreas, organs most susceptible to alcohol toxicity (69). These esters are synthesized
in the endoplasmic reticulum, and transported to the plasma membrane and then removed
from the cell by binding to lipoproteins and albumin and transported in the circulation. Fatty
acid ethyl esters can be toxic, inhibiting DNA and protein synthesis. When oxidative
metabolism of ethanol is blocked, there is an increase in ethanol metabolism to the fatty acid
ethyl ester. These esters can be detected in the blood after alcohol is no longer detectable
and therefore detection of fatty acid ethyl esters may serve as a marker of alcohol intake.

Acetaldehyde Metabolism
The balance between the various ADH and ALDH isoforms regulates the concentration of
acetaldehyde, which is important as a key risk factor for the development of alcoholism (70–
74). Most of the acetaldehyde produced from the oxidation of alcohol is further oxidized in
the liver by a family of ALDH isoforms. Major ALDH isoforms exist in the mitochondrial,
microsomal, and cytosolic compartments. Mitochondria contain a low Km ALDH in the
matrix space (class II ALDH) and a high Km ALDH in the outer membrane, microsomes
contain a high Km ALDH, while the cytosol contains an intermediate (class I ALDH) and a
high Km (class III ALDH) ALDH. Acetaldehyde can also be oxidized by aldehyde oxidase,
xanthine oxidase, and by CYP2E1, but these are insignificant pathways. The low Km
mitochondrial ALDH oxidizes most of the acetaldehyde produced from the oxidation of
alcohol, although in human liver, the class I cytosolic ALDH may also contribute (75). The
class I and II ALDHs are tetrameric enzymes, with subunit molecular weights of 54 kDa.

NIH-PA Author Manuscript

In general, the capacity of ALDH to remove acetaldehyde exceeds the capacity of
acetaldehyde generation by the various pathways of alcohol oxidation. Therefore, circulating
levels of acetaldehyde are usually very low. Chronic alcohol consumption decreases
acetaldehyde oxidation, either due to decreased ALDH2 activity or to impaired
mitochondrial function. Acetaldehyde generation is increased by chronic alcohol
consumption because of metabolic adaptation. As a result, circulating levels of acetaldehyde
are usually elevated in alcoholics because of increased production, decreased removal or
both.
The basis of action for certain alcohol-aversive drugs such as disulfiram (Antabuse) or
cyanamide is to inhibit ALDH, and therefore alcohol oxidation. The resulting accumulation
of acetaldehyde causes a variety of unpleasant effects such as nausea, sweating, vomiting,
and increased heart rate, if ethanol is consumed with these drugs. Certain individuals,
usually of Asian extraction, have an inactive mitochondrial ALDH2 becauseof a single
amino acid substitution; glutamate 487 is converted to a lysine residue; this causes a large
Clin Liver Dis. Author manuscript; available in PMC 2013 November 01.

Cederbaum

Page 12

NIH-PA Author Manuscript

decrease in affinity for the NAD+ cofactor. Thus inactive enzyme can be found in 15 to 40%
of the population of East Asia and when these individuals consume ethanol, blood levels of
acetaldehyde are 5-to 20- fold higher than those found in individuals with the active ALDH
allele. Individuals with the inactive ALDH show marked vasodilator, nausea and dysphasia
when consuming alcohol, and are virtual abstainers if homozygous for the ALDH2*2 allele.
Acetaldehyde is poorly eliminated by these individuals and as a consequence, little alcohol
is consumed. ALDH2 deficient individuals are at lower risk for alcoholism. They may have
possible increased risk for liver damage if alcohol continues to be consumed.
Acetaldehyde is a reactive compound and can interact with thiol and amino groups of amino
acids in proteins. Formation of acetaldehyde adducts with proteins may cause inhibition of
that protein's function and/or cause an immune response (73,74). ALDH is important not
only for removing acetaldehyde, but also for the removal of other aldehydes, including
biogenic aldehydes and lipid peroxidation-derived aldehydes. Effective removal of
acetaldehyde is important not only to prevent cellular toxicity, but also to maintain efficient
removal of alcohol, e.g., acetaldehyde is a product inhibitor of ADH. The class I ALDH can
oxidize retinal to retinoic acid; the possibility that high levels of acetaldehyde compete with
retinal for oxidation by class I ALDH may be of developmental significance (75).

Future Considerations
NIH-PA Author Manuscript

While much has been learned about the pathways of ethanol metabolism and how these
pathways are regulated, there are many critical questions remaining. For example:

NIH-PA Author Manuscript

•

What limits and regulates alcohol metabolism in-vivo?

•

What is the mechanism(s) responsible for metabolic tolerance?

•

Is it alcohol per se, or alcohol-derived metabolites which play a key role in organ
damage? What might be the consequences of attempting to accelerate ethanol
metabolism?

•

What is the role, if any, of the various ADH isoforms in oxidation of endogenous
substrates, alcohol metabolism and alcohol toxicity? The hypothesis that alcohol or
acetaldehyde inhibit the oxidation of physiologically important endogenous
substrates of ADH or ALDH2 and that this may contribute to the adverse action of
ethanol requires further study.

•

Can the various ADH and ALDH isozymes or polymorphic forms of CYP2E1 be of
predictive value or serve as markers to identify individuals who are susceptible to
developing alcoholism? Can non-invasive probes be developed to measure the
various isoforms present?

•

Are there population and gender differences in rates of alcohol elimination, and if
so, are such differences explained by the varying isoforms present in that
population?

•

What controls the expression of the various isoforms at the transcriptional level,
and are there posttranscriptional modifications? What dictates the turnover of these
enzymes which may be important in regulating the amount of active enzyme
present in the cells, e.g. CYP2E1?

•

Why are calories from alcohol not as efficient in providing energy as are calories
from typical nutrients? What is the mechanism by which food increases alcohol
metabolism?

•

What role, if any, does acetate play in the metabolic actions of alcohol?

Clin Liver Dis. Author manuscript; available in PMC 2013 November 01.

Cederbaum

Page 13

•

NIH-PA Author Manuscript

Can we build appropriate models and rate equations to kinetically describe the
process of alcohol elimination under various conditions? [author query: the Guest
Editor has requested this section be replaced with a “conclusions” paragraph.]

REFERENCES

NIH-PA Author Manuscript
NIH-PA Author Manuscript

1. Khanna JM, Israel Y. Ethanol. Metabolism. Int. Review of Physiol. 1980; 21:275–315.
2. Crabb DW, Bosron WF, Li TK. Ethanol Metabolism. Pharmac. Ther. 1987; 34:59–73.
3. Kennedy NP, Tipton KF. Ethanol Metabolism and Alcoholic Liver Disease. Essays in Biochemistry.
1990; 25:137–195. [PubMed: 2199191]
4. Riveros-Rosas H, Julian-Sanchez A, Pina E. Enzymology of Ethanol and Acetaldehyde Metabolism
in Mammals. Arch. Med. Res. 1997; 28:453–471. [PubMed: 9428569]
5. Kalant, H. Pharmacokinetics of ethanol: Absorption, Distribution and Elimination. In: Begleiter, H.;
Kissin, B., editors. The Pharmacology of Alcohol and Alcohol Dependence. Oxford University
Press; 1996. p. 15-58.
6. Cederbaum, A. Metabolism of Ethanol , Acetaldehyde and Condensation Products. In: Begletier, H.;
Kissin, B., editors. The Pharmacology of Alcohol and Alcohol Dependence. Oxford University
Press; 1996. p. 59-109.
7. Lands WE. A Review of Alcohol Clearance in Humans. Alcohol. 1998; 15:147–160. [PubMed:
9476961]
8. Zakhari S. Overview: How is alcohol metabolized by the body. Alcohol Res and Health. 2006;
29:245–254. [PubMed: 17718403]
9. Zakhari S, Li TK. Determinants of alcohol use and abuse: impact of quantity and frequency patterns
on liver disease. Hepatology. 2007; 46:2032–2039. [PubMed: 18046720]
10. Frezza M, Di Padova C, Pozzato G, et al. High blood alcohol levels in women. New Engl. J. Med.
1990; 322:95–99. [PubMed: 2248624]
11. Cole-Harding S, Wilson JR. Ethanol metabolism in men and women. J. Studies Alc. 1987; 48:380–
387.
12. Norberg A, Jones WA, Hahn RG, et al. Role of variability in explaining ethanol pharmacokinetics.
Clin. Pharmacokinet. 2003; 42:1–31. [PubMed: 12489977]
13. Wilkinson PK, Sedman AJ, Sakmar E, et al. Pharmacokinetics of ethanol after oral administration
in the fasting state. J. Pharmacokinet. and Biopharm. 1977; 5:207–224. [PubMed: 881642]
14. Baraona E, Abittan CS, Dohmen K, et al. Gender differences in pharmacokinetics of alcohol.
Alcoholism: Clin Exp Res. 2001; 25:502–507.
15. Kwo PY, Ramchandanl VA, O'Connor S, et al. Gender differences in alcohol metabolism:
relationship to liver volume and effect of adjusting for body mass. Gastroent. 1998; 115:1552–
1557.
16. DiPadova C, Worner TM, Julkunen RJK, et al. Effects of fasting and chronic alcohol consumption
on the first pass metabolism of ethanol. Gastroent. 1987; 92:1169–1173.
17. Levitt MD, Furne J, DeMaster E. First pass metabolism of ethanol is negligible in rat gastric
mucosa. Alcoholism: Clin Exp Res. 1997; 21:293–297.
18. Lee SL, Chau GY, Yao CT, et al. Functional assessment of human alcohol dehydrogenase family
in ethanol metabolism: Significance of first-pass metabolism. Alcoholism: Clin. Exp. Res. 2006;
30:1132–1142.
19. Morgan MY, Levine JA. Alcohol and nutrition. Proc. Nutr. Soc. 1988; 47:85–98. [PubMed:
3054901]
20. Lieber CS. Perspectives: do alcohol calories count? Am. J. Clin. Nutr. 1991; 54:976–982.
[PubMed: 1957830]
21. Lands WEM. Alcohol and energy intake. Am. Soc. Clin. Nutr. 1995; 62:1101S–1106S.
22. Addolorato G, Capristo E, Greco AL, et al. Energy expenditure, substrate oxidation and body
composition in subjects with chronic alcoholism: new findings from metabolic assessment.
Alcoholism: Clin Exp Res. 1997; 21:962–967.

Clin Liver Dis. Author manuscript; available in PMC 2013 November 01.

Cederbaum

Page 14

NIH-PA Author Manuscript
NIH-PA Author Manuscript
NIH-PA Author Manuscript

23. Salaspuro MP, Lieber CS. Non-uniformity of blood ethanol elimination: its exaggeration after
chronic consumption. Annals Clin. Res. 1978; 10:294–297.
24. Matsumoto H, Fukui Y. Pharmacokinetics of ethanol: a review of the methodology. Addiction
Biol. 2002; 7:5–14.
25. Holford NG. Clinical pharmacokinetics of ethanol. Clin. Pharmacokinet. 1987; 13:273–292.
26. Ramchandani VA, Bostron WF, Li TK. Research advances in ethanol metabolism. Pathol. Biol.
2001; 49:676–682. [PubMed: 11762128]
27. Reed TE, Kalant H, Gibbins RJ, et al. Alcohol and acetaldehyde metabolism in Caucasians,
Chinese and Amerinds. Canadian Med. Assoc. J. 1976; 6:851–855.
28. Bennion LJ, Li TK. Alcohol metabolism in American Indians and Whites. New Engl. J. Med.
1976; 294:9–13. [PubMed: 1244489]
29. Passanati GT, Wolff CA, Vesell E. Reproductibility of individual rates of ethanol metabolism in
fasting subjects. Clin Pharmacol Ther. 1990; 47:389–396. [PubMed: 2311338]
30. Wissel PS. Dietary influences on ethanol metabolism. Drug-Nutrient Interact. 1987; 5:161–168.
31. Ramchandani VA, Kwo PY, Li TK. Effect of food and food composition on alcohol elimination
rates in healthy men and women. J. Clin. Pharmacol. 2001; 41:1345–1350. [PubMed: 11762562]
32. Edenberg H. The genetics of alcohol metabolism. Alcohol Res. and Health. 2007; 30:5–13.
[PubMed: 17718394]
33. Crabb DW. Ethanol oxidizing enzymes: Roles in alcohol metabolism and alcoholic lliver disease.
Prog. Liver Dis. 1995; 13:151–172. [PubMed: 9224501]
34. Bosron W, Ehrig T, Li TK. Genetic factors in alcohol metabolism and alcoholism. Semin. Liver
Dis. 1993; 13:126–135. [PubMed: 8337601]
35. Eriksson CJP, Fukunaga T, Sarkola T, et al. Functional relevance of human ADH polymorphism.
Alcoholism: Clin Exp. Res. 2001; 25:157S–163S.
36. Zintzaras E, Stefanidis I, Santos M, et al. Do alcohol-metabolizing enzyme gene polymorphisms
increase the risk of alcoholism and alcoholic liver disease. Hepatology. 2006; 43:352–361.
[PubMed: 16440362]
37. Kimura M, Miyakawa T, Matsushita S, et al. Gender differences in the effects of ADHIB and
ALDH2 polymorphisms in alcoholism. Alcoholism: Clin. Exp. Res. 2011; 35:1923–1927.
38. Meijer AJ, Van Wuerkom GM, Williamson JR, et al. Rate-limiting factors in the oxidation of
ethanol by isolated rat liver cells. Biochem. J. 1975; 150:205–209. [PubMed: 1180914]
39. Cederbaum AI, Dicker E, Rubin E. Transfer and reoxidation of reducing equivalents as the ratelimiting steps in the oxidation of ethanol by liver cells isolated from fed and fasted rats. Arch.
Biochem. Biophys. 1977; 183:638–646. [PubMed: 921281]
40. Gordon ER. The effect of chronic consumption of ethanol on the redox state of the rat liver.
Canadian J. Biochem. 1972; 50:949–957.
41. Stubbs M, Veech RL, Krebs HA. Control of the redox of the nicotinamide adenine-dinucleotide
couple in rat liver cytoplasm. Biochem. J. 1972; 126:59–65. [PubMed: 4342386]
42. Veech RL, Guynn R, Veloso D. The time course of the effects of ethanol in the redox and
phosphorylation states of rat liver. Biochem. J. 1972; 127:387–397. [PubMed: 4342558]
43. Szabo G, Hoek JB, Darley-Usmar V, et al. Alcohol and mitochondrial metabolism: at the
crossroads of life and death. Alcoholism: Clin Exp Res. 2005; 29:1749–1752.
44. Teplova VV, Belosludtsev KN, Belosludtseva NV, et al. Role of mitochondria in hepatotoxicity of
ethanol. Cell Biophys. 2010; 55:951–958.
45. Cederbaum AI, Lieber CS, Beattie DS, et al. Characterization of shuttle mechanisms in the
transport of reducing equivalents into mitochondria. Arch. Biochem. Biophys. 1973; 158:763–781.
46. Dawson AG. Rapid oxidation of NADH via the reconstituted malate-aspartate shuttle in systems
containing mitochondrial and soluble fractions of rat liver: implications for ethanol metabolism.
Biochem. Pharmacol. 1982; 31:2733–2738. [PubMed: 7138569]
47. Cederbaum AI, Lieber CS, Toth A, et al. Effect of ethanol and fat on the transport of reducing
equivalents into rat liver mitochondria. J. Biol. Chem. 1973; 248:4977–4986. [PubMed: 4352184]

Clin Liver Dis. Author manuscript; available in PMC 2013 November 01.

Cederbaum

Page 15

NIH-PA Author Manuscript
NIH-PA Author Manuscript
NIH-PA Author Manuscript

48. Sugano T, Handler JA, Yoshihara H, et al. Acute and chronic ethanol treatment in vivo increases
malate-aspartate shuttle capacity in perfused rat liver. J. Biol. Chem. 1990; 265:21549–21553.
[PubMed: 2254313]
49. Zimatkin SM, Liopo AV, Deitrich RA. Distribution and kinetics of ethanol metabolism in rat brain.
Alcoholism: Clin. Exp. Res. 1998; 22:1623–1627.
50. Thurman RG, Handler JA. New perspectives in catalase-dependent ethanol metabolism. Drug
Metab. Rev. 1989; 20:679–688. [PubMed: 2680403]
51. Deng XS, Deitrich RA. Putative role of brain acetaldehyde in ethanol addiction. Current Drug
Abuse Reviews. 2008; 1:3–8. [PubMed: 19122804]
52. Guengerich, FR. Mammalian cytochrome P450. CRC Press Boca Raton; 1987.
53. Nelson DR, Koymans L, Kamataki T, et al. P450 superfamily: update on new sequences, gene
mapping, accession numbers and nomenclature. Pharmacogen. 1996; 6:1–42.
54. Lewis DFV, Pratt JM. The P450 catalytic cycle and oxygenation mechanism. Drug Metab. Rev.
1998; 30:739–786. [PubMed: 9844808]
55. Lieber CS. Cytochrome P4502E1: its physiological and pathological role. Physiol. Rev. 1997;
77:517–544. [PubMed: 9114822]
56. Caro AA, Cederbaum AI. Oxidative stress, toxicology and pharmacology of CYP2E1. Annu Rev.
Pharmacol. Toxicol. 2004; 44:27–42. [PubMed: 14744237]
57. Bolt M, Koos PH, Their H. The cytochrome P450 isoenzyme CYP2E1 in the biological processing
of industrial chemicals. Int. Arch. Occup. Environ. Health. 2003; 76:174–185. [PubMed:
12690492]
58. Koop DP. Oxidative and reductive metabolism by cytochrome P4502E1. FASEB J. 1992; 6:724–
730. [PubMed: 1537462]
59. Gonzalez FJ. Roles of cytochromes P450 in chemical toxicity and oxidative stress:studies with
CYP2E1. Mutat. Res. 2005; 569:101–110. [PubMed: 15603755]
60. Lu Y, Cederbaum AI. CYP2E1 and oxidative liver injury by alcohol. Free Rad. Biol. Med. 2008;
44:723–738. [PubMed: 18078827]
61. Bernstein J, Videla L, Israel Y. Role of the sodium pump in the regulation of liver metabolism in
experimental alcoholism. Ann NY Acad. Sci. 1974; 242:560–572. [PubMed: 4279606]
62. Cederbaum AI, Dicker E, Lieber CS, et al. Ethanol oxidation by isolated hepatocytes from ethanoltreated and control rats; factor contributing to the metabolic adaptation after chronic ethanol
consumption. Biochem. Pharmacol. 1978; 27:7–15. [PubMed: 563723]
63. Videla L, Israel Y. Factors that modify the metabolism of ethanol in rat liver and adaptive changes
produced by its chronic administration. Biochem. J. 1970; 118:275–281. [PubMed: 5484675]
64. Bradford BU, Rusyn I. Swift increase in alcohol metabolism (SIAM): understanding the
phenomenon of hypermetabolism in liver. Alcohol. 2005; 35:13–17. [PubMed: 15922133]
65. Kashiwagi T, Ji S, Lemasters JJ, et al. Rates of alcohol dehydrogenase-dependent ethanol
metabolism in periportal and pericentral regions of the perfused rat liver. Mol. Pharmacol. 1982;
21:438–443. [PubMed: 7048061]
66. Vaananen H, Lindros KO. Comparison of ethanol metabolism in isolated periportal or perivenous
hepatocytes: effects of chronic ethanol treatment. Alcoholism: Clin. Exp. Res. 1985; 9:315–321.
67. Chen L, Sidner RA, Lumeng L. Distribution of alcohol dehydrogenase and the low km form of
aldehyde dehydrogenase in isolated perivenous and periportal hepatocytes in rats. Alcoholism:
Clin. Exp. Res. 1992; 16:23–29.
68. Seidl S, Wurst FM, Alt A. Ethyl glucuronide- a biological marker for recent alcohol consumption.
Addict. Biol. 2001; 6:205–212. [PubMed: 11900598]
69. Laposata M. Fatty acid ethyl esters: non oxidative metabolites of ethanol. Addict. Biol. 1998; 3:5–
14.
70. Agarwal DP, Goedde HW. Human aldehyde dehydrogenases: their role in alcoholism. Alcohol.
1989; 6:517–523. [PubMed: 2688685]
71. Goedde HW, Agarwal DP. Pharmacogenetics of aldehyde dehydrogenase. Pharmac. Ther. 1990;
45:345–371.

Clin Liver Dis. Author manuscript; available in PMC 2013 November 01.

Cederbaum

Page 16

NIH-PA Author Manuscript

72. Lindros KO, Eriksson CJP. The role of acetaldehyde in the action of ethanol. Finnish Foundation
Stud. Alc. 1975; 23
73. Niemela O. Acetaldehyde adducts of proteins: diagnostic and pathogenic implications in diseases
caused by excessive alcohol consumption. Scand. J. Clin lab Invest. 1993; 53:45–54.
74. Sorrell MF, Tuma DJ. Hypothesis: alcoholic liver injury and the covalent binding of acetaldehyde.
Alcoholism: Clin. Exp. Res. 1989; 9:306–309.
75. Sophos NA, Vasiliou V. Aldehyde dehydrogenase gene superfamily: the 2002 update. Chemico
Biolog. Interact. 2002; 143–144:5–22.

NIH-PA Author Manuscript
NIH-PA Author Manuscript
Clin Liver Dis. Author manuscript; available in PMC 2013 November 01.

Cederbaum

Page 17

KEY POINTS

NIH-PA Author Manuscript

The equilibrium concentration of alcohol in a tissue depends on the relative water
content of that tissue.
The rate of alcohol absorption depends on the rate of gastric emptying, the
concentration of alcohol and is more rapid in the fasted state.
The blood alcohol concentration is determined by the amount of alcohol
consumed,the presence or absence of food and the rate of alcohol metabolism.
First pass metabolism of alcohol occurs in the stomach and is decreased in
alcoholics.
Liver alcohol dehydrogenase is the major enzyme system for metabolizing alcohol;
this requires the cofactor NAD and the products produced are acetaldehyde and
NADH.
The acetaldehyde is further oxidized to acetate, the same final metabolite produced
from all other nutrients-carbohydrates, fats and proteins; the acetate can be converted
to CO2, fatty acids, ketone bodies, cholesterol and steroids.

NIH-PA Author Manuscript

Oxidation of alcohol by cytochrome P450 pathways, especially CYP2E1 which is
induced by alcohol, are secondary pathways to remove alcohol especially at high
concentrations.
Alcohol metabolism is regulated by the nutritional state, the concentration of
alcohol,specific isoforms of alcohol dehyrogenase, need to remove acetaldehyde and
regenerate NAD and induction of CYP2E1.
Substrate shuttles and the mitochondrial respiratory chain are required to regenerate
NAD from NADH, and this can limit the overall rate of alcohol metabolism.
Metabolism of alcohol is increased in alcoholics without liver disease: this metabolic
tolerance to alcohol may involve induction of CYP2E1, elevated regeneration of
NAD or endotoxemia.

NIH-PA Author Manuscript
Clin Liver Dis. Author manuscript; available in PMC 2013 November 01.

Cederbaum

Page 18

SYNOPSIS

NIH-PA Author Manuscript
NIH-PA Author Manuscript

This review describes the pathways and factors which modulate blood alcohol (alcohol
and ethanol are used interchangeably) levels and alcohol metabolism and describe how
the body disposes of alcohol. The various factors which play a role in the distribution of
alcohol in the body, influence the absorption of alcohol and contribute to first pass
metabolism of alcohol will be described. Most alcohol is oxidized in the liver and general
principles and overall mechanisms for alcohol oxidation will be summarized. The
kinetics of alcohol elimination in-vivo and the various genetic and environmental factors
which can modify the rate of alcohol metabolism will be discussed. The enzymatic
pathways responsible for ethanol metabolism, in particular, the human alcohol
dehydrogenase alleles will be described. Rate-limiting steps in the overall metabolism of
ethanol, including the activity of alcohol dehydrogenase isoforms, and the necessity to
reoxidize NADH by substrate shuttle pathways and the mitochondrial respiratory chain
will be discussed. The impact of alcohol metabolism on other liver metabolic pathways,
and on cytochrome P450-dependent metabolism of xenobiotics and drugs will be briefly
described. Factors playing a role in the metabolic adaptation i.e., increased rate of ethanol
metabolism by chronic alcoholics will be discussed. The metabolism and role of
acetaldehyde in the toxic actions of alcohol and ethanol drinking behavior will be
discussed. Despite much knowledge of alcohol pharmacokinetics and metabolism,
numerous questions remain for further evaluation and research, including what regulates
alcohol metabolism in-vivo, the role of alcohol metabolites in organ damage, functions
and physiological substrates of the various ADH isoforms, population and gender
differences in alcohol metabolism, need for developing markers to identify individuals
susceptible to alcohol and other considerations are discussed.

NIH-PA Author Manuscript
Clin Liver Dis. Author manuscript; available in PMC 2013 November 01.

Cederbaum

Page 19

LIST 1

NIH-PA Author Manuscript

SOME SUGGESTED CAUSES FOR ALCOHOL TOXICITY
Redox state changes in the NAD/NADH ratio
Acetaldehyde formation
Mitochondrial damamge
Cytokine formation (TNFα)
Kupffer cell activation
Membrane actions of ethanol
Hypoxia
Immune actions
Oxidative stress

NIH-PA Author Manuscript
NIH-PA Author Manuscript
Clin Liver Dis. Author manuscript; available in PMC 2013 November 01.

Cederbaum

Page 20

LIST 2

NIH-PA Author Manuscript

Factors Affecting Alcohol Absorption
1.

Concentration of alcohol

2.

Blood flow at site of absorption

3.

Irritant properties of alcohol

4.

Rate of ingestion

5.

Type of beverage

6.

Food

NIH-PA Author Manuscript
NIH-PA Author Manuscript
Clin Liver Dis. Author manuscript; available in PMC 2013 November 01.

Cederbaum

Page 21

LIST 3

NIH-PA Author Manuscript

GENERAL PRINCIPLES OF ALCOHOL OXIDATION
1.

< 10 % alcohol excreted in breath, sweat and urine.

2.

~ 90 % alcohol removed by oxidation.

3.

Most of this alcohol oxidation occurs in the liver.

4.

Alcohol cannot be stored in the liver.

5.

No major feedback mechanisms to pace the rate of alcohol metabolism to the
physiological conditions of the liver cell.

NIH-PA Author Manuscript
NIH-PA Author Manuscript
Clin Liver Dis. Author manuscript; available in PMC 2013 November 01.

Cederbaum

Page 22

LIST 4

NIH-PA Author Manuscript

CYTOCHROME P4502E1 (CYP2E1)
A minor pathway for alcohol metabolism
Produces acetaldehyde, 1-hydroxyethyl radical
Responsible for alcohol-drug interactions
Activates toxins such as acetaminophen,CCl4, halothane,benzene,halogenated
hydrocarbons to reactive toxic intermediates
Activates procarcinogens such as nitrosamines, azo compounds to active carcinogens
Activates molecular oxygen to reactive oxygen species such as superoxide radical
anion, H202, hydroxyl radical

NIH-PA Author Manuscript
NIH-PA Author Manuscript
Clin Liver Dis. Author manuscript; available in PMC 2013 November 01.

Cederbaum

Page 23

LIST 5

NIH-PA Author Manuscript

SUGGESTED MECHANISMS FOR METABOLIC TOLERANCE TO ALCOHOL
Induction of alcohol dehydrogenases
Increased shuttle capacity
Increased reoxidation of NADH by mitochondria
Induction of CYP2E1
Hypermetabolic state
Increased release of cytokines or prostaglandins which elevate oxygen
consumption by hepatocytes

NIH-PA Author Manuscript
NIH-PA Author Manuscript
Clin Liver Dis. Author manuscript; available in PMC 2013 November 01.

Cederbaum

Page 24

NIH-PA Author Manuscript
Fig 1.

General scheme for alcohol oxidation. Alcohol is oxidized by alcohol and aldehyde
dehydrogenases eventually to acetyl CoA. Depending on the nutritional, hormonal, energetic
status, the acetyl CoA is converted to the indicated products.

NIH-PA Author Manuscript
NIH-PA Author Manuscript
Clin Liver Dis. Author manuscript; available in PMC 2013 November 01.

Cederbaum

Page 25

NIH-PA Author Manuscript
Fig 2.

NIH-PA Author Manuscript

The mitochondrial respiratory chain. Reducing equivalents (electrons) enter the respiratory
chain either from NADH or from succinate and are passed through a series of electron
carriers to cytochrome oxidase which reacts with molecular oxygen to produce water. The
NADH produced from the oxidation of alcohol by alcohol dehydrogenase is oxidized by the
respiratory chain. Energy, in the form of ATP, is produced during this oxidation, hence,
alcohol is of caloric value.

NIH-PA Author Manuscript
Clin Liver Dis. Author manuscript; available in PMC 2013 November 01.

Cederbaum

Page 26

NIH-PA Author Manuscript
Fig 3.

NIH-PA Author Manuscript

Substrate shuttle mechanisms for the reoxidation of NADH by the mitochondrial respiratory
chain. The alcohol dehydrogenase reaction oxidizes alcohol in the liver cytosol and therefore
produces NADH in the cytosol. This NADH cannot directly enter the mitochondria for
oxidation (Fig 2) and therefore has to be transported into the mitochondria by either the αglycerophosphate (a) or the malate-aspartate (b) shuttle.

NIH-PA Author Manuscript
Clin Liver Dis. Author manuscript; available in PMC 2013 November 01.

NIH-PA Author Manuscript

pH-optimum

Vmax
10.5

27

1.1

Ki 4-methylpyrazole, μM

min−1

13
4.2

Km ethanol, mM

αα

KmNAD+ μM

Constant

10.5

9.2

0.13

0.049

7.4

β1β1

8.5

400

-

0.94

180

β2β2

7.0

300

2.1

24

530

β3β3

10.5

87

0.1

1

7.9

γ1γ1

10

35

-

0.63

8.7

γ2γ2

10.5

20

2000

34

14

ππ

NIH-PA Author Manuscript

Kinetic constants for human liver ADH isoforms

NIH-PA Author Manuscript

TABLE 1
Cederbaum
Page 27

Clin Liver Dis. Author manuscript; available in PMC 2013 November 01.

NIH-PA Author Manuscript
>95%
85%
15%
85%

White-European

Japanese

Black-American

ADH1B*1

White-American

<5%

85%

15%

<5%

ADH1B*2

15%

<5%

<5%

<5%

ADH1B*3

85%

95%

60%

50%

ADH1C*1

15%

5%

40%

50%

ADH1C*2

NIH-PA Author Manuscript

Frequency of ADH Alleles in Racial Populations

NIH-PA Author Manuscript

TABLE 2
Cederbaum
Page 28

Clin Liver Dis. Author manuscript; available in PMC 2013 November 01.