Critical Reviews in Toxicology, 25(4):347-367 (1995)

Toxicological Effects of Ethanol on Human Health

Farid E. Ahmed*
Biology Department, Brookhaven National Laboratory, Upton, NY 11973**
* Recipient of the National Academy of Sciences' Kohelt Fund Grant. Views expressed here do not necessarily represent those of the National Academy
of Sciences, National Research Council, National Academy of Engineering, Institute of Medicine, or any of their constituent units.
** Present address: Dept. of Biochemisby, Rm. 150, Duke University Medical Center, Durham NC 27710

ABSTRACT: Moderate ethanol consumption reduces stress and increases feelings of happiness and well-being,
and may reduce the risk of coronary heart disease. Heavy consumption of alcohol, however, may cause addiction
and increases all types of injury and trauma. Environmental and genetic factors are involved in susceptibility to
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alcoholism. Ethanol can lead to malnutrition, and can exert a direct toxicological effect due to its interference with
hepatic metabolism and immunological functions. A causal effect has been observed between alcohol and various
cancers. Cessation of alcohol consumption and balanced nutrition are recommended primary nonspecific therapeu-
tic measures for alcoholics. Drug therapies for alcoholics suffering from liver injury has resulted in mixed results.
In end-stage liver disease, liver transplantation may be considered.

KEY WORDS: chronic diseases, genetics, environmental factors, metabolism, treatment.

1. INTRODUCTION problem until distillation became common around

For personal use only.

1100 A.D.3 Puritans in the American colonies

The word alcohol as used throughout this
manuscript refers to ethanol. Alcohol is both a
food and a drug. Since antiquity, alcohol has been
produced and used as a food, a beverage at social
events and festivals, and as a medicine. Beer and
wine were produced and consumed in ancient
Egypt and Mesopotamia 3000 years B.C.' Drunk-
enness was common in ancient Greece and Rome.2
In pre-Islamic Arabia, beer, fermented dates, milk,
and wine were commonly consumed until the
advent of Islam.3Alcohol had important religious,
economic, and political roles for the cultures of
the Andean South Americans, the Aztecs of
Mexico, and the Mayans of Central A m e r i ~ aIn.~
medieval Europe, drunkenness was largely con-
fined to revelry, feasting, and religious celebra-
tions, and was prevalent among the lower orders
of the clergy;2alcoholism did not become a social
considered alcoholic drinks as wholesome and
strengthening, and used alcohol to appease the
native Indians and to motivate black slaves.2 Al-
coholism became a problem in 18th century
America, when rum and whiskey became avail-
able; approximately 4000 people were reported to
have died in the U.S. from consumption of rum.3
Alcohol was used as a medicine in the U.S. mili-
tary hospitals in the middle of the nineteenth cen-
tury; however, a strong reaction against its use as
a drug occurred during the growth of the temper-
ance movement. North America Indian tribes have
reacted variably to alcohol consumption. Some
developed a changing attitude toward it; for ex-
ample, in the first decades of contact with whites,
the Iroquois of upstate New York and Southern
Canada drank in moderation, and drinking be-
came an integral part of their religion. In the early

Abbreviations: ADH, alcohol dehydrogenase; ALC, alcoholic liver cirrhosis; ATP, adenosine triphosphate; BAL, blood
alcohol level; CHD, coronary heart disease; CP, creatinine phosphate; FA, fatty acids; FABP, fatty acid binding protein; FAS,
fetal alcohol syndrome; GGTP, gamma-glutamyl transpeptidase; GSH, reduced glutathione; GSSG, oxidized glutathione; HDL,
high density lipoprotein; H,O,, hydrogen peroxide; KP, Korsakoff psychosis; MEOS, microsomal ethanol oxidizing system;
NADP, nicotinamide dinucleotide phosphate; PLC, primary liver cancer; PUL, polyunsaturated lecithin; RR, relative risk; WE,
Wernicke encephalopathy; WKS, Wemicke-Korsakoff Syndrome.

1040-8444/95/$.50
0 1995 by CRC Press, Inc.
347
 eighteenth century, following the example of white
trappers and traders, aggression became part of
their drunken behavior, and by 1800 drunkenness
became a serious social problem, which led most
of them to modify their drinking habits or to
abstinence.' Cross-cultural studies have shown
alcoholism and its related social problems to be
more prevalent in Western societies compared
with non-Western ones, and attempts at prohibi-
tion were not successful unless embedded in reli-
gious beliefs against alcohol cons~mption.~ Com-
parative ethnic studies have shown change in
drinking pattern among Jews, Italians, Poles, and
Portuguese after they migrated to the U.S.4
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Although moderate consumption of alcohol
contributes to feelings of well-being and happi-
ness, and may reduce the risk of some diseases,
heavy drinking leads to increase of trauma, and
exerts deleterious effects on various body or-
gans.
Several reviews on the subject of alcohol
and human diseases have appeared in various
journals. However, the focus has often been nar-
rowed to a specific disease in a certain organ
For personal use only.
(e.g., liver). This article, on the other hand, is
interdisciplinary in nature, and provides balanced
and broad views on topics such as the role of
environmental and genetic factors in susceptibil-
ity t o alcoholism; beneficial effects of alcohol
consumption on human health and chronic dis-
eases, and the developing fetus; nutritional defi-
ciencies resulting from alcohol intake; effects on
immune functions; and the effectiveness of di-
etary interventions and other therapies on allevi-
ating alcohol-related disorders.
TABLE 1
Amount of Ethanol in a Drink
Ethanol content
Beverage type ("10)
Whiskey (80 proof) 40
Table wine 12.1a
US. beer 3.9
a Most table wines contain 11 to 13% ethanol. Fortified wines, such as sherry and port,
contain approximately 20% ethanol.
Most brands contain 3.2 to 4.0% ethanol.
From Baum-Baicker, C.,Drug Alcohol Depend., 15, 207, 1995. With permission.
348
Alcohol consumption is difficult to quantify
accurately and reliably because different units of
measurement are often used (e.g., number of
drinks per day or volume consumed per time),
complexities of drinking behavior, role of ca-
tabolism, and types of questions asked during
~urveying.~ The Fourth Special Report of the
U.S. Congress on Alcohol and Health classified
drinkers into moderate drinkers (i.e., those who
consumed 0.22 to 0.99 oz of alcohol per day)
and light drinkers (i.e., those who consumed
0.01 to 0.21 ~ z / d )The
. ~ equivalent in drinks can
be obtained from Table 1.6 These definitions are
arbitrary, and it is important to keep in mind that
there is no universally accepted classification
system for safe levels of alcohol consumption. It
was proposed that moderate alcohol intake should
not exceed 0.8 g k g body weight per day, or an
average of 0.7 g k g body weight over a 3-day
period,' as shown in Table 2.6 Those exceeding
these limits were considered heavy drinkers8
Thus, 24% of adults, in the U.S. are considered
moderate drinkers, approximately 33% light
drinkers, 9% heavy drinkers, and approximately
33% abstainer^.^ Because there is variability in
individual tolerance to alcohol consumption, the
basis for which is explained in the following
sections, this is reflected in a similar variability
in upper limits of daily alcohol consumption as
presented in Table 2. Drinking in the preceding
hours can best be estimated from the level of
alcohol in blood (BAL). Sensations of euphoria
and well-being have been reported at BAL of
Ethanol in a drink
Unit of measure [oz and (ml)]
1-02 shot (30 ml) 0.40 (11.83)
3.5-02glass (104 mi) 0.42 (12.42)
12-02 bottle (355 ml) 0.42 (12.42)
 TABLE 2
Upper Limits of Daily Alcohol Consumption

0.8 glkg bw per day 0.7 glkg bw over a 3-d period

12% 12%
Weight of
80-proof Table 3.6% 80-proof Table 3.6%
individual
Ethanol Spirits Wine Beerb Ethanol Spirits Wine Beer

50 110 40 4.3 14 38 35 3.7 13 33

60 132 48 5.1 17 46 42 4.5 15 40
70 154 56 6.0 20 53 49 5.2 18 47
80 176 64 6.9 23 61 56 6.0 20 53
90 198 72 7.7 26 69 63 6.7 23 60
100 220 80 8.6 29 76 70 7.5 25 67
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a 1 oz = 23.34 g or 29.574mi.
By weight, or 4.5% by volume.

From Baum-Baicker, C., Drug Alcohol Depend., 15,207,1995.With permission.

0.05% (i.e., 5 parts of alcohol per 10,000 parts of believed to have a lower prevalence than other
blood); at BAL 0.1%, a person is considered drunk; groups because of their sensitivity to alcoh01.~
at 0.2 some people pass out; at 0.3% some col-
lapse into a coma; and at 0.4% death ensue^.^
Alcohol consumption peaks in the 20- to 40-year 111. ALCOHOL AND HUMAN DISEASES
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age group, with alcohol abuse most frequent in

youth and middle age.9
Alcohol use decreases in the elderly. Thus,
43% of those between 65 to 74 years of age
consumed alcohol when compared with 30% af-
ter age 75; this is believed to be due to factors
such as attrition as younger alcoholics die from
accidents or medical complications, difficulty to
define abuse among the elderly, and reluctance
of family members to report excess alcohol use
by their elderly relatives to protect their dignity
and p r i ~ a c y Approximately
.~ 28 to 60% of the
elderly reported a history of alcohol-relatedprob-
lems, which is quite alarming in view of the
increase in percentage of elderly in the U.S3
Although males are likely to drink more
heavily than females, the proportion of women
who drink has increased steadily in the past 30
years.3 Rates of excessive drinking and associ-
ated health problems for the adult black popula-
tion were similar to those of the general U.S.
population, although black youth reported higher
abstinence rates and lower rates of heavy drink-
ing than white youth.5 Native American Indians
are more likely to be heavy drinkers than the
general population, and Asian-Americans are
A. Obesity
National consumption data indicate that alco-
hol contributes 4.5% of total energy of the Ameri-
can diet, although heavy drinkers were reported
to derive at least half of their daily energy from
ethanol.lo Although the carbohydrate content is
negligible for whiskey, cognac, and vodka, it is 2
to 10 g of carbohydrate per liter for wine, 30 g/l
for beer and dry sherry, and 120 g/l for sweetened
wine.3The combustion of ethanol in a bomb calo-
rimeter yielded a value of 7.1 kcal/g, but its bio-
logical activity may be less, especially when the
dose of ethanol is high or the recipient is a chronic
alcohol abuser, or both. In nonalcoholic human
volunteers, ethanol was utilized as efficiently as
fat or carbohydrate as a source of energy, whereas
in alcoholics no weight gain was found when
alcohol was utilized as the source of the extra
energy.1° Isocaloric substitution of ethanol for
carbohydrates of up to 50% of total energy in a
balanced diet resulted in less weight gain; when
alcohol was given as additional calories, it caused
not only less of a weight gain than did calorically
equivalent carbohydrates or fats in lean individu-

349
 als, but also some weight gain in half the obese
individual^.^ l o Thus, ethanol may contribute to
excess energy intake, but it is not a common
cause of obesity.
It is believed that ethanol increases metabolic
rate Gnce ethanol ingestion in normal people in-
crea4es their oxygen consumption, with a greater
effect in alcoholics.'0 Substitution of ethanol for
carbohydrates resulted in increased metabolic rate
and thermogenesis in humans and rodents, and
although some of the energy wastage could be
attributed to brown fat thermogenesis in rats, most
of it could not be accounted for.3 Several mecha-
nisms were proposed to explain energy wastage.
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These include ( 1 ) oxidation of ethanol to acetal-
dehyde without phosphorylation by the microso-
ma1 ethanol-oxidizing system (MEOS) in the hepa-
tocytes resulting in the production of nicotin-
amide adenine dinucleotide phosphate (NADP) and
heat generation, without formation of high energy
compounds [CH,CH20H + NADPH + H+ +
CH,CHO + NADP' + 2H20]. This pathway is in
contrast to the alcohol dehydrogenase (ADH) path-
way in which high energy compound adenosine
For personal use only.
triphosphate (ATP) is generated [CH,CH20H +
NAD, -+ CH,CHO + NADH + H']; (2) uncou-
pling of mitochondria1NADH oxidation leading to
decreased production of ATP, which may be pro-
vided by either catecholamine release or a
hyperthyroid state (although less certain); (3) in-
creased ATPase activity; and (4) inhibition of gly-
colysis. which results in decreased ATP levels.'"
B. Cardiovascular Diseases
7. Hypertension and Stroke
Epidemiologic evidence indicates that adults
in the U.S. population who chronically consume
two or more drinks of alcohol daily (>30 ml of
ethanol) have higher mean blood pressure and a
higher prevalence of hypertension than those who
consume lesser quantities.' Similar findings
were reported in Australia, Finland, South Africa,
France, New Zealand, U.K., Japan, and Germany.3
Case-control studies indicate that heavy drinlung
(>3OO g/week) is associated with an increased
risk of stroke. The association, however, may be
350
due to the confounding effects of cigarette smok-
ing.I3 Cross-sectional studies showed that regular
daily consumption of >200 g of alcohol was gen-
erally associated with greater blood pressure,
which is the major risk factor for hemorrhagic
stroke and cerebral infarction.14J5Cross-sectional
studies also showed that the association between
alcohol consumption and blood pressure was
weaker in women than in men because of either
less consumption or the modifying effect of fe-
male hormones.' A prospective study of 800
middle-aged men of Japanese ancestry in Hawaii
showed that even lower levels of alcohol con-
sumption (1 to 14 oz of alcohol per month) re-
sulted in increased risk of hemorrhagic stroke.I4
A similar finding was reported for women but not
men in the Farmingham study in Massachusetts.'j
On the other hand, recent studies have shown that
moderate alcohol drinkers (i.e., <3 drinks per day)
have fewer myocardial infarctions and hemor-
rhagic strokes than abstainers.l6-'*
2. Coronary Heart Disease (CHD)
In cross-sectional epidemiologic studies, con-
sumption of alcohol showed a positive associa-
tion with blood levels of high-density lipoprotein
(HDL) cholesterol in the U.S., France, Japan,
Norway, Portugal, and China.*' Lifetime abstain-
ers as well as former drinkers who later abstained
reported a higher risk of CHD than people who
consumed <lo0 g of alcohol per week in indi-
viduals with mean cholesterol levels >200 mg/dl.
The graded nature of this association, its persis-
tence in various populations, and its consistency
after adjustment for confounding factors (e.g.,
cigarette smoking, increased blood pressure) lend
credence to the observation that consuming small
amounts of alcohol (between 1 and 99 g weekly)
may reduce susceptibility to CHD.lC2OThe mecha-
nism of this protective action was shown to be
due to increased levels of HDL, both HDL, and
HDL, subfractions. The level of each subfraction
was shown to be inversely related to the risk of a
first myocardial infarction.I69l7The high incidence
of CHD among abstainers compared with drink-
ers is believed to be due to a failure to distinguish
between former drinkers at high risk and lifelong
 abstainers.16 Alcohol could also provide protec-
tion against CHD because of its antithrombotic
effect. Moreover, epidemiologic evidence in-
dicated that heavy or problem drinkers (e.g., those
consuming >500 g/week) are associated with in-
creased risk of CHD, and with increased risk of
mortality in many populations.22Certain groups
who abstain completely from tobacco and alcohol
(e.g., Seventh-Day Adventists in California)
showed a 20 to 50% lower death rate from CHD
than for age-matched groups in the total popula-
tion of C a l i f ~ r n i aStudies
. ~ ~ conducted in several
countries showed that populations with moderate
per capita intake of 3 to 5% of calories from
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alcohol experienced very low or very high rates
of mortality from CHD.3,5
3. Alcoholic Cardiomyopathy
Alcoholic cardiomyopathy is a syndrome typi-
cally found in men between 30 to 45 years of age,
who have been chronically receiving 30 to 40%
of their calories from alcoh01.~Consumption of
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more than 85 g/d of alcohol, regardless of the type
of beverage, was a high risk factor for dilated
cardi~myopathy,~~ and lowering overall level of
alcohol consumption was shown to decrease
mortality due to cardiomyopathy in Australia25
and Seychelles.26 Some mechanisms leading to
cardiomyopathy include accumulation of triglyc-
erides, altered fatty acid composition, membrane
alterations with decreased response to Ca2+and
catecholamines, toxicity to striated muscles due
to interference with oxidative processes as well as
glycolytic activity with subsequent decrease in
ATP and creatinine phosphate (CP) levels, and
alterations in cardiac protein s y n t h e s i ~ . ~ ~ - ~ ~ ethanol, but also to other drugs such as war-
C. Liver Diseases
The following sections discuss the effects of
ethanol, or its metabolites, on hepatic tissue patho-
genesis. Toxic effects of alcohol are due to effects
on oxidation of ethanol in the liver by various
oxidation pathways, interaction of ethanol with
hormones and vitamins, toxic effects of acetalde-
hyde, and disorders of collagen metabolism lead-
ing to liver cirrhosis. These effects are discussed
next.
7. Effects Due to Microsomal Ethanol
Oxidizing System (MEOS)
Ethanol is oxidized in the liver by three dif-
ferent enzyme systems: the alcohol dehydroge-
nase (ADH), the MEOS, and catalase. Figure 1
shows various pathways of ethanol oxidation and
metabolism in the hepatocytes. The primary path-
way of ethanol metabolism was believed to in-
volve the cytosolic ADH. Another pathway in
liver microsomes attributable to H,O,-dependent
reaction mediated by peroxisomal catalase is now
believed to play a minor role in vivo because H,O,
production in the liver is relatively low under
ordinary circumstances. In chronic alcoholism,
ethanol is believed to increase H,O, in pericentral
regions of the liver lobule, in part by elevating
rates of peroxisomal P-oxidation of acyl CoA
corn pound^.^^ An inducible system dependent on
microsomal cytochrome P-450 and specific for
ethanol oxidation was characterized and desig-
nated P450IIE1 .31 Because other cytochrome
P-450 isozymes can also contribute to ethanol
oxidation, the term microsomal ethanol oxidizing
system has been used.1° The P-450IIE1 gene was
isolated, characterized, and localized on chromo-
some 7 in the rat and chromosome 10 in human.
The MEOS is involved through sharing with other
microsomal drug-metabolizing systems many
properties such as induction of P-450 isozymes,
NADPH and 0, in various drug, carcinogen, hor-
mone, and vitamin interactions.1°
Alcoholics exhibited tolerance not only to
farin, diphenylhydantoin, tolbutamide, and
isoniazid leading to increased drug clearance.
This tolerance has been attributed to either cen-
tral nervous system adaptation or to metabolic
adaptation.1° Enhanced activity of MEOS can
result in an adverse effect by converting indus-
trial solvents, halothanes, anesthetics, and
xenobiotics to hepatotoxic metabolites, as ob-
served in increased CC1, periventricular toxic-
ity, benzene toxicity in the bone marrow,
halothane-induced centrizonal necrosis in ani-
351
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FIGURE 1. Metabolism of ethanol in the liver. Broken lines indicate pathways that are
depressed by ethanol. Repeated arrows represent stimulation or activation. The symbol -[
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indicates interference or binding. (From Lieber, C. S., J. Am. Coll. Nutr., 10, 602, 1991. With
permission.)
mal\, and increased hepatotoxicity of isoniazid
and acetaminophen in alcoholics. u
Ethanol affects microsomal metabolism of
hormones leading to decreased blood testosterone
levels due to enhanced degradation and conver-
sion to estrogen, and to decreased capacity of the
testir to synthesize steroids.I0 Moreover, ethanol
alters metabolism of structurally similar com-
pounds. such as vitamin D, which may serve as a
substrate for the microsomal enzymes, leading to
alteration of their oxidative a ~ t i v i t i e s . ~ ~
Alcohol has been shown to contribute to nu-
tritional deficiencies. Hospitalized chronic alco-
holic patients had inadequate dietary protein and
exhibited symptoms of protein maln~trition.~
high in polyunsaturated fatty acids enhanced the
pathogenesis of liver damage due to the induction
of i5ozyme cytochrome P-450IIE1 by alcohol
ingestion.i4
Hepatic vitamin A levels decreased with pro-
gresion of liver injury. Experimental work on
rats and baboons suggested that mechanisms such
352
as malabsorption of the vitamin in the liver in-
creased its mobilization from the liver and its
enhanced catabolism in the liver or other organs
may be i n ~ o l v e dIntake
.~ of vitamin A was con-
sidered normal for Americans consuming up to
400 kcal of ethanol per day (i.e., ~ 2 0 %of total
energy). Those getting 24% of their calories from
alcohol consumed 75% of the RDA for vitamin
A, and those getting 50% or more of their energy
from alcohol received a smaller amount of vita-
min A.35Drugs such as phenobarbital were found
to enhance the catabolism of retinol and exert an
inducible effect on the microsomal system, simi-
lar to ethanol induction. When both ethanol and
Diet phenobarbital were combined in baboons, an ad-
ditive effect on vitamin A depletion was found.
Because alcohol abuse is often associated clini-
cally with drug abuse, this potentiation may have
significance for vitamin A depletion in alcoholic
abusers.
Another microsomal system that converts
retinol to polar metabolites (P-45OIIC8) was
 discovered in rats, deermice, and humans
(P-45011C8), which lacked the cytosolic retinol
dehydrogenase enzyme; it was insensitive to etha-
nol inhibition and thus may have contributed fur-
ther to hepatic retinol d e p l e t i ~ nBecause
.~~ alcohol
consumption potentiates the hepatotoxicity of vita-
min A, and the beneficial effect of vitamin A supple-
mentation is achievable only within a narrow thera-
peutic window, caution should be exercised in
selection of a therapeutic dose of vitamin A supple-
mentation for alcoholics.lo Moreover, ethanol also
increases the breakdown of other lipid-soluble vi-
tamins, such as a-tocopherol to produce a-toco-
pherol quinone by free radicals.37
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Although experimental studies in rats showed
that alcohol interfered with thiamin (vitamin B,)
absorption, human jejunal perfusion studies uti-
lizing 5% of total calories as alcohol did not show
such an effect, and a 3-year feeding study in
baboons in which alcohol contributed 50% of
total calories along with a nutritionally balanced
diet did not show any effect on the blood or
urinary levels of thiamin.1°Nevertheless,profound
effects of thiamin deficiency often present in al-
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coholics and contributeto neurological syndromes,
beriberi, and heart disease^.^ Thus, thiamin is given
to most alcoholics to guard against its deficiency
as thiamin supplementation is easy and safe.lo
Folic acid levels are influenced by alcohol
consumption. Studies showed that in alcoholics
38% had low serum folate and 18% had low red
blood cell folate levels.38Malnourished alcohol-
ics without liver disease absorbed folic acid less
efficiently than well-nourished individuals who
did not show signs of anemia.3Long-term feeding
studies in monkeys suggest that a decrease in
hepatic folate is due to a decreased ability to
retain folate in the liver or to an increased break-
down due to superoxide and free radical forma-
tion. Megaloblastic anemia due to folate defi-
ciency in alcoholics, as in other conditions, was
presumed to result from the inhibition of
thymidylate synthetase.lo
Although alcohol ingestion caused reduced
absorption in volunteers after several weeks of
intake, alcoholics do not usually suffer from vita-
min B 12 deficiency, probably because of the large
vitamin stores in the body and the reverse capac-
ity for ab~orption.~ Riboflavin deficiency was seen
when there was a general lack of vitamin B in-
take. Experimentally, chronic alcohol feeding in-
duced riboflavin deficiency when the intake of
the vitamin in monkeys was marginal.1°
The role of vitamin C in alcoholic diseases is
uncertain, although alteration in ascorbic acid was
reported following alcohol ingestion.lo
Alcoholics exhibit illnesses related to abnor-
malities of calcium, phosphorus, magnesium, vi-
tamin D homeostasis and decreased bone density,
decreased bone mass, increased susceptibility to
fractures, and increased osteonecr~sis.~ Vitamin
D deficiency in alcoholic liver disease is believed
to be due to decreased vitamin D substrate result-
ing from poor dietary intake, increased metabo-
lism through P-450 induction, malabsorption due
to cholestasis, pancreatic insufficiency, or dimin-
ished ~unlight.~
Alcoholics are among Americans with mar-
ginal zinc intake. Some instances of night blind-
ness that did not fully respond to vitamin A re-
placement were shown to respond to zinc
treatment.lo
2. Role of Alcohol Dehydrogenase
(AOH) in Pathogenesis
Liver ADH is present in various isozyme
forms, intra- as well as extrahepatically. How-
ever, the extrahepatic form of the enzyme has
much lower affinity, and at the level of ethanol in
blood it is inactive.1° In the mucosal lining of the
stomach wall, at least three different forms of
ADH are available. The level of ethanol in the
stomach is relatively high after alcohol ingestion,
and thus ethanol is effectively metabolized in the
stomach and presents a barrier against its sys-
temic effects. This barrier disappears after
gastrectomy, and is often decreased in alcoholics
due to a decrease in gastric ADH.l0 Medications
such as aspirin and some H, blockers such as
cimetidine and ranitidine inhibited gastric ADH
after moderate intake of alcohol. Women have
lower gastric ADH activity than men, which when
combined with different body composition (more
fat and less water and body weight in women)
may explain their increased susceptibility to de-
velop more severe alcohol-related diseases than
men. Aging was shown to strikingly decrease in
353
 vi\~>ethanol metabolism in male rats without major
effect on hepatic ADH activity.39
When ethanol is oxidized through the ADH
pathway. this results in excess production of he-
patic NADH and enhanced NADH to NAD ratio.
An elevated NADH/NAD ratio resulted in alter-
ation of the intermediary metabolism of lipids,
carbohydrates, proteins. purines, hormones, and
porphyrins.53 Increased NADH leads to an in-
crease in the lactate to pyruvate ratio, resulting in
hyperlactacidemia, which contributes to acidosis
and reduction of the capacity of the kidney to
excrete uric acid; this leads to secondary
hypeiuricemia. '') Ketosis and enhanced breakdown
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of purine due to alcohol can also promote the
hyperuricemia that leads to aggravating or pre-
cipitating gouty attacks3 Increased NADH/NAD
ratio increases the concentration of a-glycero-
phosphate that trap FA leading to accumulation
of triglycerides in the liver.
In rats and humans, protein deficiency may
result in decreased ADH activity, which may lead
to metabolic disorders such as inhibition of the
citric acid cycle. increase in the ratio of lactate to
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pyruvate, fasting hypoglycemia, and inhibition of
glucose elimination. Moreover, chronic alcohol
consumption in combination with protein and a
lipocropic-deficient diet resulted in more severe
hepatic steatosis than either deficiency alone.3
Studies in animals showed that alcohol consump-
tion accompanied by protein deficiency greatly
increased mortality of laboratory animals, with-
out hepatic fat accumulation.'
An increased NADH to NAD ratio may exac-
erbate hypoglycemia by blocking glucogenesis
by ethanol in individuals whose glycogen stores
have been depleted by either starvation or abnor-
mal carbohydrate metabolism. 10.J1 Alcohol-in-
duced hypoglycemia can be suppressed by the
ADH inhibitor 4-methyl pyrazole.' Alcohol may
also accelerate rather than inhibit glucogenesis,
resulting in hyperglycemia, although the mecha-
nism is not exactly known.'."' Increases in lipo-
protein production, hyperlipemia, and ketosis have
already been discussed.
3. Toxic Effect of Acetaldehyde
All pathways of ethanol oxidation in the liver
result in production of acetaldehyde: acetalde-
354
hyde is further metabolized into acetate. Acetal-
dehyde dehydrogenase is polymorphic and exists
in variable forms in the cytoplasm and mitochon-
dria of most species. This polymorphism explains
the intolerance to alcohol and flushing experi-
enced by Asians who have an inactive variant.42
The drug disulfiram inhibits acetaldehyde dehy-
drogenase, thus raising acetaldehyde levels in the
blood after alcohol drinhng, leading to flushing
and other adverse effects, which helps in main-
taining abstinence.43 Acetaldehyde binds co-
valently to proteins of liver microsomes of rats in
vivo, and selectively forms protein adducts in
rat liver microsomes with ethanol-inducible
P-450IIE1. Studies in animals and humans have
shown that these adducts serve as neoantigens,
which generate immune response. Thus, comple-
ment-binding acetaldehyde adducts containing
immune complex may contribute to the severity
of liver disease. Moreover, acetaldehyde binds
covalently to other adducts, such as serum albu-
min, hemoglobin, and cytoskeletal proteins, such
as tubulin, the constituent protein of microtubule.
An important function of microtubule is promot-
ing the intracellular transport of proteins and their
secretion. l o Acetaldehyde has an affinity for
sulfhydral groups of cysteine residue, and for
lysine, which may alter the capacity of tubulin to
polymerize, resulting in impairment of polymer-
ization and alteration of microtubules; this leads
to inhibition of secretion of protein, lipoprotein,
and glyceroprotein into the plasma and their accu-
mulation in the liver, thus enhancing hepatic dam-
age. In addition, binding to lipoproteins may alter
their catabolism. l o
Long-term alcohol feeding of ethanol in the
diet of rats delayed secretion of export proteins
such as albumin and transfenin into the plasma
and their retention in the liver, leading eventually
to ballooning of the hepatocytes. Another export
protein. fatty acid binding protein (FABP), in-
creased by one sixth to one third after ethanol
feeding.a However, the increase of FABP may
also favor the esterification of FA (mainly as
triglycerides) and a modest increase in non-
esterified FA, thus preventing accumulation of
potentially deleterious nonesterified FA and
FA-CoA esters secondary to ethanol-induced in-
hibition of their 0xidation.4~3~~
Although the mecha-
nism of water retention is not completely clear, a
 rise in protein, amino acids and an increase in
ions could enhance water retention by osmosis;
these increases lead to hypertrophy and balloon-
ing of the hepatocytes. This ballooning may favor
progression of liver diseases in alcoholics. lo
Mitochondria1 impairment leading to defec-
tive oxygen utilization, decreased oxidation of
FA, and alteration of oxidative phosphorylation is
also hypothesized to result as a consequence of
acetaldehyde accumulation in alcoholics, rather
than other factors such as maln~trition.~~
Acetaldehyde may induce toxicity through
interference with enzyme activities, such as by
binding to important receptors.84Increased oxy-
Critical Reviews in Toxicology Downloaded from informahealthcare.com by UB Giessen on 10/18/14
gen radicals produced by ethanol may also be
involved.49 Acetaldehyde binds with cysteine,
which is a constituent of glutathione (GSH). This
binding may contribute to depression of liver
GSH.'O GSH is important in body defenses be-
cause it acts as a scavenger for toxic free radicals,
particularly reactive oxygen species. Acute etha-
nol administration to rats inhibited GSH and led
to an increase in its loss from the liver. Chronic
treatment led to a decrease of GSH p e r o x i d a ~ e . ~ ~ dramatically. Replacement of dietary triglycer-
For personal use only.
A mechanism of ethanol-induced fatty liver in
monkeys and humans has been proposed where
severe reduction in GSH favored peroxidation
and enhanced lipid peroxidation as a result of
generation of a~etaldehyde.~~ GSH depletion was
experimentally decreased by administration
of S-adenosyl-~-methionine.~* Changes of antioxi-
dants such as vitamin C, GSH, selenium, and
vitamin E due to either direct effect of ethanol or
malnutrition associated with alcoholism have been
reported.1° Free radicals generated during the me-
tabolism of acetaldehyde by aldehyde oxidase are
believed to be a major mechanism in the initiation
of alcohol-induced liver injury.53
4. Fatty Liver
The main pathway for ethanol metabolism
involves the alcohol dehydrogenase (ADH) path-
way in which alcohol is oxidized to acetaldehyde,
which in turn loses hydrogen when it is oxidized
to acetate, most of which is released into the
bloodstream. Ethanol oxidation increases the ra-
tio of NADH to NAD, which raises the concentra-
tion of a-glycerophosphate, leading to accumula-
tion of triglycerides in the liver by trapping fatty
acids (FA). Moreover, excess NADH may also
promote synthesis of FA. Only when very large
amounts of alcohol are consumed, do FA deposit
in the liver.lO Moderate hyperlipemia can be ob-
served in early stages of alcoholic liver injury. In
some alcoholics, depending on dose and duration
of alcohol intake, severe hyperlipemia develops
as a consequence of potentiation of abnormal
metabolism of lipids or carbohydrates. Hyper-
lipemic response develops progressively and in-
volves all lipoprotein classes, including HDL.
Studies on volunteers in metabolic wards demon-
strated an increase in hepatic lipids when ethanol
was given either as a supplement or as an isoca-
loric substitute for carbohydrates in an otherwise
nutritionally balanced diet. Hepatic steatosis was
produced, even with a high protein, high vitamin
diet and was accompanied by major ultrastruc-
tural changes in the liver and by elevated liver
transaminases in the blood. If dietary fat was
decreased from 35 to 25% of total calories, he-
patic triglyceride accumulation was decreased
ides that contained long-chain FA with those con-
taining medium-chained FA resulted in marked
reduction of the capacity of alcohol to produce
fatty liver in rat~.~JOAnother way by which liver
dispenses excess lipids is through increasing
ketogenesis, which leads to mild ketosis in mod-
erate alcoholics and severe ketoacidosis in sus-
ceptible individuals.1°
5. Alcoholic Liver Cirrhosis (ALC)
Despite the high prevalence of alcoholism
and cirrhosis throughout the world, the inci-
dence of cirrhosis among alcoholics is rela-
tively low (Le., -18%).3 Thus, individual sus-
ceptibility influences development of ALC.
Genetic and environmental factors that may
influence this susceptibility include individual
differences in alcohol metabolism, consump-
tion patterns, gender, histocompatibility (HLA)
antigens, family history of alcoholism, immune
response, and poor n ~ t r i t i o n .ALC
~ is corre-
lated with both the magnitude and duration of
alcohol use.54Thus, the average cirrhogenic dose
was estimated to be 180 g ethanol per day for
355
 25 years; the risk increased five times at a dose
of 80 to 160 g/day, and 25 times at >160 g/d.55
The role of alcohol in liver cirrhosis was more
pronounced in the Americas (66%develop ALC)
than in Europe (42%), than in Asia (1 1%), al-
though the percentages seem to be on the rise in
Europe and Asia.56Women seem more suscep-
tible than men to this disease as a daily intake of
40 g by men and 20 g by women resulted in an
increased incidence of the disease in a well-nour-
ished normal p ~ p u l a t i o n although
,~~ in a normal
population a dose of 40 g/d for both men and
women was reported to have no observable ad-
verse effect on ALC.” A retrospective case-con-
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trol study in France showed that a relative risk of
liver cirrhosis was positively correlated with al-
cohol and fat consumption and negatively corre-
lated with carbohydrate and protein intakes.58A
reduced content of hepatic a-tocopherol observed
in some patients with ALC may play a role in
ethanol-induced lipid pero~idation.~~ Patients with
ALC experience increased resting metabolic rate
and enhanced thermogenesis, resulting in nega-
tive energy balance, defective glucose storage,
For personal use only.
and normal glucose oxidation, which lead to an
increased energy need.60
While the rate of malnutrition was relatively
modest in alcoholic patients without alcoholic
liver disease, it is virtually 100% in patients with
alcoholic hepatitis or ALC. Abnormalities in amino
acids were observed, depending on the degree of
hepatic damage, amount of alcohol consumed,
and intake of amino acids. Plasma concentration
of branched-chain amino acids, aromatic amino
acids, and a-amino-n-butyric acid increased,
whereas that of hydroxy amino acids, including
alanine and proline, decreased.61
Alteration in the production, site of action, or
metabolism of cytokines (regulatory polypeptides
secreted during the generation of an immune re-
sponse by lymphocytes) due to ethanol consump-
tion was observed in alcohol liver injury. Abnor-
malities in the production of interleukin- 1,
interleulun-2, interleukin-6, and tumor necrosis
factor-a were related to abnormalities in alco-
holic hepatitis, including hepatic tissue damage,
and ALC.62-M Severe protein energy malnutrition
was shown to adversely affect the production of
interleukin- 1 produced by the macrophage-mono-
356
cyte system, resulting in immunosuppression in
ALC patients.65 Interference with immunologic
functions, such as production of mesangial IgA
and deposition, were observed in rats as well as
humans.66
6. Disorders of Collagen Metabolism
Alcoholic liver cirrhosis was thought to de-
velop as a consequence of alcoholic hepatitis char-
acterized by ballooning of the hepatocytes, exten-
sive necrosis and polymorphonuclear infiltration,
and increased deposition of collagen and
glycoaminoglycolysis; however, work with ba-
boons has shown that fulminating alcoholic hepa-
titis is not necessary for the development of cir-
rhosis.’O It is now believed that alcohol affects the
metabolism of collagen, leading to fibrosis by
depositing collagen in mesenchymal cells and fat
storage cells (lipocytes or Ito cells). Accumula-
tion of collagen could be due to failure of the
process of collagen degradation to keep up with
its synthesis in the liver.’O
Addition of polyunsaturated lecithin (PUL)
to transformed lipocytes in vitro appeared to pre-
vent collagen accumulation by stimulating colla-
genase activity. PUL also attenuated accumula-
tion of collagen after alcohol administration in
viva6’ PUL contains the lipotrope choline whose
lack may play a role in alcohol liver injury. In
rats, ethanol increased choline requirement by
enhancing choline oxidation. Primates, however,
were much less susceptible to protein and lipo-
protein deficiency than rodents as very high doses
of choline and methionine treatments in alcoholic
patients and baboons suffering from hepatic in-
jury was ineffective. This is probably due to spe-
cies differences inasmuch as human liver con-
tains much less choline oxidase than that of rats.1°
Clinical data from patients with alcoholic liver
disease as well as from volunteers showed the
ineffectiveness of lipotrophic factors in the pro-
duction of alcohol-related liver injury.3 Dietary
zinc influenced hepatic prolyl hydroxylase activ-
ity and collagen deposition in alcoholic rats.6R
ALC was associated with decreased thiamin
diphosphate concentration and thiamin phospho-
rylati~n.~~
 7. Nutritional and Toxicological
Consequences of Alcoholism
Alcohol can cause malnutrition by displacing
other nutrients either due to excessive consump-
tion of empty calories, or secondary to mal-
digestion or malabsorption of nutrients resulting
from gastrointestinal complications in chronic
consumption of alcohol.70Alcohol can also cause
direct toxicity due to its interference with hepatic
metabolism. There is an interplay between toxi-
cological and nutritional factors in alcohol pro-
cessing in the body, especially the liver. Toxicity
may exacerbate malnutrition by enhancing nutri-
Critical Reviews in Toxicology Downloaded from informahealthcare.com by UB Giessen on 10/18/14
ent degradation, and malnutrition may adversely
affect the alcohol detoxification process in the
body.1° Use of a liquid diet in experimental stud-
ies overcame the natural aversion of rodents for
alcohol and established a causal role of ethanol in
the pathogenesis of liver diseases in baboons.71
Individuals with moderate alcohol intake
showed little nutritional differences from non-
drinkers. In the diet of light drinkers, alcoholic
calories were additive to the energy derived from
For personal use only.
carbohydrates or fats, but in the diets of moderate
and heavy drinkers, alcoholic calories replaced
other sources of energy (mostly carbohydrates) in
a dose-dependent manner. As alcohol intake in-
creases to >41% caloric intake, the percentage of
energy derived from protein, fat, and carbohy-
drate decreases, and intake of vitamins A, C, E,
thiamin, calcium, iron, and fiber decreases, and
nitrogen loss in the urine increases. Among min-
erals, zinc and selenium were found to be de-
creased.lo Chronic alcohol misusers accumulate
significant amount of iron due to unregulated in-
crease of intestinal iron absorption via the
noncarrier-mediated pericellular route.72Ethanol
altered mitochondrial and other liver membranes
and their enzymes, such as alkaline phosphatase
and gamma-glutamyl transpeptidase (GGTP), in
alcoholics and in ethanol-fed rats.1° Chronic etha-
nol feeding was shown to increase hepatic plasma
membrane fluidity, contrary to the homeoviscous
changes observed in brain synaptosomes, eryth-
rocytes, liver mitochondria, and microsomes, prob-
ably due to the specialized role of the liver in bile
excretion, lipoprotein metabolism, and ethanol
oxidation.lo This fluidity was associated with de-
creased membrane vitamin A and increased cho-
lesterol esters content.73
0. Cancer
An association between alcohol and cancer
came primarily from epidemiologic case-control
studies that focused on certain cancers and retro-
spective determination of prior alcohol consump-
tion, and from cohort studies that linked drinking
habits of study participants with subsequent can-
cer-induced fatalities. Additional evidence came
from descriptive studies correlating cancer rates
with average drinking patterns for various na-
tional, regional, and local groups.
Total cancer risk was shown to increase with
increasing level of alcoholic beverages consump-
tion. Table 3 shows that the relative risk (RR) to
nondrinkers of all types of cancer increases with
an increase in daily intake of alcohol after adjust-
ing for cigarette smoking. These data, which are
typical of several studies of total cancer risk, were
derived from a 12-year cohort follow-up study of
approximately 276,000 American men.74Risks,
however, vary by site of cancer induction as de-
tailed herein.
Strong association of cancer with alcohol in-
take was observed for oral and pharyngeal can-
cers. Data taken from nearly 1100 patients with
these cancers and 1300 controls in four areas of
the U.S. in the m i d - 1 9 8 0 ~and
~ ~presented in Table
4 show that RR of oral and pharyngeal cancers as
a result of a multiplicative interaction between
smoking and drinking increase in each smoking
status with an increase of alcohol intake. Ap-
proximately 75% of all oral and pharyngeal can-
cers in the U.S. are caused by interaction between
smoking and drinking, resulting in an increased
risk of consumers of both products by 37-fold
compared with abstainers from both alcohol and
t o b a c ~ o . ~Data * Table 4 strongly indicate that
~ , ~in
alcohol by itself increased the risk of cancer in
nonsmokers and exsmokers, as was reported else-
where.79However, it is possible that in nonsmok-
ers alcohol interacts with other carcinogens, al-
though the evidence is difficult to evaluate directly
in epidemiologic studies because only few of the
cancer patients are nonsmokers, which makes it
357
 TABLE 3
Relative Risks of Total Cancer Mortality According to
Number of Alcoholic Drinks Per Day

Alcohol intake Number of cancer 95% Confidence

(drinkslday) deaths RRa interval

None 4748 1.o

<I 563 0.9 0.8-1 .O
2 1026 0.9 0.9-1.1
3 458 1.I 1.o-1.3
4 345 1.3 1.2-1.5
5 178 1.5 1.3-1.7
6+ 44 1 1.6 1.5-1.8

a All risks relative to nondrinkers and adjusted for cigarette smoking.

Critical Reviews in Toxicology Downloaded from informahealthcare.com by UB Giessen on 10/18/14

From Blot, W. J., Cancer Res., 52 (Suppi.), 21 19s, 1992. With permis-
sion.

TABLE 4
Relative Risks of Oral and Pharyngeal Cancer in Males
According to Amount of Tobacco Smoking and Alcoholic
Beverage Drinking

RR
For personal use only.

Smoking status <la 1-4 5-14 15-29 30+ Totalb

Nonsmoker l.Oc 1.3 1.6 1.4 5.8 l.Oc

Ex-smoker 0.7 2.2 1.4 3.2 6.4 1.1
1-19/d for 20+ years 1.7 1.5 2.7 5.4 7.9 1.6
20-39/d for 20+ years 1.9 2.4 4.4 7.2 23.8 2.8
40+/d for 20+ years 7.4 0.7 4.4 20.2 37.7 4.4
Totald 1.0 1.2 1.7 3.3 8.8

a Number of drinkdweek.
Risk adjusted for alcohol intake.
Data from Reference 75.
Risk adjusted for smoking.

From Blot, W., Cancer Res., 52 (Suppi.),2119s, 1992. With permission.

difficult to divide them into yet smaller groups to
evaluate other exposure risk fact01-s.'~Drinking is
also believed to enhance the risk of developing
oral and pharyngeal cancers by either lowering
nutritional status due to empty calories, or depri-
vation of important vitamins, minerals and other
nutrients, or b ~ t h . ' ~ .Fewer
~" data exist on the
effect of alcohol on cancer induction according to
timing and duration of exposure because it is
often difficult to accurately identify exdrinkers
and assess when they stopped consuming alco-
holic beverages. Increased risk of oral and pha-
ryngeal cancers was associated with most types
of alcoholic beverages, suggesting that ethanol is
associated with cancer development. Differences
in the magnitude of risk were reported, however,
for various types of beverages.76 That ethanol
may be the key ingredient was also suggested by
findings of increased risk of oral cancer in users
of mouthwash.81In addition, the correlation be-
tween mouthwash and oral cancer suggests a topi-
cal rather than a systemic route of alcohol in

358
 cancer induction because few individuals swal-
low mouthwash.76
Case-control and cohort studies conducted
worldwide showed an increased risk of esoph-
ageal cancer with increased consumption of al-
cohol and smoking.82 Alcohol also seemed to
enhance the effect of poor nutrition on esoph-
ageal cancer and vice versa, consistent with a
multiplicative interaction between the t ~ o . ~ ~ mals.@
Variation in risk of esophageal cancer was ob-
served among various beverages, suggesting that
in addition to ethanol, congeners or other con-
taminants may be responsible for cancer induc-
ti~n.~,~~
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A strong correlation was found between
alcohol and cancer of the larynx, with alcohol
and tobacco having a synergistic interactions3
The risk of alcohol-induced laryngeal cancer
was shown to vary by anatomic site, with alco-
hol exerting a great effect on the extrinsic, rather the stomach, pancreas, lung, bladder, and other
than the intrinsic larynx,83suggesting that alco-
hol may act through topical exposure.76
In North America and western Europe, al-
cohol is considered the primary cause of liver
For personal use only.
cirrhosis, with deaths from liver cancer increas-
ing by approximately 50% in alcoholic^.^^^^^
There is a firm association between liver cir-
rhosis and primary liver cancer (PLC). How-
ever, not all studies of alcoholism showed an
increased risk of PLCSx5A limited interrela-
tionship between other liver cancer factors and
alcohol was deduced from epidemiologic stud-
ies, although interactive effects with smoking
(a weak hepatic carcinogen) and hepatitis B and
C viruses (strong hepatocarcinogens) were
f o ~ n d .It~ is~ believed
,~~ that alcohol exerts its intestinal microsomes extracted and used in a
effect on liver cancer through induction of cir-
rhosis or other liver damage, thus disposing
susceptible individuals to development of he-
patic tumors.76 Alcohol can influence liver
metabolism, particularly alcohol-inducible cy-
tochrome P-450,which catabolizes metabolism
of xenobiotics and alters the ability of liver to
detoxify compounds with carcinogenic poten-
tial such as nitrosamines.I0 Alcohol may also
deplete the liver’s vitamin A stores affecting
blood and tissue levels of retinol and its me-
tabolites, which were shown to influence sev-
eral types of chemically induced cancer in ani-
mals.10,76
Several epidemiologic studies correlated
breast cancer with alcohol consumption, with
significant excess risk of cancer at doses as low
as three drinks per day.3,76,82,87This evidence is,
however, controversial,16 and although the
mechanism of this association is not clear, al-
teration of hormonal status was reported to in-
crease breast cancer risk in humans and ani-
, ~ ~ , ~ ~
Several case-control and cohort studies sug-
gested an increased risk of cancer of the large
bowel, particularly rectal cancers, with con-
sumption of alcoholic beverages, particularly
beer.3,76,82 However, inconsistencies among stud-
ies and the small number of observations cast
doubt about alcohol intake as a risk factor
for large bowel ~ a n c e r . Although
~ ~ , ~ ~ some
epidemiologic studies reported a correlation
between alcohol consumption and cancers of
sites, the overall evidence does not bolster that
c~ntention.~,~~,~
Several experimental studies in animals
(e.g., mice, rats, hamsters) did not show any
positive association between consumption of
alcohol and direct carcinogenic effect. The num-
ber of animals was, however, small and the
duration of alcohol ingestion was brief.82On the
other hand, in experimental studies, alcohol
appeared to enhance the carcinogenic effect of
some carcinogens such as benzo[a]pyrene and
7,12-dimethyl benzanthracene (i.e., alcohol is a
cocarcinogen), and to promote the hepato-
carcinogenic effect of d i e t h y l n i t r ~ s a m i n e . ~ . ~ ~ . ~ ~
When ethanol was given to animals and the
short-term test, like the Ames Salmonella
typhimurium system, chronic ingestion of etha-
nol was shown to enhance the capacity of the
intestinal microsomes to activate the pro-
carcinogens 2-aminofluorene and tryptophan py-
r o l y ~ a t eAlcohol
.~ and acetaldehyde also inter-
fered with the capacity of cells and experimental
animals to repair carcinogen-induced DNA dam-
age, resulting in alkylation at the O6 position in
guanine and a decrease in 06-methyl guanine
transferase activity, processes that are associated
with both mutagenesis and carcinogenesi~.~~ Ac-
etaldehyde induced sister chromatid exchanges,
and enhanced chromosomal aberrations in cell
359
 cu1tures.l In other studies in rats, acetaldehyde
caused nasal and laryngeal carcinoma following
its inhalation, and when administered after
benzo[a]pyrene ingestion, it enhanced lung tu-
mors. 76
Epidemiologic studies and experimental work
support the following hypothesis as potential
mechanisms for alcohol-induced cancer:
1. The presence of congeners, carcinogens,
additives, and other contaminants in alco-
holic beverages (e.g., N-nitroso compounds
found in some beers, polycyclic aromatic
hydrocarbons and phenols in whiskeys,
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tannins in wines, mycotoxins in some wines
and beer, inorganic arsenic and other pesti-
cide residues, asbestos fibers in beer, wine,
sherry, and vermouth, flavoring agents, pre-
servatives, and other natural products) may
influence the carcinogenic p r o ~ e s s . ~ . ~ ~
2. Modification of metabolism of carcinogenic
and other compounds. For example, induc-
tion of cirrhosis and other liver damage
through inhibition of compounds that modify
For personal use only.
liver’s clearance function, increased expo-
sure to compounds such as N-nitrosodi-
ethylamine in other organ^,^ generation of
metabolites such as acetaldehyde, and in-
duction of enzymes (e.g., cytochrome P-
450) that catalyze the metabolic activation
of some compounds into carcinogens (i.e.,
metabolism of N-nitrosonicotine of tobacco)
possibly leading to a synergistic effect be-
tween alcohol and tobacco in cancer of the
upper aerodigestive cancers.’
3. Act as a solvent, leading to increased pen-
etration of other carcinogens as seen in in-
creased cancer risk in tissues topically ex-
posed to alcohol (e.g., mouth, pharynx,
esophagus, and extrinsic larynx) and the
synergistic effect of tobacco. Alcohol may
also influence activation and interaction of
carcinogens at the cellular level in certain
tissues (e.g.. mouth and throat), and result in
increased tissue exposure to oxidants, thereby
elevating risk of DNA damage and malig-
nant tran~formation.~.~~
4. Affecting hormonal level, function, and
metabolism resulting in increased exposure
360
to these compounds in susceptible target
organs (e.g ., breast).
5. Suppressing the immune function through
its effect on nutritional status, liver, and other
body functions. For example, vitamin B,,
which plays an important role in the produc-
tion of antibodies that influence tumor de-
velopment in the liver indirectly by affect-
ing subsequent exposure to hepatitis B-virus,
was reported to be decreased in alcohol-
ic~.~,~~
6. Reducing intake and bioavailability, and en-
hancing deficiencies of nutrients that may
influence cancer. Ethanol consumption com-
bined with vitamin A and C deficiencies
may alter epithelial cell chemistry and func-
tion, increasing susceptibility to carcinogens
as seen in ethanol-enhanced tracheal meta-
plasia in ethanol-fed, vitamin A-deficient
rats. Alcohol may also decrease delivery to
hepatic cells of nutrients and additives that
may be protective because of their antioxi-
dant properties (e.g., vitamin E, butylated
hydroxytoluene, propylgallate, and ethoxy-
quine have reduced tumor induction in sev-
eral target organs). Alcohol may also lead to
methyl deficiencies, which caused liver can-
cer in experimental animals and enhanced
the tumorigenic effect of methyl-deficient
diets.”76
E. Diseases of the Nervous System
Wernicke-Korsakoff Syndrome (WKS) is a
combination of two diseases: Wernicke encephal-
opathy (WE) characterized by paralysis of exter-
nal eye muscles, ataxia, gait disturbance, and
confusion; and Korsakoff psychosis (KP), a per-
manent brain disorder characterized by marked
abnormalities in cognitive and emotional func-
tions, such as the inability to learn new informa-
tion, to remember and retain recent events (e.g.,
episodic memory), or to recognize emotions.
Chronic heavy alcohol drinking may lead to both
diseases, although not all Korsakoff patients go
through a Wernicke phase.90 Frontal-lobe dys-
function is believed to produce a disorganization
of the retrieval process, which contributes to the
temporally extensive retrograde amnesia in
 Korsakoff patients?l Rat brain homogenates in-
cubated with ethanol (0 to 100 mM) for periods
up to 60 min showed that acetaldehyde was pro-
duced through the action of the enzyme catalase,
which may lead to the psychopharmacological
effects of It is believed that WK results
from a nutritional deficiency, especially vitamin
B,, or thiamin, an essential coenzyme in interme-
diate carbohydrate metaboli~m.~~ Variations in
clinical manifestations and the finding that most
patients with thiamine deficiency do not have the
syndrome suggest that genetic variation may be
involved in the etiology of WEe3Variants of the
enzyme transketolase, which has reduced affinity
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for its cofactor thiamin pyrophosphate, were found.
Cloned human transketolasecopy DNAs (cDNAs)
from these variants showed a single-copy gene
producing mRNA of approximately 2100 nucle-
otides. No specific nucleotide variations in the
coding region of the gene were detected in WK
patients, suggesting that allelic variants of the
transketolase gene cannot account for the bio-
chemically distinct form of the enzyme, and that
the underlying mechanism is extragenetic and may
For personal use only.
be a result of difference in posttranslational pro-
cessing, or modification of the transketolase
pol~peptide.~~ Because alcohol inhibits the active
and not the passive transfer of thiamin, supple-
mentation in amounts larger than the RDA for
this vitamin are given (i.e., 100 mg of parenteral
thiamin), especially when glucose infusions are
administered.93
Alcoholic peripheral neuropathy is a mixed
motor sensory impairment affecting the distal
regions, primarily the legs, and occurs in more
than 80% of patients with severe neurological
disorders such as WE. Thiamin deficiency is be-
lieved to be the main reason for the neuropathy,
although the direct toxic effect of alcohol cannot
be ruled
Alcohol dementia involve severe intellectual
deterioration, change in behavior and personality,
and cognitive impairment in chronic heavy alco-
holic consumption. It is attributed to combination
of a nutritional disorder (i.e., thiamin deficiency)
and a direct toxic effect of alcohol on the
Abstinence from alcohol and proper nutrition
are the cornerstones of treatment against alcohol-
induced nervous system diseases, although phar-
macological modification of neurotransmitter
function and/or enhancement of cerebral metabo-
lism combined with behavioral methods may be
beneficial. Serotonergic approaches to improve
episodic memory in detoxified alcoholics also
may reduce alcohol intake.96
F. Fetal Alcohol Syndrome (FAS)
Fetal alcohol syndrome (FAS) causes a dis-
tinct pattern of physical and behavioral anomalies
characterized by craniofacial, limb, central ner-
vous system, and cardiovascular defects in the
fetus in addition to growth delay and mental retar-
dation. The worldwide incidence of FAS is 1.9
cases per 1000 live birth^.^,^^ Direct and indirect
biological effects of alcohol exposure in utero
seem to work with other factors such as genetic
variations, alteration in DNA methylation, nutri-
tional status, impaired placental transport, abnor-
mal muscle organogenesis, pattern of exposure to
smoking and use of drugs (e.g., nicotine and co-
caine), fetal hypoxia, autoimmune reaction, and
alteration in metabolic enzyme activities and cell
functions important in cell division and mem-
* . ~ ~roles of prostaglandins
brane i n t e g ~ i t y . ~The
and hormones are not clearly understood.lW
A small percentage of women who drink ex-
cessively (>180 g of alcohol per day) deliver
babies with mild FAS. Tolerance to alcohol may
be due to metabolic or biochemical and structural
adaptations at cellular membranes after chronic
alcohol consumption.lo* Epidemiologic surveys
showed a high prevalence of FAS in some native
Americans and in people from lower socioeco-
nomic backgrounds. Factors such as persistent
drinking during pregnancy, history of excessive
alcohol consumption, number of previous deliv-
eries, and race affect development of FAS and
increase the probability of its incidence by 50%.
Alcohol-related neurological and biological ef-
fects are less frequent among women with mod-
erate level of alcohol con~umption.~
Experimental work showed suppression of
immune response, as measured by a decrease in
the thymocyte number in splenic T-cell-prolifera-
tive response to the hemagglutininhitogen con-
canavalin A and plasma insulin-like growth fac-
361
 tor in rats exposed irz utero to e t h a n ~ l . ' ~ ' J ~ ~its intake is the first step in treatment of alcoholic
Epidemiologic and experimental studies have
linked ethanol-induced teratogenicity with mater-
nal/fetal deficiencies in zinc and methionine.
Moreover, ADH is a zinc metalloenzyme, and
zinc deficiency decreases ADH activity, slowing
down the elimination of ethanol. The essential
amino acid methionine is a lipotrope as well, and
serves as a universal methyl donor that is in-
volved in hepatic detoxification.lm
IV. GENETICS OF ALCOHOLISM
Evidence gathered over the last 25 years shows
Critical Reviews in Toxicology Downloaded from informahealthcare.com by UB Giessen on 10/18/14
that alcoholism is due to an interaction between
environmental and genetic factoms The role of
genetics in predisposition to alcoholism was de-
rived from studies of adoptees separated from
their biological parents at an early age, familial
studies, studies on twins, and animal breeding
studies.' Studies of adopted children indicated
that natural sons of alcoholics were more likely to
be alcoholics than natural sons of nonalcoholics,
irrespective of whether the sons were raised by
For personal use only.
their alcoholic biological parents or by their non-
alcoholic adoptive parents. Twin studies have
provided views that are less clear for the role of
genetic factors than adoption studies.' Animal
studies have shown that alcohol elimination and
alcohol consumption are partially determined by
genetics.
Many studies have been conducted on identi-
fying neurophysiological (e.g., electrical brain
patterns), neuropsychological (e.g., abstracting,
problem solving, perception), and biochemical
(e.g., genetic variation in alcohol-metabolizing
enzymes, especially ADH and aldehyde dehydro-
genase) markers of susceptibility to alcoholism.s
Molecular cloning techniques have identified
five human ADH genes on the region q21-25 of
chromosome 4; markers for these genes have also
been identified.IMPolymorphism among various
ethnic groups may explain variations in their abil-
ity to metabolize alcohol.107
V. POTENTIAL THERAPIES OF
CHRONIC ALCOHOLISM
Because chronic alcohol consumption affects
the nutritional status of its users, cessation from
362
diseases. Thus, balanced nutrition is the first ra-
tional nonspecific therapy for alcoholics. Methion-
ine and zinc supplementation have been hypoth-
esized to protect fetuses of pregnant alcoholic
mothers.lM If this hypothesis proves to be correct
in further testing in animals, then the size of the
supplement and the timing of the supplement
administration with respect to the timing of alco-
hol ingestion will need to be worked out before
clinical applications can be made. Thiamin supple-
mentation has been recommended for alcoholic
patients with diseases of the central nervous sys-
tem and liver.93.95Jos In patients with liver disease,
nutritional intervention in the form of parenteral
or enteral supplementation to correct for energy,
amino acid, and vitamin deficiencies has been
p r e ~ c r i b e d . ' ~A
~ Jnutritional
'~ evaluation method
using a correlation between real body weight,
lean body mass and arm muscular area was help-
ful in evaluating patients suffering from alcoholic
liver disease because of its ability to correct errors
due to the presence of ascites."l Specific thera-
pies for alcoholic hepatitis with corticosteroids,
cyanidanol, penicillamine, synthetic thyroid an-
tagonists, hormones, and amino acids have been
tried; results were either negative or contradic-
tory."? In cirrhotic patients, colchicine treatment
slowed and reduced mortality."* Therapy with
agents such as the polyunsaturated phosphatidyl-
choline and S-adenosyl-L-methionine (a precur-
sor of glutathione) for alcoholic hepatitis and cir-
rhosis shows promise but requires further
investigation.10Ji2J l 3 In end-stage liver disease,
orthotropic liver transplantation should be con-
sidered because these patients do as well as other
nonalcoholic patients with other forms of end-
stage liver disease.los
VI. DIRECTIONS FOR FUTURE
RESEARCH
Research should be directed to expand and
develop the following areas:
Explore the effect of moderate and excessive
ethanol intake on well-being and human health.
The mechanism(s) by which alcohol influences
chronic diseases.
 Genes and genetic markers necessary to iden-
tify individual susceptibility for alcoholism.
Biochemical, clinical, and immunological
markers for diagnoses of alcoholic diseases.
Role of nutritional and therapeutic factors in
the treatment of alcoholic diseases.
Role of environmental factors in the develop-
ment of alcoholic diseases.
VII. CONCLUSIONS AND
RECOMMENDATIONS
Moderate alcohol consumption seems to re-
duce stress, increases feelings of happiness, well-
Critical Reviews in Toxicology Downloaded from informahealthcare.com by UB Giessen on 10/18/14
being, and euphoria, decreases tension and de-
pression, improves certain types of cognitive
performance, improves psychological well-being,
and may reduce the risk of coronary heart dis-
ease.5 On the other hand, heavy consumption of
alcohol and addiction increase all types of injury
and trauma, and induce deleterious effects on
various organs and the developing fetus.3Attempts
to prohibit consumption of alcohol have usually
For personal use only.
failed, unless they were based on religious doc-
t r i n e ~Thus,
. ~ prudence dictates lowering of alco-
hol consumption in the general population and
abstinence in those with alcohol-related diseases.
Environmental and genetic factors are in-
volved in the susceptibility to alcoholism. Alco-
hol can lead to malnutrition either primarily due
to consumption of empty calories, or secondary to
maldigestion or malabsorption of nutrients due to
gastrointestinal complications. Alcohol can also
exert a direct toxicological effect due to its inter-
ference with hepatic metabolism. Interferencewith
immunological functions was also observed in
humans and experimental animals. A causal ef-
fect has been observed between alcohol and vari-
ous cancers (e.g., oropharynx, esophagus, larynx,
liver, breast, and large bowel). Alcohol-induced
nervous system disorders are believed to be due
to depletion of thiamin. Deficiencies in zinc and
methionine have been reported in FAS.
ACKNOWLEDGMENTS
I express my gratitude to Drs. Charles S.
Lieber, Cynthia Baum-Baicker, and William J.
Blot for the tables and the figure that they pro-
vided; to members of the NAS Committee on
Diet and Health for some of their contributions to
the substance of this article; and to the reviewers
of this manuscript for their insightful comments.
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