Alcohol Sensitivity in Different Alcohol and Aldehyde Dehydrogenase Genotypes
ALCOHOL SENSITIVITY IN TAIWANESE MEN
WITH DIFFERENT ALCOHOL AND
ALDEHYDE DEHYDROGENASE GENOTYPES
Giia-Sheun Peng, Jiu-Haw Yin,1 Ming-Fang Wang,2 Jiuun-Tay Lee, Yaw-Don Hsu, and
Shih-Jiun Yin2
Background and Purpose: Previous studies demonstrated that ADH2*2, encoding for
high-maximal velocity (Vmax) β2-alcohol dehydrogenase (ADH) activity, and mutant
ALDH2*2, encoding for null aldehyde dehydrogenase (ALDH) 2 activity, independently influence susceptibility to alcoholism. A single copy of the ALDH2*2 allele
may protect less strongly than a single copy of ADH2*2 in individuals carrying only
one copy of either ALDH2*2 or ADH2*2. Individuals with various ADH2 and ALDH2
gene status may exhibit different alcohol metabolism and alcohol sensitivity, which
affects drinking behavior. To explore the underlying pharmacogenetic mechanism,
alcohol metabolism and alcohol sensitivity were tested using ethanol challenge in
Taiwanese men with different ADH2 and ALDH2 genotypes.
Methods: Twenty-four adults, matched by age, body mass index, nutritional state,
and homozygosity at ADH3, were recruited from a population base of 304 men. Six
individuals were chosen with each of the different ADH2 and ALDH2 genotypes:
ADH2*1/*1, ALDH2*1/*1; ADH2*2/*2, ALDH2*1/*1; ADH2*1/*1, ALDH2*1/*2;
and ADH2*2/*2, ALDH2*1/*2. After a low-to-moderate challenge with ethanol
(0.3 g/kg), blood ethanol and acetaldehyde concentrations, heart rate, and facial
capillary blood flow (FCBF) were measured for 130 minutes.
Results: All heterozygous ALDH2*2 individuals were found to be strongly responsive
to low-to-moderate ethanol, as evidenced by pronounced increases in heart rate and
FCBF. Conversely, there were no significant differences in alcohol metabolism and
alcohol sensitivity between the ADH2*2 and ADH2*1 homozygotes with identical
ALDH2 genotype.
Conclusion: Individuals heterozygous for ALDH2*2 exhibit strong alcohol hypersensitivity caused by persistent accumulation of large amounts of acetaldehyde, but
homozygosity for ADH2*2 is not dependent upon this pathway against alcoholism.
Epidemiologic studies have indicated that heavy drinking is a risk factor for hypertension [1], coronary artery
disease [2], and stroke [3]. Alcohol metabolism is a
biologic determinant that can significantly affect drinking behavior and alcohol-related organ damage [4–6].
Alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH) are the major liver enzymes
responsible for ethanol elimination in humans [6–8].
Both enzymes exhibit genetic polymorphism and ethnic variation [9].
(J Formos Med Assoc
2002;101:769–74)
Key words:
alcoholism
alcohol dehydrogenase
aldehyde dehydrogenase
genotype
alcohol sensitivity
Four genes of the ADH family, coding for class I
(ADH1-3; Km < 5 mM) and class II (ADH4; Km = 34 mM)
enzymes, are significantly involved in the liver metabolism of ethanol [10]. Three allelic variants occur at the
ADH2 locus: ADH2*1, ADH2*2 and ADH2*3. Two variants occur at the ADH3 locus: ADH3*1 and ADH3*2.
ADH2*1 is the predominant allele (~ 90%) among
most world populations, but ADH2*2 is the predominant allele (~ 70%) in East Asian populations. ADH3*1
is the predominant allele among East Asians and
Department of Neurology, Tri-Service General Hospital and 2Department of Biochemistry, National Defense Medical Center,
and 1Division of Neurology, Department of Medicine, Armed Forces Tao-Yuan General Hospital, Taipei.
Received: 24 June 2002.
Revised: 2 August 2002.
Accepted: 10 September 2002.
Authors Giia-Sheun Peng and Jiu-Haw Yin contributed equally to this study.
Reprint requests and correspondence to: Dr. Giia-Sheun Peng, Department of Neurology, Tri-Service General Hospital,
325, Section 2, Cheng-Kung Road, Neihu 114, Taipei, Taiwan.
J Formos Med Assoc 2002 • Vol 101 • No 11
769
G.S. Peng, J.H. Yin, M.F. Wang, et al
Africans (~90%), whereas in whites, it is approximately
equally distributed with ADH3*2. Enzyme ADH2 2-2
exhibits 20-fold greater maximal velocity (Vmax) of
ethanol oxidation than ADH2 1-1, and the Vmax of
ADH3 1-1 is about twice that of ADH3 2-2 [6]. These
functional polymorphisms are all attributed to singlenucleotide substitutions.
Human ALDH also constitutes a complex family.
The major forms responsible for oxidation of acetaldehyde in liver are low-Km mitochondrial ALDH2
(0.20 µM) and cytosolic ALDH1 (33 µM) [11]. A
functional single-nucleotide polymorphism (SNP)
occurs within exon 12 of ALDH2, resulting in a
260-fold increase in Km for oxidized nicotinamide
adenine dinucleotide (NAD+) and an 11-fold reduction in Vmax compared with the normal enzymes [12].
About half of several East Asian populations carry
this variant ALDH2*2 allele, which is rarely seen in
other ethnic groups. Functional polymorphism for
the cytosolic ALDH1 has not been reported in
humans.
Studies have shown that the allele frequencies
of ADH2*2 and ALDH2*2 are significantly decreased
in alcohol-dependent individuals as compared to
the general population of East Asians, including
ethnic Han Chinese [10, 13, 14], Koreans [15] and
Japanese [16–23]. Our previous studies on alcoholism and alcohol-metabolizing genes have demonstrated
that protection against alcoholism afforded by
ADH2*2 is independent of that afforded by ALDH2*2
[10].
Alcohol sensitivity, including facial and upper limb/
trunk flushing, palpitation, nausea, vomiting, dizziness
and other uncomfortable symptoms [24, 25], play
protective roles against alcohol-related problems and
alcoholism among ethnic Han Chinese [9]. This has
been ascribed to the deficiency of mitochondrial
ALDH2 activity [26] and high acetaldehyde concentrations in blood [27–29]. In a survey of 1,300 Japanese
alcoholics, none were found to be homozygous for
ALDH2*2 [17]. The strong protection afforded by
homozygosity of ALDH2*2 has been attributed to increased alcohol sensitivity ascribable to the prolonged
accumulation of large amounts of acetaldehyde in
blood [9].
The mechanisms underlying protection against alcoholism afforded by heterozygous ALDH2*2 and homozygous ADH2*2 are still unclear. To evaluate the
possible protective roles of homozygous ADH2*2 and
heterozygous ALDH2*2 gene status against heavy
drinking, the relationships between alcohol sensitivity
and blood ethanol and acetaldehyde concentrations
were examined after consumption of a low-to-moderate dose of alcohol (0.3 g/kg) by individuals with
different ADH2 and ALDH2 genotypes.
770
Materials and Methods
Subjects
Medical, dental, and pharmacy students (n = 304)
underwent genotyping at the ADH2, ADH3 and ALDH2
gene loci. Briefly, DNA was extracted from leukocytes,
and allelotypes of the polymorphic ADH2, ADH3 and
ALDH2 loci were determined using polymerase chain
reaction (PCR)-directed mutagenesis and restrictionfragment-length polymorphism (RFLP), as described
previously [9]. ALDH2 allelotypes were confirmed by a
recently improved PCR-RFLP method [30].
Twenty-four adult male subjects were recruited for
the study from these 304 students. Six subjects with the
ADH2*1/*1, ALDH2*1/*1 genotype (Group 1), six
with ADH2*2/*2, ALDH2*1/*1 genotype (Group 2),
six with ADH2*1/*1, ALDH2*1/*2 genotype (Group
3), and six with the ADH2*2/*2, ALDH2*1/*2 genotype (Group 4) volunteered for the experiments. All 24
subjects were homozygous for ADH3*1.
Subjects were requested not to consume alcohol for
at least 1 week prior to testing and, on the day of testing,
were asked to eat a light lunch before 11:30 AM and to
arrive at the testing site at 2 PM, where the room
temperature was maintained around 26°C. After measuring body weight and height, fixing the probe holder
to the left ear lobe, and setting a retention venous
catheter in the right antecubital vein, the subject relaxed on a couch for 30 minutes. Baseline facial capillary blood flow (FCBF) and heart rate were measured
and blood was drawn for ethanol and acetaldehyde
content. Ethanol solution (10%, v/v) was freshly prepared in natural orange juice, and was orally administered within 10 minutes, with five aliquots at 2-minute
intervals (0.3 g/kg). Repeat measurements were conducted at 40, 70 and 130 minutes after the start of
ethanol ingestion. Blood was collected from the indwelling catheter into syringe tubes. The experimental
procedures were approved by the Institutional Review
Board for Human Studies, and informed consent was
obtained from each subject after the nature and possible consequences of participation in the study had
been explained.
Determination of blood ethanol and acetaldehyde
Ethanol concentration was determined using headspace
gas chromatography as described elsewhere [9]. Acetaldehyde in blood was determined as a fluorescent
adduct, formed by reaction with 1,3-cyclohexanedione
and ammonium ion, using high-performance liquid
chromatography [9], in a procedure modified from
Ung-Chhun and Collins [31].
J Formos Med Assoc 2002 • Vol 101 • No 11
Alcohol Sensitivity in Different Alcohol and Aldehyde Dehydrogenase Genotypes
The area under the curve (AUC) of the blood
ethanol and acetaldehyde concentrations was calculated using the trapezoidal method from the start of
ethanol administration to 130 minutes thereafter using Excel software (Microsoft Corp., Redmond, WA,
USA). In order to calculate the AUC, the curve was
divided into one triangle and two trapezoids according
to the four time points: 0, 40, 70 and 130 minutes. The
AUCs of the concentration-time curve were then
summed to give the total AUC.
Measurement of alcohol response
Heart rate was recorded by monitoring pulsation of the
radial artery for 1 minute. Blood flow in facial capillaries was monitored using noninvasive laser Doppler
flowmetry (PeriFlux 4001 Master/4002 Satellite,
Perimed AB, Järfälla, Sweden). The basic unit of measurement was the perfusion unit (PU); 1 PU was an
arbitrary value equal to an analogue output of 10 mV.
To reduce the influence of inter-individual variation,
alcohol responses were expressed as percent changes;
i.e., difference between the value obtained after alcohol ingestion and that at preingestion divided by the
latter value and multiplied by 100.
Statistical analysis
Data for the six subjects in each of the four genotypic
groups at each time point for blood ethanol and acetaldehyde concentrations (excluding zero value points),
for peak concentration, and for AUC, as well as for
percent change in heart rate and FCBF, were evaluated
using SPSS one-way ANOVA with Scheffe’s test. The
homogeneity of variance for the data was checked
using SPSS Levene’s test (SPSS Inc., Chicago, IL, USA).
The correlation between peak blood ethanol and acetaldehyde concentrations and highest percent change
in heart rate and FCBF was evaluated using partial
correlation with the SPSS software.
Results
All 24 participants had normal findings on cardiovascular
examination. There were no significant differences with
regard to age, body weight, and body mass index among
the four genotype groups (age: 22.0 ± 1.3 vs. 20.3 ± 0.5 vs.
21.7 ± 1.4 vs. 20.7 ± 1.0 yr; body weight: 66.9 ± 9.9 vs.
66.3 ± 5.8 vs. 71.7 ± 9.9 vs. 62.8 ± 5.7 kg; body mass index:
2
22.7 ± 3.2 vs. 22.6 ± 1.5 vs. 24.9 ± 3.3 vs. 20.9 ± 1.2 kg/m ;
all values mean ± standard deviation [SD]). None of the
subjects had a family history of alcoholism or drank
alcoholic beverages more than occasionally. None of the
subjects smoked or used drugs.
J Formos Med Assoc 2002 • Vol 101 • No 11
The Figure shows the time course of blood ethanol
and acetaldehyde concentrations following ingestion
of alcohol. In general, neither Groups 3 nor 4 showed
significantly higher blood ethanol concentrations than
Groups 1 and 2 (Figure, A). However, heterozygous
ALDH2*2 subjects (Groups 3 and 4) exhibited significantly higher acetaldehyde concentrations than did
homozygous ALDH2*1 subjects (Groups 1 and 2) during the entire 130 minutes of study (Figure, B). Both
homozygous ALDH2*1 groups had undetectable blood
acetaldehyde at most time points. However, at 130
minutes, ALDH2*2 heterozygotes still showed detectable blood acetaldehyde (Group 3, 8.8 ± 3.4 µM; Group
4, 8.2 ± 1.2 µM; mean ± standard error, SE). The
pharmacokinetic parameters of blood ethanol and
acetaldehyde after alcohol intake are summarized in
the Table. The AUC for the blood acetaldehyde concentration-time curve in ALDH2*2 heterozygotes was
about 226-fold greater than that in ALDH2*1
homozygotes. On the other hand, there was no difference in blood ethanol and acetaldehyde concentrations between homozygous ADH2*1 and ADH2*2
subjects with identical ALDH2 genotype after ethanol
ingestion.
Heart rates in all heterozygous ALDH2*2 subjects
were persistently faster during the entire test period
when compared with those of homozygous ALDH2*1
subjects (Figure, C). FCBF was also increased in all
heterozygous ALDH2*2 subjects examined. Group 3
subjects showed 1.6-fold greater change in FCBF than
Group 4 subjects (Figure, D), but showed 13.4-fold and
11.8-fold greater change in FCBF than Group 1 and 2
subjects, respectively (Table). The highest percent
changes in heart rate and FCBF were found to be
significantly associated with the elevation of blood
acetaldehyde (partial correlation coefficients, 0.87 and
0.65, respectively), but not associated with the change
in blood ethanol concentration (–0.07 and –0.28).
Discussion
The pharmacologic and toxicologic effects of alcohol
are dependent upon the duration of exposure and the
concentrations of alcohol and its metabolites attained
in body fluids and tissue within that period. The AUC
for the blood concentration-time curve can best describe an individual’s exposure to ethanol after a single
dose. All heterozygous ALDH2*2 subjects exhibited a
greater increase in AUC for ethanol concentration
compared with homozygous ALDH2*1 subjects (Table;
Figure, A), indicating slower alcohol elimination and
longer and heavier exposure in heterozygous ALDH2*2
771
G.S. Peng, J.H. Yin, M.F. Wang, et al
B 80
A
Blood acetaldehyde (µM)
Blood ethanol (mM)
10
●
▲
●
▲
5
●
▲
b, e
60
▲
●
b, e
40
a, d
▲
●
20
a, d
a, d
●
▲
a, d
0
▲
●
0
20
40
60
80
Time (min)
100
120
0
140
20
40
60
80
Time (min)
100
120
140
D
80
c, f
▲
c, f
60
●
b, f
▲
b, e
40
●
b, d
●
▲
20
b, d
0
▲
●
0
20
40
60
80
Time (min)
100
120
140
Change in facial capillary blood flow (%)
C
Change in heart rate (%)
▲
●
0
1000
800
a, d
b, e
●
●
600
▲
400
▲
200
0
●
▲
▲
●
0
20
40
60
80
Time (min)
100
120
140
Figure. Concentrations of A) blood ethanol and B) acetaldehyde, and percent change in C) heart rate and D) facial capillary blood flow after
administration of a low-to-moderate dose of ethanol (0.3 g/kg) to men with different ADH2 and ALDH2 allelotypes during a 2-hour period.
All subjects were homozygous for ADH3*1. ❍ = ADH2*1/*1, ALDH2*1/*1 (n = 6); ∆ = ADH2*2/*2, ALDH2*1/*1 (n = 6); ● =
ADH2*1/*1, ALDH2*1/*2 (n = 6); ▲ = ADH2*2/*2, ALDH2*1/*2 (n = 6). Vertical bars (only the upper or lower portion shown)
represent standard errors of the means. ap < 0.05 vs. ADH2*1/*1, ALDH2*1/*1; bp < 0.01 vs. ADH2*1/*1, ALDH2*1/*1; cp < 0.001
vs. ADH2*1/*1, ALDH2*1/*1; dp < 0.05 vs. ADH2*2/*2, ALDH2*1/*1; ep < 0.01 vs. ADH2*2/*2, ALDH2*1/*1; fp < 0.001 vs.
ADH2*2/*2, ALDH2*1/*1 by ANOVA.
subjects. This is probably caused by a reduction in ADH
activity due to product inhibition by acetaldehyde in
the liver (Figure, B) [32].
It is well established that blood acetaldehyde rises
rapidly in ALDH2-deficient Asians following ingestion of
alcoholic beverages [27–29, 33]. This study showed that
elevation of acetaldehyde was much greater and much
more prolonged in heterozygous ALDH2*2 subjects than
in homozygous ALDH2*1 subjects (Table; Figure, B).
The AUC of blood acetaldehyde concentration for all
homozygous ALDH2*1 subjects was 226-fold less than
that in heterozygous ALDH2*2 subjects (Table). This
finding indicates that mitochondrial ALDH2 activity in
normal homozygotes is sufficient to oxidize acetaldehyde
derived from ethanol via cytosolic ADH in liver. Hence,
virtually no build-up of blood acetaldehyde is found in
772
normal homozygous individuals (Figure, B).
Heterotetrameric ALDH2 enzymes in heterozygous individuals have residual activity, but they cannot efficiently
remove the blood acetaldehyde via the liver because the
ALDH2*2 allele encoding the mutant ALDH2 is dominant and the heterotetrameric enzymes have extremely
low activity [11, 34]. Cytosolic ALDH1 appears to be
responsible for acetaldehyde removal in ALDH2*2
heterozygotes. These explanations are primarily based on
the enzymatic properties of human ALDH1 and ALDH2,
which differ widely in Km (33 vs. 0.20 µM) as well as in
catalytic efficiency (Vmax/Km, 1.05 vs. 129 µM-1min-1) for
oxidation of acetaldehyde [11].
Cardiovascular responses and facial flush are the
most conspicuous physical symptoms presenting in Asians
showing alcohol sensitivity [24, 25, 35]. In this study, with
J Formos Med Assoc 2002 • Vol 101 • No 11
Alcohol Sensitivity in Different Alcohol and Aldehyde Dehydrogenase Genotypes
Table. Pharmacokinetic parameters of blood ethanol and acetaldehyde, and peak percent change in heart rate and facial
capillary blood flow in men with different ADH2 and ALDH2 allelotypes after alcohol intake (0.3 g/kg)
Genotype
ADH2*1/*1,
ALDH2*1/*1
Peak ethanol (mM)
AUC for ethanol (mM x hr)
Peak acetaldehyde (µM)
AUC for acetaldehyde (µM x hr)
Heart rate (% change)
Facial capillary blood flow (% change)
7.08
8.71
0.33
0.28
11.5
60.5
±
±
±
±
±
±
0.82
0.81
0.13
0.44
1.7
39.1
ADH2*2/*2,
ALDH2*1/*1
7.12
8.83
0.17
0.25
7.7
68.6
±
±
±
±
±
±
0.61
0.64
0.17
0.25
2.3
34.3
ADH2*1/*1,
ALDH2*1/*2
8.82
11.42
59.84
57.36
53.9
809.7
±
±
±
±
±
±
0.81
1.03
10.76b, e
12.70b, e
7.3c, f
218.3a, d
ADH2*2/*2,
ALDH2*1/*2
8.22
10.12
59.72
59.53
66.1
495.2
±
±
±
±
±
±
0.51
0.66
14.31b, e
14.11b, e
4.6c, f
175.7
All subjects were ADH3*1/*1. Mean ± standard error; n = 6 for each genotypic group. ap < 0.05 vs. ADH2*1/*1, ALDH2*1/*1; bp < 0.01
vs. ADH2*1/*1, ALDH2*1/*1; cp < 0.001 vs. ADH2*1/*1, ALDH2*1/*1; dp < 0.05 vs. ADH2*2/*2, ALDH2*1/*1; ep < 0.01 vs. ADH2*2/*2,
ALDH2*1/*1; fp < 0.001 vs. ADH2*2/*2, ALDH2*1/*1 by one-way ANOVA.
low-to-moderate dose ethanol challenge (0.3 g/kg), homozygous ALDH2*1 subjects showed no noticeable effects on heart rate and FCBF (Fig. C and D). Heterozygous
ALDH2*2 subjects exhibited a significant increase in
heart rate and FCBF, corresponding to the time course of
blood acetaldehyde concentrations (Fig. B). At least
400% increases in the flow rate in facial capillaries were
found during peak blood acetaldehyde concentration in
ALDH2*2 heterozygotes (Fig. D). Interestingly, only
Group 3 subjects showed significantly higher FCBF than
ALDH2*1 homozygotes. On the other hand, all ALDH2*2
heterozygotes exhibited significantly higher heart rate
than ALDH2*1 homozygotes, even up to 130 minutes
after ingestion. Heart rate increase may be a better
indicator of alcohol reaction than FCBF. The response of
FCBF to alcohol is stronger than that of heart rate, but its
sensitivity is still limited due to: the larger basal individual
variation (9.4 to 143.0 PU at baseline); unequal distribution of capillary vessels; various numbers of capillary
vessels monitored; different capacity for full dilatation in
capillaries; and sensitivity too high to respond to external
stimulation. In this study, all heterozygous ALDH2*2
subjects exhibited persistently high blood acetaldehyde
concentrations and increased heart rate, similar to the
responses of homozygous ALDH2*2 subjects after ingestion of a small amount of ethanol (0.2 g/kg) in our
previous study [9]. Peak blood acetaldehyde concentration and increase in heart rate in Group 4 subjects and
ALDH2*2 homozygotes (our previous study) showed
comparable results (59.7 ± 14.3 vs. 75.4 ± 10.6 µM and
66.1 ± 4.6 vs. 54.2 ± 9.9% (mean ± SE), respectively
(Figure, B and C) [9].
Human tissue ADH activities show large variations
with respect to isozyme patterns and genetic
polymorphism. ADH activities of subjects with the
homozygous ADH2 2-2 phenotype are about 2-fold and
20-fold higher than those with the heterozygous ADH2
J Formos Med Assoc 2002 • Vol 101 • No 11
2-1 and homozygous ADH2 1-1 phenotype, respectively
[6]. This previous finding suggests that ADH2*2 homozygotes with high enzyme activity may oxidize ethanol to acetaldehyde more efficiently than ADH2*1
homozygotes. However, the results of this study showed
no significant difference in alcohol metabolism and
alcohol sensitivity between ADH2*2 and ADH2*1 homozygotes with identical ALDH2 genotype.
In conclusion, heterozygous ALDH2*2 individuals
present strong alcohol sensitivity after low-to-moderate
alcohol ingestion that can be ascribed to prolonged
accumulation of large amounts of acetaldehyde in the
blood. This explains the partial protection against
alcoholism in individuals heterozygous for ALDH2*2.
Conversely, ADH2*2 gene status does not appear to be
related to alcohol metabolism and alcohol sensitivity
reaction. Further studies are required to elucidate the
molecular mechanisms underlying the protection
against alcoholism afforded by the ADH2*2 variant
allele.
ACKNOWLEDGMENTS: This work was supported by
grants from the National Defense Medical Center
(DOD-90-59, DOD-91-77) and the Armed Forces TaoYuan General Hospital (No. 049008).
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J Formos Med Assoc 2002 • Vol 101 • No 11