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doi:10.1152/physrev.00017.2013
INTRODUCTION
MOUSE MODELS WITH MODIFIED...
PHARMACOLOGICAL MODULATORS...
DISEASES ASSOCIATED WITH ALDH2
CONCLUDING REMARKS
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I. INTRODUCTION
Throughout their lifespan, every organism is exposed to
numerous damaging agents. Some are formed endogenously, while others accumulate following ingestion of food
or exposure to environmental pollutants. There are three
sets of active responses to these damaging events. The first
set provides a shield from these damaging agents by quickly
detoxifying them through enzymatic reactions or through
sequestration of these agents (e.g., phase I and II detoxifying
enzymes). The second set of responses involves a damage
repair system (e.g., proteolysis, DNA repair), and the third
set activates programmed cell death (e.g., apoptosis), thus
preventing propagation of the injury. It is not surprising
that many diseases are associated with a failure of one or
more of these three sets of protective mechanisms.
Many recent reviews cover literature on the repair mechanisms and on programmed cell death activation (52, 92,
263, 328). In this review, we focus on one detoxifying enzyme that provides a critical shield from damaging agents
that arise both endogenously and exogenously from exposures to the environment: aldehyde dehydrogenase-2
(ALDH2). However, many other detoxifying enzymes have
also evolved. The best characterized detoxification enzymatic system (also termed phase I system) is encoded by the
cytochrome P-450 gene superfamily, consisting of 57 different genes, that encode the enzymes involved in 75% of
all drug metabolism in humans (103, 104, 340). Aldehyde
dehydrogenase (ALDH) is another gene superfamily of
phase I oxidizing enzymes that is responsible for the detoxification of biogenic and xenogenic aldehydes. Over the
years, the field of ALDH research has been frequently reviewed and updated. Notably, Dr. Vasilis Vasilious laboratory at the University of Colorados Health Sciences Center has maintained a database of the ALDH gene superfamily for public viewing at www.aldh.org. TABLE 1 lists these
ALDHs and some of their characteristics.
ALDH has an ancient origin and is found in all living organisms from Archaea and Eubacteria to eukaryotes (131,
291). Complete human genome and expression studies revealed that there are 19 functional ALDH genes with a wide
range of tissue expression and substrate specificity. The
ALDH gene superfamily has been reviewed recently (for
comprehensive reviews on ALDH, see Refs. 59, 194, 320).
Here, we focus solely on the physiology and pathology associated with one member of this family, the mitochondrial
CHEN ET AL.
Subcellular
Location
Preferred Substrate
Cytosol
Retinal
ALDH1A2
Cytosol
Retinal
ALDH1A3
Cytosol
Retinal
ALDH1B1
ALDH1L1
Mitochondria
Cytosol
Aliphatic aldehydes
10-Formyl tetrahydrofolate
ALDH1L2
ALDH2
Unknown
Mitochondria
ALDH3A1
Cytosol, nucleus
ALDH3A2
ALDH3B1
Microsomes,
peroxisomes
Cytosol
Unknown
Acetaldehyde, 4-HNE and
MDA
Aromatic, aliphatic
aldehydes
Fatty aldehydes
ALDH3B2
ALDH4A1
ALDH5A1
ALDH6A1
Unknown
Mitochondria
Mitochondria
Mitochondria
Unknown
Glutamate -semi-aldehyde
Succinate semi-aldehyde
Malonate semi-aldehyde
ALDH7A1
Cytosol, nucleus,
mitochondria
-Aminoadipic semi-aldehyde
ALDH8A1
ALDH9A1
ALDH16A1
ALDH18A1
Cytosol
Cytosol
Unknown
Mitochondria
Retinal
-Aminobutyr-aldehyde
Unknown
Glutamic -semi-aldehyde
Unknown
Chromosome
GeneBank
Accession No.
9q21.13
NM_000689
15q22.1
NM_003888
15q26.2
NM_000693
9q11.1
3q21.2
NM_000692
NM_012190
12q23.3
12q24.2
NM_001034173
NM_000690
17p11.2
NM_000691
Sjgren-Larsson syndrome
17p11.2
NM_000382
11q13.2
NM_000694
11q13.2
1p36.13
6p22.2
14q24.3
NM_000695
NM_003748
NM_001080
NM_005589
5q31
NM_001182
6q23.2
1q23.2
19q13.33
10q24.3
NM_022568
NM_000696
NM_153329
NM_002860
ALDH, aldehyde dehydrogenases. Data from the following sources: Marchitti et al. (194), Marchitti et al.
(195), http://www.aldh.org/.
ALDH1A1
Disease, Mutational
Phenotypes, Functions
Ethanol
Acetaldehyde
[ADH]
Alcohol dehydrogenase
Acetic acid
Ethanol
Acetaldehyde
ALDH2
ADH
ALDH2 is better known for its critical role in ethanol metabolism. The ethanol detoxifying pathway in humans occurs mainly in the liver and is carried out by two enzymatic
steps. The first step is catalyzed by alcohol dehydrogenase
(ADH), and the second step is mainly catalyzed by ALDH2
(FIGURE 1). The ALDH2 gene was first identified and fully
characterized in 1987 (20, 21), and the X-ray crystal structure of ALDH2 was fully elucidated in 1999 (222). Among
the 19 human ALDH isozymes, ALDH2 is the most efficient
one for the metabolism of ethanol-derived acetaldehyde; it
has the lowest Km (0.2 M) towards this substrate (72).
This Km is 900-fold lower than that of the abundant cytosolic ALDH, ALDH1, and therefore, in humans, ALDH2 is
probably the only ALDH enzyme that contributes significantly to acetaldehyde metabolism (149). Less known is
that ALDH2 is also capable of metabolizing numerous
other short-chain aliphatic aldehydes, as well as some aromatic and polycyclic aldehydes (148), thus providing an
important protective enzymatic function against these toxic
agents. In particular, ALDH2 plays a key role in oxidizing
endogenous aldehydic products that arise from lipid peroxidation under oxidative stress, such as 4-hydroxy-2-nonenal
(4-HNE) and malondialdehyde (MDA) as well as environmental aldehydes, such as acrolein (present, for example, in
tobacco smoke and in car exhaust; Refs. 41, 368).
Acetate
[ALDH2]
Aldehyde dehydrogenase
Acetic acid
Acetaldehyde
ALDH2*2
Ethanol
ADH
FIGURE 1. Ethanol metabolism. A: ethanol metabolism occurs in two steps: ethanol is metabolized quickly by
alcohol dehydrogenase (ADH) to generate acetaldehyde. Acetaldehyde is then metabolized by the mitochondrial
aldehyde dehydrogenase 2 (ALDH2) to acetate. The first step of metabolism, catalyzed by ADH, is a reversible
reaction. The second step, catalyzed by ALDH2, is the rate-limiting step in ethanol metabolism, and it takes 1
h to metabolize the amount of ethanol that is found in a single alcoholic beverage. B: ethanol metabolism occurs
mainly in the liver. In normal ALDH2 individuals, acetaldehyde is quickly oxidized to nontoxic acetate. In ALDH2
enzyme-deficient (ALDH2*2) individuals, a significant amount of acetaldehyde is rapidly accumulated even after
a moderate amount of alcohol ingestion. Acetaldehyde, which is very diffusible and crosses biological membranes, can be circulated in the blood and metabolized in all tissues, as ALDH2 is present in all mitochondria.
CHEN ET AL.
ALDH2*2 East Asians carry the identical single nucleotide
mutation, which can be traced back to the Han Chinese in
Southeast China 2,000 3,000 years ago (184).
As discussed above, although human mitochondrial aldehyde dehydrogenase was first described in the early 1980s,
much of the work on the enzyme relates to its role in ethanol
metabolism. In particular, these studies investigated the
negative health impacts of the ALDH2*2 mutation associated with alcohol consumption and reduced prevalence
of alcoholism among ALDH2*2 carriers, due to alcohol
avoidance because of the unpleasant effect of acetaldehyde
accumulation following alcohol consumption.
hyde observed in the ALDH2*2 East Asians can be reproduced in the ALDH2 knockout (denoted ALDH2/)
mouse model. Pronounced susceptibility to ischemia-reperfusion injuries and accumulation of aldehydic adducts are
also demonstrated in the ALDH2/ mice. Two independent ALDH2 knockout alleles, tagged with a neomycinresistant marker within the ALDH2 gene, were introduced
to the C57BL/6 mouse genome to disrupt the gene function
(80, 147). Western blot analyses confirmed that no immunoreactive ALDH2 protein was produced in the homozygous ALDH2/ mice. ALDH2 knockout mice provided
useful research tools to explore the physiology, phenotypes,
and pathologies derived from a complete lack of ALDH2
function. However, these mice may not completely reflect
the phenotype of the human ALDH2*2 population, since
the ALDH2*2 allele in human carries residual enzyme activity. It is conceivable that subtle biological differences may exist between the genotypes of ALDH2/,
ALDH2/, and ALDH2*1/*2, which represents the largest affected human population. A comprehensive review on
the ALDH2 knockout mouse has been published recently
by Yu et al. (371).
Endogenous wild-type
ALDH2 gene
replaced by an
inactivated ALDH2
gene
ALDH2*2 transgenic
Multiple insertions of
overexpressed
ALDH2*2 gene,
endogenous wildtype ALDH2 gene
is intact
ALDH2 overexpression
Multiple insertions of
overexpressed
ALDH2 wild-type
gene, endogenous
wild-type ALDH2
gene is intact
Endogenous wild-type
ALDH2 gene
replaced by an
ALDH2*2 gene
Endogenous wild-type
ALDH1A1 and
ALDH2 genes
replaced by
inactivated
ALDH1A1 and
ALDH2 genes
Reference Nos.
ALDH2 knockout
Phenotype
Unpublished data
335
107, 138, 173, 185, 186, 260, 372, 375, 376). Overall, this
different genetic model demonstrated the critical role of
ALDH2 in the protection against toxic aldehydes and oxidative stress in various organs and physiological conditions.
As expected, the outcomes were, in general, the opposite of
what were observed in the ALDH2 knockout or the
ALDH2*2 overexpressing mice, which showed increased
susceptibility to aldehydes and pathological conditions.
The studies in ALDH2 overexpressing mice demonstrated,
in principle, that enhancing the ALDH2 activity can ameliorate many of the deleterious effects of aldehydes and may
provide a better protection against both acute and chronic
injuries induced by ethanol toxicity or oxidative stress.
CHEN ET AL.
A. Inhibitors
B. Activators
ALDH2 protein to the wild-type mice. However, the enzymatic activity of the knock-in animal is dramatically reduced as expected from the dominant-negative effect of the
E487K mutation. The ALDH2 knock-in mice carry a single
amino acid substitution that is equivalent to the E487K
substitution that defines the human ALDH2*2 mutation.
Unlike ALDH2 knockout or ALDH2 overexpression, the
overall level of ALDH2 gene expression in the ALDH2*2
knock-in mice is not affected and should mimic the expression level of human ALDH2*2. The enzymology, structural
defect, and phenotype of the ALDH2*2 mice are, therefore,
a true representation of the human ALDH2*2 carriers. Because of the identical nature of the genetic defect, the
ALDH2*2 knock-in mice can serve as an ideal experimental
model for the research of human diseases associated with
ALDH2 deficiency, and also for efficacy studies using small
molecule activators (Aldas, described below in the section
of pharmacological modulators of ALDH2 activity) in animal. Indeed, in our in vitro enzyme assays, Alda-1 was
capable of activating both human and mouse ALDH2*2
recombinant enzymes and with similar potency profile and
activation kinetics. In our view, the ALDH2*2 knock-in
mice should be the best model for the studies of human
ALDH2*2 mutation phenotype.
Ni
co
tin
Cl am
eft ide
Trp177
Wild-type
Glu268
Alda-1
Cys302
ALDH2*2
FIGURE 2. Alda-1, an allosteric agonist of ALDH2, corrects the structural defect in the ALDH2*2 mutant
present in 8% of the human population. Top: crystal structure of Alda-1 (stick presentation) in the catalytic
tunnel (shown as filled structure) of ALDH2 (Protein Data Bank Accession Code PDB: 3INJ). Highlighted are the
critical amino acids in this interaction. Bottom: crystal structure of wild-type ALDH2 (left panel, Protein Data
Bank Accession Code PDB: 1O05) and mutant ALDH2*2 (middle panel, Protein Data Bank Accession Code,
PDB: 1ZUM). Co-crystal structure of ALDH2*2 with Alda-1 (shown as a ball-filled structure and highlighted in
yellow; see arrows) is provided in the right panel (PDB: 3INL). Circles focus on the alpha helix structure (G)
that is missing in the mutant ALDH2*2 enzyme (middle panel vs. left panel) and is restored (right panel) when
Alda-1 is bound to ALDH2*2. Images produced using UCSF Chimera package from the Computer Graphics
Laboratory, University of California, San Francisco.
CHEN ET AL.
and cinnamon are aldehydes, and aldehydes are also products of frying or smoking meat and fish. Finally, aldehydes
are also present in our environment in a variety of aromas
and perfumes, in cigarette smoke and car exhaust, and in a
variety of chemicals and pollutants.
A. Cardiovascular Diseases
1. Myocardial infarction, heart failure, and stroke
Cardiovascular diseases, including myocardial infarction,
cardiac hypertrophy, and heart failure, are a major cause of
morbidity and mortality worldwide. Although early research efforts focused on the damaging effects of free radicals in the heart (19, 280), recent findings revealed that
ROS
4
4-HNE
Proteasome
2
ROS
1
4-HNE
ETC
5
6
KGDH
7
ALDH2
8
Nucelus
FIGURE 3. 4-HNE, an aldehydic product of lipid peroxidation, causes cytotoxicity. Buildup of aldehydes, such
as 4-hydroxynonenal (4-HNE), due to oxidative stress promotes cell death. Listed are steps in aldehydic injury
to cells, using 4-HNE (depicted as a zigzag line), as an example. 1) 4-HNE is produced through ROS-mediated
lipid peroxidation of mitochondrial and plasma membranes. 4-HNE can in turn 2) reduce membrane integrity,
3) inhibit proteasomal function, 4) trigger unfolded protein accumulation, 5) inhibit electron transport chain
activity, 6) reduce Krebs cycle activity, 7) inhibit ALDH2 activity, 8) increase mitochondrial permeability and
dysfunction, or 9) cause DNA damage.
CHEN ET AL.
Oxidative Stress
Reactive Aldehydes
Myocardial
infarction
Ethanol toxicity/
intoxication
Nitroglycerin
intolerance
Radiation dermatitis
ALDH2
ALDH2
Osteoporosis
Cardiac arrhythmia
Hypertension
Stroke
Drug toxicity
Pain
Diabetic
complications
Parkinsons
disease
Alzheimers
disease
FIGURE 4. Diseases in which activators of ALDH2 may be beneficial. See text for full discussion. Red
highlights diseases where the evidence for ALDH2 role came from preclinical proof-of-concept studies. Blue
highlights diseases where ALDH2 role was supported by clinical observations. Black highlights diseases where
evidence from both preclinical studies and from human epidemiological or pathohistological studies supports
a role for ALDH2.
10
lowing ischemia-reperfusion along with increased formation of mitochondrial reactive oxygen species and endothelial dysfunction (185, 334). In agreement with the cardioprotective role ALDH2, Endo et al. (69) reported that mice
overexpressing the inactive ALDH2*2 exhibited impairment in mitochondrial bioenergetics along with increased
oxidative stress, and elevated levels of 4-HNE-protein adducts.
Although not tested for resistance to acute myocardial infarction injury, adult transgenic mice overexpressing
ALDH2, which results in increased ALDH2 enzymatic activity by fourfold, are more resistant to acute ethanol cardiotoxicity (186). Acute intraperitoneal ethanol injection (3
g/kg) in mice with wild-type ALDH2 expression drastically
increases cardiac acetaldehyde levels along with reduced ex
vivo left ventricular developed pressure and mitochondrial
uncoupling (186, 187). This cardiac toxicity was attenuated
and accentuated in ALDH2 overexpressing and ALDH2
knockout mice, respectively (186, 187). Mice overexpressing ALDH2 exhibited a significantly reduced ethanol-mediated cardiac damage by decreasing acetaldehyde levels, thus
improving myocardial contractility and restoring mitochondrial membrane potential (186).
The sensitivity of the myocardium to aldehydic load has
also been examined in another animal model, in which
Ethanol-induced cardiotoxicity
ALDH2*2 knock-in
or
Alda-1
Ethanol
ADH
ALDH2 knock-out
or
ALDH2 over-expression
Toxic aldehydes
ALDH2
Toxic aldehydes
Toxic aldehydes
Non-reactive acids
pAkt
pAMPK
mTOR
Foxo3
Hypertrophic
PP2A
PP2C
GSK3
pNotch1
pSTAT3
Contractile dysfunction
Cardiac hypertrophy
Excessive autophagy
Normal
FIGURE 5. Ethanol-induced cardiotoxicity. ALDH2 confers protection against ethanol toxicity by affecting the
activity of key proteins in cardiac myocytes. The scheme summarizes data from transgenic mice that elucidated
the potential pathways that are regulated by ALDH2 and acetaldehydes. Activation of ALDH2 or ALDH2
overexpression were found to confer cardiac protection by regulating autophagy and apoptosis through the
balance between Akt and AMPK and their downstream substrates, such as mTOR, STAT3, Notch1, PP2A,
and PP2C (93, 98, 112).
11
CHEN ET AL.
cyte contractile dysfunction possibly through reduction of
autophagy (317).
12
Consistent with the role of ALDH2-mediated cardioprotection against ischemia-reperfusion injury, ALDH2 overexpression prevents 4-HNE-protein adduct formation and attenuates myocardial damage from ischemia-reperfusion
also via the Akt- and AMPK-mTOR signaling cascades
(185). Hence, ethanol toxicity and ischemia-reperfusion appear to trigger a common molecular signaling event that
leads to mitochondrial dysfunction, apoptosis, and autophagy. These studies illustrate the intricacy of signaling
networks that are elicited by acetaldehyde and/or oxidative
stress-derived 4-HNE. These rodent models of cardiac damage associated with increased aldehydic load recapitulate
well the pathological findings in humans (see in the following segment), and the data therefore suggest that ALDH2
activation may benefit patients with any of these cardiac
diseases.
The ALDH2*2 allele has also been linked to chronic cardiovascular pathophysiologies. In a large scale meta-analysis of genome-wide association studies from 19,608 subjects, ALDH2*2 (G to A exchange, which is also designated
as SNP rs671) was identified as the most prominent SNP
that is associated with blood pressure variation in East
Asians (139). Other studies confirmed that ALDH2*2 is a
strong risk factor for elevated blood pressure and hypertension among males who consume ethanol excessively (118,
217, 305). Chang et al. (38) recently reported that homozygous carriers of the ALDH2*2 allele were more likely to
progress to hypertension compared with noncarriers over a
follow-up period of 5.7 yr. The risk associated with the
ALDH2*2 mutation is the strongest in alcohol drinkers
relative to nondrinkers, providing further evidence for an
association between ALDH2 genetic variants and alcohol
3. Nitroglycerin tolerance
Another aspect relevant to cardiac disease and ALDH2 relates to nitroglycerin metabolism. Nitroglycerin has been
widely used as a vasodilator to treat ischemic and congestive cardiac diseases, including angina pectoris, myocardial
infarction, and heart failure (82, 242). Chen et al. (48)
demonstrated that ALDH2 plays an essential role for the
bioconversion of nitroglycerin to NO to achieve its vasodilating effects. However, nitroglycerin is a potent ALDH2
inhibitor, and continued treatment of nitroglycerin leads to
insensitivity to its vasodilating effect in patients with angina
pectoris (82). As expected, in East Asian patients carrying
the inactivating ALDH2*2 mutation, nitroglycerin is less
effective in eliciting a cardiovascular response compared
with ALDH2 wild-type subjects receiving the same treatment (106, 174, 374). Yet nitroglycerin use in East Asia for
patients with acute myocardial infarction and in congestive
heart failure is very common.
Because nitroglycerin is widely used in patients with acute
myocardial infarction, its inactivating effect on the cytoprotective enzyme ALDH2 may be of concern. Chen et al. (40)
examined this question using a rat model of myocardial
infarction. It was found that 16 h use of nitroglycerin (7.2
mgkg1day1) just prior to acute myocardial infarction
resulted in an infarct size that was 31% bigger than in
nontreated rats (40). Furthermore, a worse cardiac function
was observed in rats treated with nitroglycerin overnight, at
clinically relevant concentrations (298). Importantly, we
found that a sustained treatment with Alda-1 (16
mgkg1day1) during nitroglycerin use blocked nitroglycerin-induced inhibition of ALDH2 activity and prevented
13
CHEN ET AL.
consumption was required to develop insulin resistance
(135). Hemoglobin A1C, a long-term marker of glycemic
control, was also higher for those ALDH2*2 diabetics
who drank a light to moderate amount of ethanol compared with carriers of the wild-type enzyme (212). These
studies further lead to determining whether ALDH2*2,
independent of alcohol consumption, is a risk factor for
diabetes.
B. Diabetes Mellitus
Generally considered a disease of the Western world, diabetes is now a global epidemic, predicted to affect 380 million people by 2025, and Asian countries are predicted to
make up 60% of the diabetic worlds population (36). Unlike the Western countries, the diabetic population in Asian
countries is proportionally younger (36). A number of potential genes identified in the Asian population may link to
developing diabetes. These include ALDH2*2, which may
be a risk factor for non-insulin-dependent diabetes mellitus
(NIDDM).
Initial observations by Pyke and Leslie (171, 254) in 1978
for a Caucasian population suggested that chlorpropamide,
a sulfonylurea anti-diabetic agent, taken prior to consumption of alcohol, caused a high percentage of NIDDM to
have facial flushing. The initial studies identified this effect
to be specific for chlorpropamide, and in a study where
patients first received a placebo instead of chlorpropamide
prior to alcohol consumption, facial flushing was not observed. The researchers also found that this flushing effect
of chlorpropamide did not occur in insulin-dependent diabetics. Although chlorpropamide is no longer used clinically, in 2001, chlorpropamide was found to inhibit ALDH,
suggesting a possible link between ALDH and diabetes.
Another study investigating the correlation between ethanol and diabetes concluded that, among those with a
normal ALDH2 genotype, ethanol consumption greater
than 20 drinks per week may increase insulin resistance.
Among those with the ALDH2*2 genotype, less ethanol
14
C. Neurodegenerative Diseases
Brain is an organ that is rich in polyunsaturated fatty acid
and, at the same time, harbors a relatively high concentration of oxygen in the lipid bilayer (257). Oxidative stressinduced lipid peroxidation, mitochondria dysfunction, and
accumulation of aldehydic products are key features in aging, memory loss, cognitive decline, and neurodegeneration
(133, 258, 379). The role of ALDH2 and aldehydic load in
a variety of neurodegenerative diseases has been suggested
based on animal studies, human pathological findings, and
data from epidemiological studies. Here we focus on two
neurodegenerative diseases, Parkinsons disease and Alzheimers disease.
2. Alzheimers disease
Alzheimers disease is a degenerative disease for which there
is currently no cure. It is the most common cause of dementia, and although a less prevalent early-onset form exists, it
is the most common form of dementia afflicting people over
the age of 65. More than 4.5 million Americans are believed
to have Alzheimers disease. By 2050, because of the increase in life span, the number is expected to increase to
13.2 million (22). Currently, the only therapeutic treatment
of Alzheimers disease involves managing the symptoms,
with limited success.
Progressive loss of mitochondrial function or defects in mitochondrial metabolism in the later stages of Alzheimers
disease can lead to the generation of reactive oxygen species
resulting in oxidation of membrane lipids and accumulation of 4-HNE in the brain (232) and blood (205). Additionally, 4-HNE accumulates in the hippocampal regions of
patients with mild cognitive impairment and patients with
early Alzheimers disease (342). 4-HNE adduction was
found on amyloid proteins (277), and this 4-HNE adduction is thought to contribute to amyloid plaque formation in
a later stage of the disease (5, 205). The accumulation of
amyloid plaques over time correlates with neurodegeneration and subsequent atrophy of the affected regions of the
brain. It is therefore possible that diminishing 4-HNE accumulation during the early stages of Alzheimers disease may
reduce or prevent the disease progression.
15
Parkinsons disease is a progressive neurodegenerative disease manifested as a loss of movement control and varying
degree of dementia. Parkinsons disease afflicts 1% of the
population at age 65, and the incidence increases to 4 5%
of the population at age 85 (74, 76). The disease is associated with a progressive loss of neurons in deep nuclei in the
brain, in particular dopaminergic neurons in the substantia
nigra. Both genetic and environmental toxins have been
associated with the disease. Relevant to this review, a number of years ago, Burke and collaborators proposed and
have since accumulated substantial evidence that toxic aldehydes play a causal role in the disease (2729, 153, 238).
In particular, a very reactive aldehyde, 3,4-dihydroxyphenylacetaldehyde (DOPAL), has been implicated in the disease. DOPAL is a dopamine metabolite and a product of
monoamine oxidase in dopaminergic neurons of the brain
(29). Studies in animals demonstrated that DOPAL is a
neutoxin, and its injection induces Parkinsonism (238,
336). As DOPAL is converted to its nontoxic metabolite
3,4-dihydroxyphenylacetic acid (DOPAC) by ALDH2, increasing the activity of ALDH2 may provide a means to
reduce dopaminergic neuronal cell death. Indeed, accumulation of DOPAL in the substantia nigra is documented in
animal models of and in humans with Parkinsons disease
(28, 29, 93, 193, 335, 336).
CHEN ET AL.
D. Alcohol-Induced Pathophysiology
An estimated 1.9 billion adults (15 yr old) worldwide
consume at least a daily average of one alcoholic beverage
(13 g of ethanol) regularly (11, 338). About 140 million
people consume ethanol in excess, which results in alcoholism or alcohol dependence (337, 339). The mechanism by
which ethanol addiction (alcoholism) relates to activation
16
As we discussed earlier (see also FIGURE 3), ALDH2 protects mitochondrial functions through the detoxification of
4-HNE that accumulate in this organelle. Recent human
epidemiological studies correlate a higher incidence of Alzheimers disease in Asian patients with the inactivating
ALDH2*2 mutation (110, 136, 324). In a Japanese study
involving more than 2,200 subjects between the ages of 40
and 70 yr, levels of serum lipid peroxides were clearly
higher in female ALDH2*2 carriers, after exclusion of alcohol drinking behavior (230). There is also a synergistic
risk increase of Alzheimer disease between ALDH2*2 and
APOE-4 allele (136, 324). Apolipoprotein E protein,
APOE-4, is the least effective 4-HNE-eliminating apolipoprotein, compared with APOE-2 and APOE-3 proteins
(245). This may explain the increased risk of Alzheimers
disease associated with the APOE-4 allele and its combined vulnerability with ALDH2*2 to this disease.
Hypersensitivity to acetaldehyde vapor was also demonstrated in ALDH2 knockout mice when exposed to vapor
inhalation (129). Blood acetaldehyde levels were 2- to 3.2fold higher in ALDH2 knockout mice compared with wildtype mice, when measured after 4 h of inhaling acetaldehyde at a concentration of 5,000 ppm. Concomitantly, behavioral and physiological symptoms of augmented acute
acetaldehyde toxicity, such as staggering gaits, prone position, hypoactivity, abnormal deep breathing, and dyspnea,
were observed in the ALDH2 knockout mice relative to
wild-type mice (129). These symptoms of acetaldehyde toxicity were reproduced by a single injection of a sublethal
dose of acetaldehyde. In a study of intraperitoneal injection
of 400 mg/kg acetaldehyde, ALDH2 deficiency delayed the
recovery of physiological and behavioral symptoms and the
elimination of acetaldehyde compared with wild-type mice
(130). Interestingly, mitochondrial liver homogenates derived from these ALDH2 knockout mice also showed a
dramatic deficiency in catalytic activity toward 2-methoxy-
Acute exposure to acetaldehyde causes much of the unpleasant effects associated with ethanol intoxication, including nausea, palpitations, vomiting, dizziness, and headaches (24). These negative effects of acetaldehyde are also
deterrents, preventing reinstatement of alcoholism. After
excessive drinking was interrupted, the drug disulfiram, an
inhibitor of ALDH2, is used to trigger aversion to ethanol
consumption (297), as it causes acute acetaldehyde accumulation and the corresponding unpleasant effects. Disulfirams effects in the presence of ethanol are not different
from the Asian Acetaldehyde (Flushing)-Toxicity Syndrome, which results from the inactivating point mutation
in ALDH2 (ALDH2*2) (24). The finding that alcoholism
was less common in ALDH2*1/*2 and is nonexistent in
ALDH2*2/*2 individuals led to the notion that acetaldehyde is a strong deterrent from ethanol drinking (39, 114,
115). However, social pressure and changes in the work
and life-style of urban East Asians led to a greatly increased
incidence of alcoholism in this population. Higuchi reported a significant increase of alcoholics in Japan from 2.5
to 13% in the ALDH2*1/*2 heterozygous group from
1979 to 1992 (114). In a more recent study conducted in
Japan in 2002, 26% of the heavy drinkers (400 g ethanol
consumption per week) in the Tokyo area were ALDH2*1/*2
heterozygotes (356); ALDH2*1/*2 in the general population
is 30%. A similar trend was observed in Taiwan, where
17% of alcoholics were found to carry the ALDH2*1/*2
heterozygous genotype in 1999 (39). As will be discussed later,
ALDH2*1/*2 subjects that drink excessively are at a much
great risk of developing esophageal and other upper aerodigestive track cancers, a likely result of DNA damaging effects
of acetaldehyde.
2. Alcoholism
Another mechanism by which ALDH2 inhibitors can be
beneficial for the treatment of alcoholism has been recently
reported. A study by Yao et al. (354) suggests that alcoholism may be induced, in part, by chemical adduction of dopamine, and its monoamine oxidase aldehyde metabolite
DOPAL, to form tetrahydro-papaveroline (THP) in the
neurons of the ventral tagmental area. Inhibition of ALDH2
leads to an increase of DOPAL and hence accumulation of
THP, which selectively decreased dopamine release and
17
acetaldehyde, a major metabolite of toxic 2-methoxyethanol (ethylene glycol monoethyl ether), which is commonly
used as a water-soluble solvent in the chemical industry
with known adverse reproductive and central nervous system effects in factory workers (147). These data confirm
that ALDH2 is the major acetaldehyde-metabolizing enzyme in mice and that deficiency in ALDH2 leads to elevated acetaldehyde levels after ethanol intake, and to increased susceptibility to prolonged exposure to acetaldehyde and other toxic aldehydes. They also highlight the
potential health risks of toxic aldehydes for human carriers
of ALDH2*2 relative to the rest of the population.
CHEN ET AL.
hence led to inhibition of pro-addiction reward signaling
through a negative-feedback loop (7, 354). As previously
mentioned, CVT-10216 is a potent ALDH2 inhibitor with
IC50 of 30 nM. In these studies, CVT-10216 prevented
the increase of alcohol-induced rewarding dopamine release in brain in the absence of acetaldehyde (7, 235). Because of this unique property, CVT-10216 may therefore be
developed as a drug lead for alcoholism. In an animal model
of drug addiction, CVT-10216 also suppressed cocaine selfadministration and prevented relapse-like behavior, possibly by a similar ALDH2 inhibition-mediated increase of
THP via DOPAL and dopamine condensation (354).
18
The molecular mechanism underlying acetaldehyde-induced UADT cancers in ALDH2*2 subjects has been actively studied (310, 370). There is direct evidence showing
increased DNA modification and chromosomal damage in
ALDH2*2 individuals relative to subjects with active
ALDH2 after they consume the same amount of alcohol
(200). Matusta et al. (200) identified three acetaldehydederived DNA adducts that are significantly higher in blood
lymphocyte samples of 44 alcoholic patients. One of the
acetaldehyde-modified DNA adducts, N(2)-ethyl-2=-deoxyguanosine (200), was identical to its more stable precursor,
N(2)-ethylidene-2=-deoxyguanosine, detected in gastric and
hepatic samples of ALDH2 knockout mice fed with
20% ethanol for 5 wk (198, 216). N(2)-ethyl-2=-deoxyguanosine is a known blocker of translesion DNA synthesis
and may contribute to the hindrance of DNA repair (199,
288, 316). Chromosomal damage or genome instability in
ALDH2*2 subjects who consume ethanol were also measured by biomarkers such as cytokinesis-block micronucleus assay (126) or by alkaline comet assay using peripheral blood lymphocytes from the ALDH2*2 subjects (287,
333). Blocked micronuclei frequency was significantly
higher in the heavy or moderate alcohol drinkers with the
ALDH2*2 allele compared with their ALDH2*1 wild-type
counterparts (126). Similarly, using the alkaline comet assay to measure the mobility of DNA as an index of DNA
damage in peripheral mononuclear cells in a study of 122
healthy volunteers, increased DNA damage was noted in
ALDH2*2 subjects who were frequent alcohol drinkers
(333). Although these data paint a clear connection between ethanol consumption, ALDH2 activity, and cancer,
much research is still required to identify key genetic and
epigenetic changes, which contribute to the high incidence
of UADT cancers among the ALDH2*2 populations.
In recent years, UADT cancer prevention has become a
public health priority in East Asian countries such as Japan
F. Radiation Dermatitis
Ionized radiation used as a treatment for solid tumors often
causes burnlike injury to the skin due to cellular oxidative
stress. This painful and debilitating side effect occurs in
95% of patients receiving radiation therapy for cancer,
and ranges in severity from mild erythema to severe ulceration (274). Although intensity-modulated radiotherapy
enables better sparing of normal tissues, this burnlike skin
reaction is unavoidable (13). Meta-analysis of 20 clinical
trials involving 3,000 patients demonstrated that both
prophylactic and treatment trials to prevent radiation dermatitis failed when using a variety of topical agents (188).
The trials analyzed in that meta-analysis study included use
of topical agents such as mometasone furoate, beta-methasone, and beclomethasone (all anti-inflammatory corticosteroids); Gentian violet (a topical antiseptic agent); urea,
Lianbai liquid, and aloe vera (traditional medicine remedies
with possible antioxidative stress properties); hyaluronic
acid, Biafine, dexpanthenol, and Sucralfate (agents that induce wound barrier and/or are moisturizers); and Trolamine (a barrier and analgesic agent) (188). The failure of all
these clinical trials emphasizes that radiation dermatitis remains an unmet clinical problem in cancer patients undergoing radiation therapy.
Ionizing radiation causes a robust production of reactive
oxygen species (341), which then triggers an inflammatory
response as well as a local cell proliferative response, especially keratinocytes. Since anti-inflammatory agents appear
to provide little benefit (see above), the source of injury lies
elsewhere, perhaps an increased aldehydic load. Early studies attributed the sustained radiation-induced skin injuries
to increased levels of aldehydes, such as 4-HNE and MDA,
19
CHEN ET AL.
the lipid peroxidation products (2, 58). Therefore, prophylaxis and treatment with agents that prevent aldehyde accumulation, such as activators of ALDH2, may be beneficial for these patients.
G. Fanconi Anemia
Fanconi anemia (FA) is a rare genetic disease, first discovered by Guido Fanconi, a Swiss Physician, in 1927. FA is
characterized by a progressive bone marrow failure (BMF)
accompanied by increased risk of cancer as well as developmental abnormalities, such as short stature and malformations of the thumbs, forearms, skeletal system, eyes, kidneys, and urinary tract. In addition to hematological abnormalities, FA is clinically diagnosed by the presence of
chromosomal breakage, and by hypersensitivity to DNA
cross-linking agents such as mitomycin C, diepoxybutane,
and cisplatin (140, 141). No effective treatment is currently
available for this rare genetic disorder, which occurs in
1/350,000 individuals in all ethnic groups (10, 321).
In the United States, 31 newborns are diagnosed with
Fanconi anemia (FA) each year (270). Based on International Fanconi Anemia Registry, the average life expectancy
of FA patients is 29 years. With blood transfusions, many
patients can live at times twice as long as life expectancy. FA
is caused by homozygous recessive mutations in any of the
15 identified FA genes (FNAC genes), which encode proteins that serve an essential function in DNA repair of damages caused by DNA cross-linking agents (206). The FA
gene products play a crucial role in guarding the integrity of
the human genome; mutations in any of the FA genes invariably lead to catastrophic consequences of genomic instability due to failure to repair DNA crosslinking damage.
Until recently, the source and chemical agents that cause
excessive genomic instability leading to the phenotype of
developmental abnormality, BMF, and predisposition to
20
Chronic exposure to low concentration of acetaldehyde vapor at 125 and 500 ppm for 6 12 days led to a significant
elevation of the DNA damage marker 8-hydroxydeoxyguanosine (8-OHdG) in urine samples of the ALDH2
knockout mice (228). As discussed earlier, acetaldehyde,
commonly found in many food sources (81), environmental
pollutants (121, 311), cigarette smoke (264), or as a metabolite of drinking alcohol, can also react in cells to generate
interstrand DNA crosslinks (309). Acetaldehyde can also be
generated as a by-product of endogenous metabolism from
alanine by myeloperoxidase (112) or from deoxyribose
phosphate by aldolase (226). Marietta et al. (196) showed
that exposure to acetaldehyde at biologically relevant concentrations (0.11 mM) resulted in concentration-dependent FANCD2 mono-ubiquitination, in phosphorylation of
the FANC gene product BRCA1, and in appearance of a
hallmark of DNA damage, histone H2AX phosphorylation, in human lymphoblastoid cells.
Exactly what types of xenogenic or biogenic reactive aldehydes that may serve as potent physiological triggers for
different pathological features of FA remain to be identified
(244). Regardless, the relationship between acetaldehyde
toxicity and DNA damage is likely to be especially relevant
to the health of East Asian FA patients who carry the
ALDH2*2 mutation (FIGURE 6).
H. Pain
Solid tumors
O
DNA
damage
ALDH2
Acetate
H3C
Fanconi
mutations
Leukemia
Acetaldehyde
Damaged DNA
Fetal alcohol syndrome
ALDH2*2
Developmental abnormalities
FIGURE 6. ALDH2 and Fanconi anemia. In a mouse model of Fanconi anemia (FANCD), ALDH2 is essential
in counteracting acetaldehyde toxicity. In the absence of a functional ALDH2, DNA damage triggered by
elevated acetaldehyde toxicity cannot be repaired efficiently due to Fanconi mutations. Accumulation of such
unrepaired damaged DNA leads to the manifestation of multiple pathological conditions and health complications seen also in patients with Fanconi anemia (95, 161, 244).
21
CHEN ET AL.
1. Peripheral neuropathy
One side effect of disulfiram in humans is peripheral neuropathy, which can be reversed by stopping or reducing the
disulfiram dose (83, 89). The largest case report of 37 patients with disulfiram-induced neuropathy showed that the
effect is dose-dependent, with doses greater than 250 mg/
day being the greatest factor in causing neuropathic symptoms (89). Since this form of neuropathy is drug induced,
given that the disulfiram metabolite S-methyl-N,N-diethylthiocarbamate inhibits ALDH2 (204), these data suggest
that decreased ALDH2 activity is sufficient to induce peripheral neuropathy in humans.
Indeed, some reports suggest that individual carriers of the
ALDH2*2 mutation are more susceptible to developing
alcohol- or diabetic-induced peripheral neuropathy (197,
303). Chronic alcoholism in ALDH2*1/*2 subjects is associated with reduced sensory nerve action potential amplitude, a characteristic of peripheral neuropathy (273), compared with chronic alcoholics with wild-type ALDH2
(197). Although this study included a small number of subjects (21 per group), the findings suggest that further studies
are needed to investigate ALDH2 as a genetic cause of alcohol-induced neuropathy. A study of 158 type 2 diabetics
investigated how ADH and ALDH2 activity altered diabetic clinical symptoms, including neuropathy (303).
Among the patients studied, although hemoglobin A1C,
age, and weight were similar between groups, patients with
an ALDH2*2 mutation with normal ADH activity had the
highest incidence of peripheral neuropathy (16 of 32 people
or 50%). The lowest incidence of neuropathy occurred in
those patients who had normal ADH and ALDH2 activity
(8 of 44 or 18.2%). Although an increase in ADH activity
was also considered in this study to contribute to diabetic
pathology, reanalyzing the groups in this study without
considering ADH activity suggests that an inactive ALDH2
enzyme is correlated with a higher incidence of diabeticinduced neuropathy (36 vs. 26%).
Studies regarding ethnicity and neuropathy prevalence are
at best inconclusive (292). Although in both alcohol- and
22
2. Inflammatory pain
As compared with other ethnic populations, Asians are
more sensitive to painful stimuli such as skin irritation
(271), capsaicin treatment (325), exposure to heat (329),
cold (122), or mechanical pressure (343). These differences
are attributed primarily to social or cultural factors (37,
56). However, the high prevalence of the ALDH2*2 inactivating mutation among East Asians [36% on average
(24) and in some regions as high as 45% (70)] suggests that
increased pain sensitivity in Asians may be attributed to the
ALDH2*2 genotype. We recently tested this hypothesis in
our laboratory using a C57/BL6 mouse with a knock-in
mutation for the ALDH2*2 gene and found that male
ALDH2*1/*2 heterozygotic mice subjected to carrageenaninduced inflammation were more hyperalgesic compared with matched male littermates with ALDH2*1/*1
(wild-type) genotype (unpublished data). Although more
studies are needed, our findings suggest that ALDH2 activity may regulate inflammatory-induced pain sensation. If
correct, restoring the ALDH2 activity in East Asians in
particular and increasing ALDH2 activity for subjects with
a wild-type ALDH2 could provide a novel means to treat
pain.
I. Osteoporosis
Osteoporosis is a disease characterized by decreased bone
mineral density, bone mass, and bone strength, which leads
to increased risk of bone fracture. Osteoporotic fractures
are associated with high morbidity and mortality, as well as
a high burden of health care costs, especially with the aging
population worldwide (57). There are multiple causes for
osteoporosis, including environmental, dietary, and genetic
factors. Relevant to this review, excess alcohol consumption and oxidative stress are associated with osteoporosis,
decreased bone density, and increased fracture incidence
(63, 91, 137, 165, 191); heavy ethanol drinking was found
to be a significant risk factor for increased hip fracture and
vertebrate deformation in large cohorts of Japanese and
Chinese women (91, 165).
In humans, both bone mineral density and osteoporotic fractures have high genetic determinants (180, 349). In a genetic
screening of osteoporosis and DNA polymorphism among
403 elderly Japanese, ALDH2*2 was the only mutation that
was associated with osteoporosis among 11 other known osteoporosis-related genes (351). This association is particularly
pronounced in individuals with the homozygous ALDH2*2/*2
genotype and in women.
PPAR expression, a transcription factor that inhibits osteoblastogenesis. These studies indicated that aldehydic stress resulting from ALDH2*2 mutation leads to impaired osteoblastogenesis and osteoporosis. Independently, severe ethanol-induced suppression of osteoblast differentiation, mineralized
nodule formation, and osteogenic gene expressions that led to
osteopenia was also observed in ALDH2 knockout mice
(284). This is in agreement with the hypothesis that ALDH2
protects normal development and differentiation of osteoblastic stem cells in the bone marrow and maintenance of bone
homeostasis.
Interestingly, in a genome-wide association study involving
11,500 individuals from well-defined and homogeneous
populations, Guo et al. (108) recently identified a SNP in
ALDH7A1 as a highly significant susceptible gene for osteoporosis. These studies provided insights into the crucial
function of ALDH in protecting osteoblasts against toxic
aldehydes, oxidative stress, and perhaps maintaining
proper osmotic pressure and homeostasis for osteoblastic
bone marrow cells.
J. Aging
Denham Harman in 1956 proposed the free radical theory of
aging, suggesting that oxygen free radicals cause the aging
process (111). This theory is also supported by the premature
aging disease Hutchinson Gilford progeria, where the average
human life span is only 13 yr. Fibroblasts of progeria patients have a 1.6-fold higher fluorescence emission measured
by intracellular oxidation of 2,7-di-chlorofluorescein (DCF)
and a 1.7- to 4-fold increase in carbonylated proteins compared with age-matched control fibroblasts (322). Moreover,
in 2007, an inverse correlation was found in 12 species between the rate of hydrogen peroxide (H2O2) generation by the
myocardium mitochondria and maximum life span (160).
This inverse correlation (R2 0.54) existed when measuring
H2O2 formation by reverse electron transfer from succinate to
complex I in diverse species. In turn, therapeutics that reduce
mitochondrial reactive oxygen species generation are considered potential means to reduce aging-induced damage, and
mitochondrial targeted anti-oxidants, such as SkQ1, have
been under development in an attempt to slow down the aging
process (289). As discussed earlier, reactive oxygen generation
triggers lipid peroxidation and accumulation of reactive aldehydes (73, 194).
Protecting the mitochondria from reactive oxygen species
may increase life span. Decrease in mitochondrial detoxification of lipid peroxidative aldehydes has been observed
and proposed as an underlying mechanism of aging in animals (231, 369). It was shown in rats that the capacity of
4-HNE removal by mitochondrial ALDH declines with aging in rats (42). Therefore, ALDH2 activation may slow
down, at least to some extent, the aging process. To that
end, specifically targeting mitochondrial ALDH2 may re-
23
CHEN ET AL.
duce or prevent many biological effects associated with free
radical-induced aging. Indeed, deleting the ALDH2 homolog in Drosophila reduced survival and longevity when
flies were challenged with hyperoxia or with starvation
(35). There was also a reduced reproductive rate and increased protein carbonyl level in flies in which ALDH2 was
deleted compared with wild-type ALDH2 flies. Consistent
with these findings, transgenic mice that overexpress
ALDH2*2 (called DAL101) showed a significant reduction
in median life span compared with control mice; their life
span was 96 wk compared with 126 wk for the wild-type
mice. In addition, the ALDH2*2 mice showed a greater
muscle weakness and hair discoloration in males (231).
24
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25, 40
149
355
349
223
302
167
227, 301
230
V. CONCLUDING REMARKS
acknowledged for their critical reading of and useful comments for the manuscript.
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DISCLOSURES
D. Mochly-Rosen and C.-H. Chen are founders of ALDEA
Pharmaceuticals. C.-H. Chen is also a consultant to the
company.
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