Journal of Inorganic Biochemistry 104 (2010) 12291233

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Journal of Inorganic Biochemistry

j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / j i n o r g b i o

Review Article

Potential molecular mechanisms for combined toxicity of arsenic and alcohol

Lingzhi Bao, Honglian Shi
Department of Pharmacology & Toxicology, University of Kansas, Lawrence, KS, USA

a r t i c l e

i n f o

Article history:
Received 19 May 2010
Received in revised form 30 July 2010
Accepted 6 August 2010
Available online 14 August 2010
Keywords:
Arsenic
Alcohol
Co-exposure
Reactive oxygen species
Toxicity

a b s t r a c t
Arsenic is a ubiquitous environmental factor that has been identied as a risk factor for a wide range of
human diseases. Alcohol is clearly a toxic substance when consumed in excess. Alcohol abuse results in a
variety of pathological effects, including damages to liver, heart, and brain, as well as other organs, and is
associated with an increased risk of certain types of cancers. In history, arsenic-contaminated beers caused
severe diseases. There are populations who are exposed to relatively high levels of arsenic in their drinking
water and consume alcohol at the same time. In this focused review, we aim to discuss important molecular
mechanisms responsible for arsenic toxicity and potential combined toxic effects of alcohol and arsenic.
2010 Elsevier Inc. All rights reserved.

1. Introduction
Arsenic is a naturally occurring element that is present in food, soil,
and water. Epidemiological studies have indicated that people
exposed to high levels of arsenic are prone to develop skin, bladder,
liver, lung cancers, etc. [1]. In addition to its carcinogenic effects,
arsenic exposure has been suggested to play a role in black foot
disease, type II diabetes mellitus, and cardiovascular diseases [24]. In
the United States, over 350,000 people are exposed to water with
arsenic greater than 50 g/L and over 2.5 million to water with arsenic
greater than 25 g/L [5]. Chronic alcohol consumption is also a major
health issue in the U.S. [6] Based on the data from Centers for Disease
Control and Prevention in 2002, about 62.4% of U.S. adults were
current drinkers; about 5% of adults were heavier drinkers [7].
Although there are no available published data revealing the number
of individuals co-exposed to arsenic and alcohol, the high prevalence
of arsenic exposure and the alcohol epidemic make it highly possible
that the co-exposure exists and probably contributes to the reported
diseases and death caused by arsenic and alcohol. This review
emphasizes the mechanisms of the risk and toxicity of the coexposure, and it's our intention to draw more lab-based studies and
epidemiologic studies on this subject.
Several past epidemics and case reports indicate that co-exposures
to arsenic and alcohols cause severe diseases. During the early 1900s,
there were over 6000 cases and 70 deaths from heart diseases
attributed to drinking arsenic-contaminated beer in England [8,9].
Corresponding author. Department of Pharmacology and Toxicology, University of
Kansas, School of Pharmacy, 1251 Wescoe Hall Drive, Malott Hall 5044, Lawrence, KS
66045, USA. Tel.: + 1 785 864 6192; fax: + 1 785 864 5219.
E-mail address: hshi@ku.edu (H. Shi).
0162-0134/$ see front matter 2010 Elsevier Inc. All rights reserved.
doi:10.1016/j.jinorgbio.2010.08.005

Arsenic as a contaminant of wines also has a long history. Peripheral

vascular disease and cardiomyopathies were seen in a group of German
vintners in the 1920s who drank wine fermented from grapes treated
with arsenical fungicides [2]. A recent study reported the presence of As
in sweet little Gabonese palm wine [10]. In the U.S., arseniccontaminated moonshine was implicated as the cause of a dozen
cases of cardiovascular diseases in the state of Georgia [11]. In these
incidents, had the patients taken the amount of arsenic in their drinks
alone or the amount of alcohol alone, damages would not have
occurred. It is the co-exposure that made alcohol and arsenic toxic at
their non-toxic concentrations. Experimentally, combined toxic effects
of arsenic and alcohol have been explored by several laboratories. Klei
et al. have reported that co-exposure, but not exposure to arsenic or
alcohol alone, increased active Fyn tyrosine kinase, phosphorylation of
important proteins such as PKC, membrane localization of phospholipase C1, vascular endothelial cell growth factor, and insulin-like
growth factor-1 [12]. Flora et al. have observed that co-exposure of
arsenic and ethanol elevates more signicantly the activities of serum
transaminases and induces more liver lesions than arsenic or ethanol
alone [13]. The exact mechanisms responsible for the combined toxicity
of arsenic and alcohol exposures are not understood. The aim of this
focused review is to discuss the potential mechanisms responsible for
the combined toxicity of alcohol and arsenic.
2. Alcohol promotes the absorption of arsenic
As a solvent, alcohol can enhance the penetration of carcinogenic
compounds into the mucosa. An epidemiological investigation in
Taiwan carried out by Hsueh et al. reveals higher total urinary arsenic
in alcohol consumers than non-alcoholics [14]. Using animal models
exposed to ethanol and arsenic, Flora et al. have reported that ethanol

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L. Bao, H. Shi / Journal of Inorganic Biochemistry 104 (2010) 12291233

affects arsenic kinetics by increasing its uptake and retention in the

liver and kidneys [13]. Alcohol may facilitate the uptake of arsenic
through cell membranes that are damaged and changed in their
molecular composition by the direct effect of alcohol. Chronic
alcoholism also leads to atrophy and lipomatous metamorphosis of
the parenchyma of the parotid and submaxillary gland. These cause
insufciently rinsed mucosal surface and result in higher concentrations of locally acting carcinogens. Alcohol consumption may also
alter the methylation of arsenic, affecting its distribution and
retention in tissues [15]. Thus, there is high possibility that alcohol
consumption may elevate the arsenic absorption.
3. Alcohol consumption and arsenic methylation
Arsenic distributed in the environment (food, water and soil)
exists in inorganic and organic forms. Combined with oxygen,
chlorine, and sulfur, arsenate (As5+) and arsenite (As3+) represent
the most common forms of inorganic arsenic [16]. Dimethylarsinic
acid (DMA) is a major form of organic arsenic in the environment
and has been used as a general herbicide or pesticide for many
years. It is also a major metabolite of inorganic arsenic in the urine
of some mammals, including humans [17]. Previous results from
both human and experimental animal studies indicate that ingested
inorganic arsenic is quickly absorbed and rapidly enters the blood
stream [17]. In the liver, mainly in the cytosol of hepatocytes,
arsenite undergoes methylation to monomethylarsonic acid (MMAIII
and MMAV) and subsequently to dimethylarsinic acid (DMAIII and
DMAV) with S-adenosylmethionine as the methyl donor [17].
The toxicity of arsenic is highly dependent on its oxidation state
and chemical composition [18]. Arsenite is therefore considerably
more toxic and carcinogenic than arsenate [19]. It is also believed that
inorganic arsenic is more toxic than organic arsenic and the
methylation of inorganic arsenic is thought to be a detoxication
process [20,21]. However, recent studies have shown that MMAIII and
DMAIII are actually more cytotoxic, more genotoxic, and more potent
inhibitors of the activities of some enzymes isolated from a variety of
human and animal cell types [22]. The LD50 of MMAIII is lower than
that of arsenite in hamster [23].
Available epidemiological investigation suggests that the methylation capability of arsenic may be altered by alcohol consumption.
Comparing with non-drinkers, alcohol drinkers have urinary arsenic
prole indicating a poorer methylation capacity with signicantly
higher inorganic arsenic percentage, MMAV percentage, MMAV/DMAV
ratio, and lower DMAV [24]. But the alcohol effect is not independent in
multivariate analyses [24]. The alcohol effect on arsenic methylation
cannot be conrmed in recent Taiwanese hospital-based case-control
studies evaluating the association between exposure to low arsenic
level and urothelial cancer [25,26] and in a 12-year prospective followup study conducted in the southwest arseniasisendemic areas [27].
These results indicate that chronic consumption of alcohol may change
the toxicity of arsenic through the change to the methylation capability
of arsenic.
4. Both arsenic and alcohol increase reactive oxygen species (ROS)
generation
ROS refers to superoxide radical anion (O
2 ), hydrogen peroxide
(H2O2), hydroxyl radical (OH), peroxyl radical (LOO), etc. Excessive
generation of ROS causes oxidative injury leading to various diseases,
including cardiovascular diseases and cancer. Experimental results
show that O
2 and H2O2 are produced in various cellular systems
exposed to arsenite (see detailed review [1]). For example, using
electron paramagnetic resonance spectroscopy, Barchowsky et al.
have shown that arsenic at environmentally relevant concentrations
or at non-lethal concentrations (below 5 M) increases oxygen
consumption and the formation of O
and H2O2 in vascular
2

endothelial cells [28]. An arsenic treatment can result in a 3-fold

increase in intracellular ROS production in human-hamster hybrid
(AL) cells as analyzed by confocal scanning microscopy using a
uorescent probe, which can be quenched by dimethyl sulfoxide, an
oxygen radical scavenger [29]. We have detected the formation of O
2
and H2O2 in keratinocytes incubated with arsenite [30]. Several
mechanisms have been suggested for arsenic-induced ROS generation. First, mitochondria have been considered a main source of
ROS production from arsenic exposure. For example, Lynn et al. have
demonstrated that the treatment with arsenite increases intracellular O
2 levels and that this increase is probably due to activation of
NADH oxidase because inhibition of the expression of NADH oxidase
remarkably reduces O
production [31]. Second, ROS may form
2
from intermediary arsine species. Dimethylarsine can react with
molecular oxygen to form (CH3)2AsOO, which itself is a reactive
peroxyl radical and can produce superoxide anion. Third, methylated arsenic species can release redox-active iron from ferritin and
have synergic effect with ascorbic acid to do so. Free iron plays a
central role in generating harmful oxygen species by promoting the

conversion of O
2 and H2O2 into the highly reactive OH. Fourth, the
oxidation of arsenite to arsenate produces H2O2. Moreover, arsenic
treatments have been shown to enhance the expression of heme
oxygenase and to increase the uorescence intensity of dichlorouorescein in cells, indicating an elevated intracellular peroxide
level [32].
Besides ROS, arsenic exposure can also affect the generation of
reactive nitrogen species (RNS). NO is a messenger molecule that
plays an important role in vasodilation, neurotransmission, and
immune response. NO also possesses toxic effect such as prooxidation, genotoxicity and mutagenicity. Production of NO is mainly
catalyzed by NO synthases, which consist of neuronal, endothelial,
and inducible forms. Arsenic has been reported to impair production
of endothelial NO in human blood [33], although opposing results
have also been reported [28]. These inconsistent discoveries indicate
that the effect of arsenite on NO generation is likely cell type-specic
and arsenic concentration-dependent.
It is well known that ROS plays an important role in alcohol-induced
cell injury (see review [34] for detail). Several sources are responsible
for alcohol-induced ROS formation. Increased electron leakage from the
mitochondrial respiratory chain associated with the stimulation of
NADH shuttling into mitochondria can create ROS. The induction of
sphingomyelinase by TNF increases levels of ceramide, an inhibitor of
the activity of the mitochondrial electron transport chain, leading to
increased mitochondrial production of ROS. Alcohol increases activated
hepatic phagocytes as in alcoholic hepatitis, which are signicant
sources of ROS [35]. Alcohol consumption increases iron overload
[36,37]. Iron, especially low-molecular-weight non-protein iron complexes, primes hepatic macrophages to produce ROS [38] and
exacerbates oxidative damage [39]. Furthermore, ethanol induces
cytochrome P450 2E1 (CYP2E1), which has a high NADPH oxidase
activity. CYP2E1 produces O2, H2O2, and hydroxyethyl radicals [40].
Chronic ethanol consumption can result in a 1020 fold increase in
hepatic CYP2E1 in animals and humans. In addition, NO production is
increased by the effect of ethanol on inducible nitric oxide synthase,
leading to the formation of the highly reactive peroxynitrite (ONOO).
Based on the above analyses, both arsenic and alcohol facilitate
ROS production. They stimulate ROS generation through either
common mechanisms (e.g. mitochondria) or by their own unique
sources (e.g., arsenic intermediate for arsenic or activated phagocytes
for alcohol). When cells are co-exposed to alcohol and arsenic, they
are likely to potentiate their individual effects on reactive species
generation. Although there is no direct experimental evidence
showing co-exposure generates more reactive species than individual
exposures, indirect evidence from measuring glutathione (GSH)
levels (see following paragraph) suggests that it is most likely the
case.

L. Bao, H. Shi / Journal of Inorganic Biochemistry 104 (2010) 12291233

5. Both arsenic and alcohol deplete GSH levels

Many reports have revealed that exposure to arsenic reduces blood
and cellular antioxidant levels [1]. An epidemiological study has found a
decreased antioxidant level in plasma from individuals exposed to
arsenic in Taiwan [41]. There are many antioxidative enzymes and small
molecules in plasma, extracellular and intracellular spaces. Among these
molecules, GSH is particularly important in protecting cells from
oxidative injures due to its high concentration, high reduction potential,
and its functions as a co-factor for important antioxidative enzymes, e.g.
glutathione peroxidases. Arsenic reduces plasma and cellular GSH
levels. For instance, arsenic drinking (12 mg/kg) for 12 weeks depletes
GSH levels in the liver and the brain of rats [42]. Several factors account
for arsenic-induced GSH depletion. First, GSH can be oxidized in
converting pentavalent to trivalent arsenicals. Second, arsenite has high
afnity to GSH and thus reduces free GSH level by binding it. Third, ROS
induced by arsenic oxidizes GSH.
Similarly, possible contributions of impaired antioxidant defenses
to ethanol-induced oxidative stress have been extensively investigated. Besides lowering vitamin E level, impairing catalase and
superoxide dismutase (SOD) activities, alcohol depletes cellular
GSH. Fernandez-Checa et al. have found that alcohol intake can
lower the hepatic mitochondrial GSH (mtGSH) content by 5085% in
rats [43]. The research group has also reported that the depletion of
GSH precedes the development of mitochondrial dysfunctions and
lipid peroxidation [44]. The selective depletion of the mtGSH pool may
be the consequence of a defect in GSH transport from the cytosol to
the mitochondrial matrix in cells exposed to alcohol. The importance
of GSH homeostasis in preventing alcohol-mediated oxidative injury
is supported by the observation that the stimulation of GSH resynthesis in rats by supplementation with either of the GSH precursors
L-2-oxothiazolidine-4-carboxylic acid or N-acetylcysteine prevents liver
injury in the enteral alcohol model [45]. The binding of acetaldehyde, a
major metabolite of alcohol in the liver, to GSH is another cause of GSH
reduction. Other contributors to the lowered GSH may include increased
ROS generation and lowered GSH synthesis.
A combined exposure of arsenic and alcohol would decrease
cellular GSH levels. In fact, in animals exposed to arsenic and alcohol,
hepatic and plasma GSH decreased more markedly with the combined
exposure compared to ethanol or arsenic alone [13]. This is robust in
supporting that alcohol and arsenic potentiate each other in
promoting reactive species generation and impairing cellular antioxidative defense system. This combined effect on GSH depletion may
be responsible for toxic effects of the co-exposure observed by Klei et
al. [12] and Flora et al. [13].
6. Both arsenic and alcohol impairs mitochondrial function
Mitochondria are intimately involved in the generation of and
defense against ROS. Meanwhile, they are themselves targets of
oxidative stress and also involve in cell signaling that control cell fate.
ROS induces mitochondrial membrane depolarization and permeability changes [46,47]. Loss of membrane potential and mitochondrial permeability transition are now recognized as a key step in
apoptosis [48].
It is known that mitochondria are important targets of arsenicinduced carcinogenesis and cell death [4952]. Arsenic has been
shown to alter mitochondrial membrane potential and induce
apoptosis in various human cancer cells by Hei's group [52,53].
Arsenic is accumulated in mitochondria via phosphate transport
proteins and the dicarboxylate carrier [54,55]. Once accumulated in
mitochondria, arsenic uncouples the oxidative phosphorylation
because ATP synthase undergoes oxidative arsenylations [56].
Ethanol affects normal energy metabolism and causes mitochondrial damages. Ethanol metabolism promotes a substantial reduction
of both cytosolic and mitochondrial NAD, substantially increasing the

1231

NADH level. This increase poses an acute metabolic challenge for energy
metabolism. Conditions that increase the supply of mitochondrial NADH
and enhance the reducing pressure on electron transport chain without
increasing the rate of respiration promote the formation of ROS through
the electron transport chain (see detailed discussion in the review
article [57]). Meanwhile, ethanol increases utilization of oxygen mainly
through ethanol oxidation, resulting in localized and transient hypoxia,
which further enhances ROS formation and ATP deciency [57].
Uncontrolled mitochondrial formation of ROS promotes the inappropriate activation of the mitochondrial permeability transition, increasing the sensitivity of cells to other toxicants or damage signals [58].
Ethanol induces mitochondrial membrane depolarization and permeability changes in cultured hepatocytes [59] through promoting ROS
formation [57]. In recent studies, the mitochondria permeability
transition has been identied as a key step for the induction of
mitochondrial cytochrome c release and caspase activation by ethanol
[60,61]. Another signicant target of ethanol related increases in
oxidative stress is mitochondrial DNA [62]. Ethanol-induced damage
to mitochondrial DNA, if not adequately repaired, impairs mitochondrial
function, which further increases oxidative stress in the cell, leading to a
vicious cycle of accumulating cell damage that is more apparent with
advancing age [62]. In combination with ethanol-induced defects in
mitochondrial function, these alterations may promote both apoptotic
and necrotic cell death and contribute to the onset or progression of
alcohol-induced injury.
This aforementioned metabolic shift induced by ethanol may
signicantly increase the susceptibility of mitochondria to other
stressor such as arsenic. The harmful effects of arsenic on the enzymes
of antioxidant defense systems such as thioredoxin reductase will
potentiate ethanol's effects on membrane permeability, mtDNA
damage and mitochondrial dysfunction, which will cause more
mitochondrial dysfunction and damage. As a result, more ROS release
and aggravated injury are predicable.
7. Both arsenic and alcohol affects cellular DNA methylation
DNA methylation is an important determinant in controlling gene
expression whereby hypermethylation has a silencing effect on genes
and hypomethylation may lead to increased gene expression. Alcohol
has a marked impact on hepatic methylation capacity, as reected by
decreased levels of S-adenosylmethionine, an important methyl group
donor. Several mechanisms have been suggested by which ethanol
could interact with one carbon metabolism and DNA methylation and
thereby enhance carcinogenesis: (1) alcohol reduces the activity of
methionine synthase which remethylates homocysteine to methionine
with methyltetrahydrofolate as the methyl donor;(2) alcohol decreases
GSH levels, and thereby enhances the susceptibility of the liver towards
alcohol related peroxidative damage; and (3) alcohol can inhibit the
activity of DNA methylase which transfers methyl groups to DNA in rats.
Arsenic is also able to induce DNA hyper- and hypomethylation
[63]. Arsenic interferes with DNA methyltransferases, resulting in
inactivation of tumor suppressor genes through DNA hypermethylation. Other studies suggest that arsenic-induced malignant transformation is linked to DNA hypomethylation after the depletion of Sadenosyl-methionine, which results in aberrant gene activation,
including oncogenes [64].
When co-exposed to alcohol and arsenic, cells are exposed to
combined effects on modication of DNA methylation. These would
cause more overexpression of oncogenes and silence of tumor
suppressor genes.
8. Effects of arsenic and alcohol on DNA damage and DNA repair
The immediate product of the metabolism of ethanol by alcohol
dehydrogenase is acetaldehyde. Acetaldehyde is a potent cancercausing agent. Acetaldehyde interferes with DNA synthesis and repair.

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L. Bao, H. Shi / Journal of Inorganic Biochemistry 104 (2010) 12291233

In vitro studies have shown that acetaldehyde causes cytogenetic

abnormalities in eukaryotic cells. It causes point mutations in the
hypoxanthine phosphoribosyltransferase 1 locus in human lymphocytes, and induces sister chromatid exchanges and gross chromosomal
aberrations. It also binds to proteins, resulting in structural and
functional alterations. This includes enzymes involved in DNA repair
(e.g. O-6-methylguanine-DNA methyltransferase), DNA cytosine methylation, as well as glutathione, an important antioxidative peptide.
To counteract DNA damage from endogenous and exogenous
sources, cells have evolved a number of elaborate DNA repair
mechanisms to maintain the integrity and stability of genomic DNA
over time. Such mechanisms are of crucial importance in protecting
cells from the additional DNA damage resulting from alcohol abuse
described previously. Base excision repair and nucleotide excision
repair system are very important to the recovering of alcoholinduced oxidative DNA damage and DNA adducts. There is a high
possibility that arsenic exposure may enhance the alcohol-induced
DNA damage because arsenic interferes with DNA repair system.
Inhibition of DNA repair also contributes to genetic damage induced
by arsenic exposure. A link between the enhancing effects and
inhibition of DNA repair processes has been documented by Okui and
Fujiwara [65]. Regarding possible mechanisms of repair inhibition,
Lee-Chen et al. have proposed an impairment of the ligation step in
the presence of arsenite. They observed delayed rejoining of repairmediated DNA strand breaks after UV irradiation in CHO cells
exposed to arsenic. The interaction of arsenite with the removal of
DNA damage induced by N-methyl-N-nitrosourea (MNU) has been
characterized by Li and Rossman [66,67]. They observed an
accumulation of DNA strand breaks after MNU treatment in the
presence of arsenite in permeabilized V79 cells, indicating the
inhibition of a later step of base excision repair. When using nuclear
extracts from arsenic treated V79 cells, Abernathy et al. observed a
reduced ligase activity compared with control cell extracts when
annealing synthetic oligonucleotides.
Methylation of arsenic is an important aspect of the actions of
arsenic as a carcinogen. The arsenic methylation processes replace the
ionizable hydroxyl groups by uncharged methyl groups leading to the
formation of less negatively charged arsenic species, which can
interact directly with negatively charged molecules such as DNA at
physiological condition. Methylated arsenic species can be very toxic
to DNA [68]. Alcohol consumption may alter the methylation of
arsenic [15]. As a result, it is predicable that alcohol consumption may
alter the genotoxicity of arsenic.
In addition, both alcohol and arsenic induce oxidative DNA
damage [69]. ROS is associated with a range of DNA damage including
double strand and single strand DNA breaks [31,70], the induction of
DNAprotein cross-links [71], hydroxylation of 2'-deoxyguanosine
[72], and deletion mutations [73].
9. Summary
Alcohol consumption and arsenic are two high risk factors for
human health. Through focused analyses of epidemiological results
and molecular mechanism of the toxicology of alcohol and arsenic, we
summarize the mechanisms of combined toxic effects of alcohol and
arsenic as follows. 1) Alcohol consumption elevates arsenic absorption as alcoholism leads to the mucosal surface insufciently rinsed
and therefore, exposed to higher concentrations of arsenic. 2) Alcohol
and arsenic may potentiates the toxic effects of each other through
induction of ROS, depression the level of antioxidant defense, and
aggravation of mitochondrial dysfunction. 3) There is a high
possibility that arsenic exposure may enhance the alcohol-induced
DNA damage through the interference with DNA repair system, DNA
methylation, and oxidative DNA damages. Alcohol consumption may
also affect arsenic-induced DNA damage through altering of arsenic
methylation. These interaction and aggravated toxicity may account

for potentiated toxicity observed in human incidents and experimental animals co-exposed to arsenic and alcohol. Future studies are
needed to clarify the exact mechanisms and identify potential
pathways for prevention and therapeutic treatments for co-exposure
of arsenic and alcohol.
Abbreviations
ROS
O
2
H2O2

OH
LOO
NADH
RNS
CYP2E1
ONOO
GSH
SOD
mtGSH
mtDNA
MNU

reactive oxygen species

superoxide radical anion
hydrogen peroxide
hydroxyl radical
peroxyl radical
reduced Nicotinamide adenine dinucleotide
reactive nitrogen species
Cytochrome P450 2E1
peroxynitrite
glutathione
superoxide dismutase
mitochondrial GSH
mitochondria DNA
N-methyl-N-nitrosourea

Acknowledgement
This study was supported in part by a startup fund from KUCR.
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