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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 b s t r a c ta r t i c l e i n f o

Article history:Received 19 May 2010Received in revised form 30 July 2010Accepted 6 August 2010Available online 14 August 2010

Keywords:ArsenicAlcoholCo-exposureReactive oxygen speciesToxicity

Arsenic is a ubiquitous environmental factor that has been identi ed 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 avariety 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 causedsevere diseases. There are populations who are exposed to relatively high levels of arsenic in their drinkingwater and consume alcohol at the same time. In this focused review, we aim to discuss important molecularmechanisms responsible for arsenic toxicity and potential combined toxic effects of alcohol and arsenic.

© 2010 Elsevier Inc. All rights reserved.

1. Introduction

Arsenic is a naturallyoccurring 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 footdisease, type II diabetes mellitus, and cardiovascular diseases [2– 4]. Inthe United States, over 350,000 people are exposed to water witharsenic greater than 50 μ g/L and over 2.5 million to water with arsenicgreater than 25 μ g/L [5]. Chronic alcohol consumption is also a majorhealth issue in the U.S. [6] Based on the data from Centers for DiseaseControl and Prevention in 2002, about 62.4% of U.S. adults werecurrent drinkers; about 5% of adults were heavier drinkers [7].Although there are no available published data revealing the numberof individuals co-exposed to arsenic and alcohol, the high prevalenceof arsenic exposure and the alcohol epidemic make it highly possiblethat the co-exposure exists and probably contributes to the reporteddiseases and death caused by arsenic and alcohol. This reviewemphasizes the mechanisms of the risk and toxicity of the co-exposure, and it's our intention to draw more lab-based studies andepidemiologic studies on this subject.

Several past epidemics and case reports indicate that co-exposuresto arsenic and alcohols cause severe diseases. During the early 1900s,there were over 6000 cases and 70 deaths from heart diseasesattributed to drinking arsenic-contaminated beer in England [8,9].

Arsenic as a contaminant of wines also has a long history. Peripheralvascular disease and cardiomyopathies were seen in a group of Germanvintners in the 1920s who drank wine fermented from grapes treatedwith arsenical fungicides [2]. A recent studyreported the presenceof As

in sweet little Gabonese palm wine [10] . In the U.S., arsenic-contaminated moonshine was implicated as the cause of a dozencases of cardiovascular diseases in the state of Georgia [11] . In theseincidents, had the patients taken the amount of arsenic in their drinksalone or the amount of alcohol alone, damages would not haveoccurred. It is the co-exposure that made alcohol and arsenic toxic attheir non-toxic concentrations. Experimentally, combined toxic effectsof arsenic and alcohol have been explored by several laboratories. Kleiet al. have reported that co-exposure, but not exposure to arsenic oralcohol alone, increased active Fyn tyrosine kinase, phosphorylation of important proteins such as PKC δ, membrane localization of phospho-lipase Cγ 1, vascular endothelial cell growth factor, and insulin-likegrowth factor-1 [12] . Flora et al. have observed that co-exposure of arsenic and ethanol elevates more signi cantly the activities of serumtransaminases and induces more liver lesions than arsenic or ethanolalone [13] . Theexact mechanisms responsible for the combined toxicityof arsenic and alcohol exposures are not understood. The aim of thisfocused review is to discuss the potential mechanisms responsible forthe combined toxicity of alcohol and arsenic.

2. Alcohol promotes the absorption of arsenic

As a solvent, alcohol can enhance the penetration of carcinogeniccompounds into the mucosa. An epidemiological investigation inTaiwan carried out by Hsueh et al. reveals higher total urinary arsenicin alcohol consumers than non-alcoholics [14] . Using animal modelsexposed to ethanol and arsenic, Flora et al. have reported that ethanol

Journal of Inorganic Biochemistry 104 (2010) 1229 – 1233

⁎ Corresponding author. Department of Pharmacology and Toxicology, University of Kansas, School of Pharmacy, 1251 Wescoe Hall Drive, Malott Hall 5044, Lawrence, KS66045, 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

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affects arsenic kinetics by increasing its uptake and retention in theliver and kidneys [13] . Alcohol may facilitate the uptake of arsenicthrough cell membranes that are damaged and changed in theirmolecular composition by the direct effect of alcohol. Chronicalcoholism also leads to atrophy and lipomatous metamorphosis of the parenchyma of the parotid and submaxillary gland. These causeinsuf ciently rinsed mucosal surface and result in higher concentra-tions of locally acting carcinogens. Alcohol consumption may also

alter the methylation of arsenic, affecting its distribution andretention in tissues [15] . Thus, there is high possibility that alcoholconsumption 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 (As 5+ ) and arsenite (As 3+ ) representthe most common forms of inorganic arsenic [16] . Dimethylarsinicacid (DMA) is a major form of organic arsenic in the environmentand has been used as a general herbicide or pesticide for manyyears. It is also a major metabolite of inorganic arsenic in the urineof some mammals, including humans [17] . Previous results fromboth human and experimental animal studies indicate that ingestedinorganic arsenic is quickly absorbed and rapidly enters the bloodstream [17] . In the liver, mainly in the cytosol of hepatocytes,arsenite undergoes methylation to monomethylarsonic acid (MMA III

and MMA V ) and subsequently to dimethylarsinic acid (DMA III andDMAV ) with S-adenosylmethionine as the methyl donor [17] .

The toxicity of arsenic is highly dependent on its oxidation stateand chemical composition [18] . Arsenite is therefore considerablymore toxic and carcinogenic than arsenate [19] . It is also believed thatinorganic arsenic is more toxic than organic arsenic and themethylation of inorganic arsenic is thought to be a detoxi cationprocess [20,21] . However, recent studies have shown that MMA III andDMAIII are actually more cytotoxic, more genotoxic, and more potentinhibitors of the activities of some enzymes isolated from a variety of human and animal cell types [22] . The LD50 of MMAIII is lower thanthat of arsenite in hamster [23] .

Available epidemiological investigation suggests that the methyla-tion capability of arsenic may be altered by alcohol consumption.Comparing with non-drinkers, alcohol drinkers have urinary arsenicpro le indicating a poorer methylation capacity with signi cantlyhigher inorganic arsenic percentage, MMA V percentage, MMA V /DMAV

ratio, and lower DMA V [24] . But the alcohol effect is not independent inmultivariate analyses [24]. The alcohol effect on arsenic methylationcannot be con rmed in recent Taiwanese hospital-based case-controlstudies evaluating the association between exposure to low arseniclevel and urothelial cancer [25,26] and in a 12-year prospective follow-up study conducted in the southwest arseniasisendemic areas [27].These results indicate that chronic consumption of alcohol may changethe 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

(H 2 O2 ), hydroxyl radical (•

OH), peroxyl radical (LOO•

), etc. Excessivegeneration of ROS causes oxidative injury leading to various diseases,including cardiovascular diseases and cancer. Experimental resultsshow that O 2

• − and H 2 O2 are produced in various cellular systemsexposed to arsenite (see detailed review [1]). For example, usingelectron paramagnetic resonance spectroscopy, Barchowsky et al.have shown that arsenic at environmentally relevant concentrationsor at non-lethal concentrations (below 5 μ M) increases oxygen

consumption and the formation of O 2• −

and H 2 O2 in vascular

endothelial cells [28] . An arsenic treatment can result in a 3-foldincrease 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, anoxygen radical scavenger [29] . We have detected the formation of O 2

• −

and H 2 O2 in keratinocytes incubated with arsenite [30] . Severalmechanisms have been suggested for arsenic-induced ROS gener-ation. First, mitochondria have been considered a main source of

ROS production from arsenic exposure. For example, Lynn et al. havedemonstrated that the treatment with arsenite increases intracel-lular O 2

• − levels and that this increase is probably due to activation of NADH oxidase because inhibition of the expression of NADH oxidaseremarkably reduces O 2

• − production [31] . Second, ROS may formfrom intermediary arsine species. Dimethylarsine can react withmolecular oxygen to form (CH 3 ) 2 AsOO

•

, which itself is a reactiveperoxyl radical and can produce superoxide anion. Third, methyl-ated arsenic species can release redox-active iron from ferritin andhave synergic effect with ascorbic acid to do so. Free iron plays acentral role in generating harmful oxygen species by promoting theconversion of O 2

• − and H 2 O2 into the highly reactive •

OH. Fourth, theoxidation of arsenite to arsenate produces H 2 O2 . Moreover, arsenictreatments have been shown to enhance the expression of hemeoxygenase and to increase the uorescence intensity of dichloro-

uorescein in cells, indicating an elevated intracellular peroxidelevel [32] .

Besides ROS, arsenic exposure can also affect the generation of reactive nitrogen species (RNS). NO is a messenger molecule thatplays an important role in vasodilation, neurotransmission, andimmune response. NO also possesses toxic effect such as pro-oxidation, genotoxicity and mutagenicity. Production of NO is mainlycatalyzed by NO synthases, which consist of neuronal, endothelial,and inducible forms. Arsenic has been reported to impair productionof endothelial NO in human blood [33] , although opposing resultshave also been reported [28] . These inconsistent discoveries indicatethat the effect of arsenite on NO generation is likely cell type-speci cand arsenic concentration-dependent.

It is well known that ROS plays an important role in alcohol-inducedcell injury (see review [34] for detail). Several sources are responsiblefor alcohol-induced ROS formation. Increased electron leakagefromthemitochondrial respiratory chain associated with the stimulation of NADH shuttling into mitochondria can create ROS. The induction of sphingomyelinase by TNF α increases levels of ceramide, an inhibitor of the activity of the mitochondrial electron transport chain, leading toincreased mitochondrial production of ROS. Alcohol increases activatedhepatic phagocytes as in alcoholic hepatitis, which are signi cantsources of ROS [35]. Alcohol consumption increases iron overload[36,37] . Iron, especially low-molecular-weight non-protein iron com-plexes, primes hepatic macrophages to produce ROS [38] andexacerbates oxidative damage [39] . Furthermore, ethanol inducescytochrome P450 2E1 (CYP2E1), which has a high NADPH oxidaseactivity. CYP2E1 produces O 2

•

, H2 O2 , and hydroxyethyl radicals [40].

Chronic ethanol consumption can result in a 10 – 20 fold increase inhepatic CYP2E1 in animals and humans. In addition, NO production isincreased 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 facilitateROS production. They stimulate ROS generation through eithercommon mechanisms (e.g. mitochondria) or by their own uniquesources (e.g., arsenic intermediate for arsenic or activated phagocytesfor alcohol). When cells are co-exposed to alcohol and arsenic, theyare likely to potentiate their individual effects on reactive speciesgeneration. Although there is no direct experimental evidenceshowing co-exposure generates more reactive species than individualexposures, indirect evidence from measuring glutathione (GSH)levels (see following paragraph) suggests that it is most likely the

case.

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5. Both arsenic and alcohol deplete GSH levels

Many reports have revealed that exposure to arsenic reduces bloodand cellular antioxidant levels [1]. An epidemiological study hasfound adecreased antioxidant level in plasma from individuals exposed toarsenic in Taiwan [41] . There aremany antioxidativeenzymes andsmallmoleculesin plasma, extracellular andintracellular spaces. Amongthesemolecules, GSH is particularly important in protecting cells from

oxidative injures dueto itshigh concentration,high reduction potential,and its functionsas a co-factor for important antioxidativeenzymes, e.g.glutathione peroxidases. Arsenic reduces plasma and cellular GSHlevels. For instance, arsenic drinking (12 mg/kg) for 12 weeks depletesGSH levels in the liverand thebrain of rats [42] . Several factors accountfor arsenic-induced GSH depletion. First, GSH can be oxidized inconvertingpentavalent to trivalent arsenicals. Second, arsenite has highaf nity to GSH and thus reduces free GSH level by binding it. Third, ROSinduced by arsenic oxidizes GSH.

Similarly, possible contributions of impaired antioxidant defensesto ethanol-induced oxidative stress have been extensively investigat-ed. Besides lowering vitamin E level, impairing catalase andsuperoxide dismutase (SOD) activities, alcohol depletes cellularGSH. Fernandez-Checa et al. have found that alcohol intake canlower the hepatic mitochondrial GSH (mtGSH) content by 50 – 85% inrats [43] . The research group has also reported that the depletion of GSH precedes the development of mitochondrial dysfunctions andlipid peroxidation [44] . Theselective depletionof themtGSHpool maybe the consequence of a defect in GSH transport from the cytosol tothe mitochondrial matrix in cells exposed to alcohol. The importanceof GSH homeostasis in preventing alcohol-mediated oxidative injuryis supported by the observation that the stimulation of GSH re-synthesis in rats by supplementation with either of the GSH precursorsL-2-oxothiazolidine-4-carboxylicacid or N-acetylcysteinepreventsliverinjury in the enteral alcohol model [45]. The binding of acetaldehyde, amajor metabolite of alcohol in the liver, to GSH is another cause of GSHreduction.Othercontributors to the lowered GSHmayinclude increasedROS generation and lowered GSH synthesis.

A combined exposure of arsenic and alcohol would decreasecellular GSH levels. In fact, in animals exposed to arsenic and alcohol,hepatic and plasma GSHdecreased more markedly with thecombinedexposure compared to ethanol or arsenic alone [13] . This is robust insupporting that alcohol and arsenic potentiate each other inpromoting reactive species generation and impairing cellular anti-oxidative defense system. This combined effect on GSH depletion maybe responsible for toxic effects of the co-exposure observed by Klei etal. [12] and Flora et al. [13] .

6. Both arsenic and alcohol impairs mitochondrial function

Mitochondria are intimately involved in the generation of anddefense against ROS. Meanwhile, they are themselves targets of oxidative stress andalso involve in cell signaling thatcontrol cell fate.

ROS induces mitochondrial membrane depolarization and perme-ability changes [46,47] . Loss of membrane potential and mitochon-drial permeability transition are now recognized as a key step inapoptosis [48] .

It is known that mitochondria are important targets of arsenic-induced carcinogenesis and cell death [49– 52] . Arsenic has beenshown to alter mitochondrial membrane potential and induceapoptosis in various human cancer cells by Hei's group [52,53] .Arsenic is accumulated in mitochondria via phosphate transportproteins and the dicarboxylate carrier [54,55] . Once accumulated inmitochondria, arsenic uncouples the oxidative phosphorylationbecause ATP synthase undergoes oxidative arsenylations [56] .

Ethanol affects normal energy metabolism and causes mitochon-drial damages. Ethanol metabolism promotes a substantial reduction

of both cytosolic and mitochondrial NAD, substantially increasing the

NADH level.This increase poses an acute metabolicchallenge forenergymetabolism. Conditions that increase thesupplyof mitochondrial NADHand enhance the reducing pressure on electron transport chain withoutincreasing therate of respiration promote theformationof ROS throughthe electron transport chain (see detailed discussion in the reviewarticle [57] ). Meanwhile, ethanol increases utilization of oxygen mainlythrough ethanol oxidation, resulting in localized and transient hypoxia,which further enhances ROS formation and ATP de ciency [57].

Uncontrolled mitochondrial formation of ROS promotes the inappro-priate activation of the mitochondrial permeability transition, increas-ing the sensitivity of cells to other toxicants or damage signals [58].Ethanol induces mitochondrial membrane depolarization and perme-ability changes in cultured hepatocytes [59] through promoting ROSformation [57] . In recent studies, the mitochondria permeabilitytransition has been identi ed as a key step for the induction of mitochondrial cytochrome c release and caspase activation by ethanol[60,61] . Another signi cant target of ethanol related increases inoxidative stress is mitochondrial DNA [62]. Ethanol-induced damageto mitochondrial DNA,if not adequatelyrepaired, impairs mitochondrialfunction,which further increasesoxidativestressin thecell, leading to avicious cycle of accumulating cell damage that is more apparent withadvancing age [62]. In combination with ethanol-induced defects inmitochondrial function, these alterations may promote both apoptoticand necrotic cell death and contribute to the onset or progression of alcohol-induced injury.

This aforementioned “ metabolic shift ” induced by ethanol maysigni cantly increase the susceptibility of mitochondria to otherstressor such as arsenic. Theharmful effects of arsenic on theenzymesof antioxidant defense systems such as thioredoxin reductase willpotentiate ethanol's effects on membrane permeability, mtDNAdamage and mitochondrial dysfunction, which will cause moremitochondrial dysfunction and damage. As a result, more ROS releaseand aggravated injury are predicable.

7. Both arsenic and alcohol affects cellular DNA methylation

DNA methylation is an important determinant in controlling geneexpression whereby hypermethylation has a silencing effect on genesand hypomethylation may lead to increased gene expression. Alcoholhas a marked impact on hepatic methylation capacity, as re ected bydecreased levels of S-adenosylmethionine, an important methyl groupdonor. Several mechanisms have been suggested by which ethanolcould interact with one carbon metabolism and DNA methylation andthereby enhance carcinogenesis: (1) alcohol reduces the activity of methionine synthase which remethylates homocysteine to methioninewith methyltetrahydrofolate as the methyl donor;(2) alcohol decreasesGSHlevels, and thereby enhances the susceptibility of the liver towardsalcohol related peroxidative damage; and (3) alcohol can inhibit theactivity of DNAmethylase which transfersmethyl groupsto DNAin 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 hypermethyla-tion. Other studies suggest that arsenic-induced malignant transfor-mation is linked to DNA hypomethylation after the depletion of S-adenosyl-methionine, which results in aberrant gene activation,including oncogenes [64] .

When co-exposed to alcohol and arsenic, cells are exposed tocombined effects on modi cation of DNA methylation. These wouldcause more overexpression of oncogenes and silence of tumorsuppressor genes.

8. Effects of arsenic and alcohol on DNA damage and DNA repair

The immediate product of the metabolism of ethanol by alcoholdehydrogenase is acetaldehyde. Acetaldehyde is a potent cancer-

causing agent. Acetaldehyde interferes with DNA synthesisand repair.

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