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Year : 2017  |  Volume : 2  |  Issue : 2  |  Page : 91-96

Is it possible to avert arsenic effects on cells and tissues bypassing its toxicity and suppressive consequences of energy production? A hypothesis

Department of Physiology, University of Gour Banga, Malda; Experimental Medicine & Stem Cell Research Laboratory, Department of Physiology, West Bengal State University, Kolkata, West Bengal, India

Date of Submission11-Oct-2017
Date of Acceptance27-Oct-2017
Date of Web Publication15-Dec-2017

Correspondence Address:
Dr. Biplab Giri
Department of Physiology, University of Gour Banga, Malda - 732 103, West Bengal
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/bjhs.bjhs_28_17

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Arsenic, a sulfhydryl reactive metalloid, found primarily in two forms: arsenite and arsenate, causing several human health problems, is considered as a dreaded agent against public health. It mainly spreads through groundwater contamination and affects human mainly through drinking water. Arsenic contaminated groundwater is now a major threat in some parts of India (the river basin of Ganga and Brahmaputra) and Bangladesh. The current authors belong to the region where arsenic poisoning and its consequences are spreading in an uncontrolled way. We are helpless to stop the spreading of geogenic groundwater arsenic contamination at present. Although most of the research on arsenic removal from drinking water and on toxicity profile has been carried out, very few preventive measures have been reported till date to balance the arsenic-induced cellular energy deficiency and oxidative stress-mediated cell death and cellular senescence. And, therefore, we need to think about alternative remedial to address such problems, which propel us to propose the current hypothesis that the adverse effects of energy imbalance due to arsenic toxicity in cells could be dodged by intake of moderate amount of alcohol. While pyruvate dehydrogenase complex is blocked by arsenic, glucose cannot be utilized through Kreb's cycle. However, alcohol can produce energy by bypassing the aerobic adenosine triphosphate (ATP) production machinery. In addition, arsenic poisoning incurs cellular oxidative stress which needs to be scavenged further. So to meet this secondary problem, we also suggest consuming red grape juice (a potent antioxidant and cytoprotective agent) in addition to alcohol (as per International Center for Alcohol Policies (ICAP) Drinking Guidelines) in our second part of the hypothesis. In conclusion, it can be suggested that the red wine which contains moderate amount of alcohol and high levels of red grape polyphenols, galic acid, resveratrol, and other antioxidants could be the best alternative to tackle the arsenic-induced cellular aging, senescence, and death.

Keywords: Arsenic, arsenic toxicity, ethanol, galic acid, polyphenol, red grape, red wine

How to cite this article:
Giri B, Dey S. Is it possible to avert arsenic effects on cells and tissues bypassing its toxicity and suppressive consequences of energy production? A hypothesis. BLDE Univ J Health Sci 2017;2:91-6

How to cite this URL:
Giri B, Dey S. Is it possible to avert arsenic effects on cells and tissues bypassing its toxicity and suppressive consequences of energy production? A hypothesis. BLDE Univ J Health Sci [serial online] 2017 [cited 2023 Jun 6];2:91-6. Available from: https://www.bldeujournalhs.in/text.asp?2017/2/2/91/220945

Arsenic is one of the greatest concerned environmental pollutants and is considered to be a causative agent for serious worldwide health hazards. Arsenic can exist in both organic and inorganic forms. The inorganic forms of arsenic consist of arsenate and arsenite compounds, which are known to be harmful to human. High level of arsenic in groundwater has been reported from several countries, including Bangladesh, India, China, Chile, and some parts of the United States.[1] Human get exposure to arsenic mainly from drinking water and food. Drinking water get contaminated with arsenic from arsenical pesticides, natural minerals deposit or inappropriately disposed arsenical chemicals. In the World Health Organization fact sheet (1999) arsenic contamination was considered as major issue for the public health which needs to be corrected in an emergency basis. The maximum permissible limit of Arsenic is 10 μg/ml in drinking water.[2] However, elevated arsenic level in drinking water is the major cause of arsenic toxicity around the globe. The major areas affected severely due to acquaintance with arsenic contaminated groundwater, having up to 800 μg/ml of arsenic content are in the river basin, Ganga, Brahmaputra in India and Meghna in Bangladesh with an approximated 6 million people in West Bengal, India and 25 million people in Bangladesh.[3],[4] Arsenic poisoning is a contributing factor for skin lesions, hyperkeratosis, cerebrovascular and cardiovascular disease, liver cirrhosis, renal dysfunction, neurological problems (headache, lethargy, mental confusion, hallucination, and seizures), gastrointestinal problems (burning lips, painful swallowing, thirst, nausea, and severe abdominal colic), anemia, leukopenia, carcinogenenesis (skin cancer and lung cancer) and other chronic conditions.[5],[6] Arsenic impedes durability of living cells by inhibiting essential metabolic enzymes allosterically. As 3+ primarily targets pyruvate dehydrogenase, thiolase, and glutathione (GSH) reductase in mammalian systems.[7] As a result, the cellular energy production machinery is being interrupted, which may leads to less availability of ATP in cells and tissues, consequently produces oxidative stress by forming reactive oxygen species (ROS) as well as reactive nitrogen species (RNS) and ultimately cell death starts through the process of apoptosis, cellular senescence and aging. Recent research showed that there is a positive interaction between arsenic and ethanol co-exposure that affect endothelial signaling and induces expression of vascular endothelial cell growth factor (VEGF), insulin-like growth factor-1 (IGF-1) and a number of angiogenic genes in vitro.[8] Most of the research till date tried to explain how arsenic could be removed from drinking water and what kind of toxicity it does. However, very few preventive measures have been reported to compensate the arsenic-induced cellular energy deficiency and oxidative stress-mediated cell death and cellular senescence.

Hence, we are enthusiastically proposing our hypothesis that the adverse effect of energy imbalance due to arsenic toxicity in cells could be dodged by intake of moderate amount of ethanol. In the human body, in a simple oxidative way, ethanol can be converted easily into acetaldehyde and rapidly metabolized to acetate and subsequently into acetyl-CoA which enters the citric acid (TCA) cycle and generate ATP in cells. However, arsenic poisoning and ethanol metabolism both produce reactive species including acetaldehyde, hydroxyl radicals, superoxide anions, H2O2 which needs to be scavenged further. So to meet this secondary problem, we introduced red grape juice as a potent antioxidant and cytoprotective agent in our second part of the hypothesis.

  Basis for the Hypothesis Top

Arsenic (arsenite/arsenate) and its effects on energy-yielding pathway

Arsenic can interfere with cellular longevity by inhibiting essential metabolic enzymes of cells. Arsenite, a sulfhydryl reactive metalloid, is one of the highest alarming environmental toxicants. This compound is poisonous because it can covalently bind to the vicinal dithiols or sulfhydryls groups of lipomide (a cofactor of dihydrolipoyl dehydrogenase enzyme), forming bidentate adducts which leads to inactivation of dihydrolipomide dehydrogenase (DLD) of pyruvate dehydrogenase complex.[9],[10] As a result, cellular gluconeogenesis and oxidative phosphorylation are impaired. This inhibits the conversion of pyruvate to acetyl coenzyme A (acetyl-CoA) thereby affecting ATP production by Krebs's cycle [Figure 1]. Apart from the above effects, arsenic also inhibits cellular glucose uptake, gluconeogenesis, oxidation of fatty acid, and further acetyl-CoA production.[11]
Figure 1: Mode of arsenic toxicity on cellular energy metabolism

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Pentavalent inorganic arsenic (iAs) can exert its toxicity by two different ways, first by its reduction to trivalent arsenic and secondly due to its structural similarity with inorganic phosphate, it gets substituted in the position of phosphate in various metabolic pathways.[11] Arsenate replaces phosphate when it reacts with glucose and gluconate. This produces glucose-6-arsenate and 6-arsenogluconate, which act as analog for glucose-6-phosphate and 6-phospho-gluconate, respectively. Glucose-6-arsenate binds to glucose-6-phosphate dehydrogenase and impedes hexokinase activity through negative feedback mechanism during glycolysis. Unlike phosphate, the presence of arsenate restricts the generation of ATP by formation of an unstable anhydride product while reacting with glyceraldehyde-3-phosphate. The produced anhydride 1-arsenato-3-phospho-glycerate readily hydrolyzes due to the longer bond length of As-O compared to P-O.[10] 1,3-bisphosphoglycerate is one of the intermediate products which is produced from glyceraldehyde 3-phosphate. Arsenite readily binds to glyceraldehyde 3-phosphate and produce 1-arseno-3-phosphoglycerate which spontaneously go through nonenzymatic hydrolysis, thereby hindering ATP production.[11] In mitochondria, arsenate binds to ADP in the presence of succinate, forms an unstable compound which uncouples and thereby markedly reduced the synthesis of ATP [10] [Figure 1].

Arsenic (arsenite/arsenate) and its effects on oxidative stress pathway

Inhibition of energy-yielding metabolic pathways due to arsenic toxicity causes less ATP availability in cells or tissues, resulting in oxidative stress due to the formation of ROS, RNS and insufficiency of natural cellular antioxidants like reduced GSH to eradicate those free radicals.[12],[13] Mitochondria is the main target site of arsenic in the cell. Arsenic induces cell death by depolarizing mitochondrial membrane potential and releasing cytochrome-c. Arsenic exposure upsurges the lipid peroxidation, H2O2 production, NO concentration, and mitochondrial swelling. The exposure also increases the concentration of arsenic in cardiac tissue and mitochondria which causes alteration of the mitochondrial lipid profile, reduction of mitochondrial antioxidants and Kreb's cycle enzymes, cytochrome-c-oxidase, Ca 2+, and ATP levels.[14] Arsenic induces the formation of superoxide anion radicals such as singlet oxygen, the peroxyl radical, hydroxyl radicals, NO, H2O2, dimethyl-arsinic-peroxyl radicals, and also the dimethyl-arsinic radicals in a dose-dependent manner.[15],[16] GSH proposed to act as an electron donor during the reduction of pentavalent to trivalent arsenic compounds. Since arsenite possesses a high affinity to GSH, it renders subsequent reactions.[11]

The consequences of these energy imbalance and oxidative stress cause cellular degenerative changes, senescence, and aging of the people suffering from arsenicosis.[17] With the DLD enzyme inhibition during arsenic poisoning, suppressed acetyl-CoA (the source of substrate of TCA cycle) production resulting in onset of cellular apoptosis due to reduced ATP formation. The aerobic fate of pyruvate into acetyl Co-A through PDH complex is blocked due to arsenic poisoning. Therefore, lactic acid fermentation is only anaerobic fate of pyruvate in mammalian system to utilize pyruvate and generate ATP. Such poisoning ultimately raises lactate level and leads to lactic acidosis.[18],[19]

  Evaluation of the Hypothesis Top

Hypothesis of alternative energy source

Now the question is - how can we save and protect the arsenic affected cells/tissues from arsenic toxicity? Is there any alternative way of energy/ATP production in those arsenic affected cells and could we stimulate those energy-yielding pathways by any food/drinks/nutrients which can bypass most/any of the affected pathways? Our first approach is to ameliorate the adverse effects of energy imbalance formed due to arsenic toxicity. In liver, ethanol is metabolized and converted into acetyl-CoA bypassing PDH-enzyme complex. The produced acetyl-CoA readily enters TCA cycle and generates ATP. Hence, cellular energy imbalance can be circumvented by ethanol administration. Therefore, ethanol metabolism could be one of the alternative ways of energy/ATP production in those arsenic affected cells.

Ethanol as an alternative source of energy during arsenic toxicity

The adverse effect of cellular energy imbalance due to arsenic toxicity can be passed up by intake of moderate amount of ethanol (e.g., in the USA, up to 250 ml/week/man is considered safe as per the guidelines of the International Center for Alcohol Policies). In the human body, liver is the main site of alcohol (ethanol) metabolism via a simple oxidative pathway. Ethanol can be converted to acetaldehyde by three different enzymes located in three different sites of cells, namely, alcohol dehydrogenase (located in cytosol), catalase (located in peroxisomes), and cytochrome P450 2E1 of Microsomal ethanol-oxidizing system (located in microsome/peroxisome). Acetaldehyde gets metabolized rapidly to acetate by the enzyme aldehyde dehydrogenase (ALDH). This acetate can readily enter TCA cycle and generate ATP for the arsenic affected cells helping them to survive. There are two classes of ALDH among them ALDH1 located in cytosol having a high KM value for acetaldehyde and ALDH2 located in mitochondria having a low KM value for acetaldehyde.[20] Ethanol metabolism also produces reactive species including acetaldehyde, hydroxyl radicals, superoxide anions, and H2O2. The acetaldehyde can be further metabolized to nontoxic acetate by ALDH which can produce energy on entering TCA cycle [Figure 2]. Recent observations also suggest that ethanol decreases the arsenic-induced elevation of hepatotoxicity marker enzymes (alkaline phosphatase, alanine transaminase, and aspartate aminotransferase) significantly as compared to the groups of experimental rats treated with sodium arsenite alone.[21] In an in vitro experiment, it has been shown that co-exposure of ethanol and arsenic stimulates mRNA levels for several angiogenic genes including VEGF and IGF1.[8] This indicates the fact that ethanol not only suppresses the toxic effects of arsenic but also acts as an alternative energy source of the cells to help them survive.
Figure 2: Energy production by alcohol metabolism

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Hypothesis on cytoprotection during arsenic-induced oxidative stress

Ethanol can be able to generate ATP even in the presence of arsenic in the affected cells where normal cellular metabolism and ATP production are being arrested due to its inhibitory effect on pyruvate dehydrogenase multienzyme complex. However, arsenic causes oxidative stress to the cells in addition to its inhibitory effect on energy production. Hence, both the effects could not be counteracted by ethanol alone, although it has more efficiency in ATP/energy production machinery. On the contrary, ethanol in high doses has got similar oxidative stress-inducing capacity as discussed above. However, that high amount of doses could not be recommended at all for this context. One should follow the guidelines of the International Center for Alcohol Policies to consider the safe dose of alcohol intake. It is therefore evident that ethanol helps cells to survive from the arsenic-induced cellular energy deficiency though it has no effect in alleviating oxidative stress [Figure 3].
Figure 3: Proposed model of averting arsenic toxicity

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Hence, the next inevitable question is - how could the stabilization and protection of cells can be possible from both arsenic and ethanol-induced oxidative stress? As per the therapeutic approach, the toxic effects which are created by the production of increased amount of ROS resulting from the arsenic exposure and therapeutic ethanol exposure (if any) in the cellular microenvironment, can be ameliorated by the dose-dependent usage of grape juice. We know that the consumption of grapes and its foodstuffs are associated with a lower occurrence of cardiovascular disease, certain types of cancers and degenerative diseases. The bioactive phenolic compounds in grapes including anthocyanins, flavanols, and resveratrol are the most important grape polyphenols which possess potent antioxidant, anti-aging, cardioprotective, anti-inflammatory, anti-cancer, and antimicrobial properties.[22],[23],[24] The antioxidant activity of red grape juice and red wine have been reported as they possess major bioactive phenolic compounds such as galic acid, rutin, ferulic acid, tannic acid, resveratrol, and quercetin out of which galic acid possessed maximum free radical scavenging capacity. Among all the red grape components and product tested, red wine showed highest free radical scavenging capacity [25] [Figure 3].

  Conclusion Top

The aforesaid observations supported by evidences establish the fact that, ethanol produces energy as an alternative way to bypass arsenic-induced energy imbalance and red grape juice can protect efficiently from both arsenic and alcohol-induced oxidative stress. Among all the red grape components and product tested, red wine showed highest free radical scavenging capacity. Therefore, it can easily be assumed and hypothesized that, the red wine which contains moderate amount of ethanol (within the limit of International Center for Alcohol Policies (ICAP) Drinking Guidelines)[26] and high levels of polyphenols, anthocyanins, flavanols, flavonols, galic acid, resveratrol, quercetin, etc. present in the red grape juice, could be useful in preventing arsenic-induced aging, senescence and other degenerative changes of the cells and tissues [Figure 3].

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  References Top

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  [Figure 1], [Figure 2], [Figure 3]

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