Chemoprevention of Arseniasis-Past, Present and Future (Mini Review)

Abstract

Clinical management of arsenic poisoning has been a major concern especially in countries like Bangladesh., India., Taiwan., Chile, Hungary and Argentina. In recent past, therapeutic efficacy of chelating agents, vitamins, nutrients, antioxidants and hormones has been investigated in many laboratories. Whereas, arsenic can be chelated by several agents viz: British Anti Lewisite (BAL), unithiol (DMPS), succimer (DMSA), monoisoamyl dimercaptosuccinic acid (MiADMSA), monocyclohexyl dimercaptosuccinic acid (MchDMSA), coadministration of quercetin and MiADMSA and taurine and MiADMSA have been found to reduce arsenic burdeon more effectively than their individual treatments. There are convincing reports that non-enzymatic antioxidants i.e. ascorbic acid, alpha tocopherol, B carotene, N-acetyl cysteine, alpha lipoic acid, curcumin, GSH and selenium offer protection against arseniasis by reducing oxidative stress. Melatonin, a product of pineal gland being a strong free radical scavenger possesses immense therapeutic importance against arseniasis. Thyroid hormones too influence arsenic toxicity. All these studies made in experimental animals have been briefly described in this review. However, cohorts made in human population are insignificant. Suitable clinical trials using these therapeutic agents individually or in combination may lead to the discovery of a “magic bullet” against arseniasis.

Keywords: Arseniasis; Chelating agents; Antioxidants; Nutrients; Amino acids and hormones

Introduction

Arsenic is present in Earth’s crust at an average concentration of 5 parts per million (ppm). It ranks 54th in abundance in Earth’s crust. Arsenic is a component of 245 minerals associated most frequently with other minerals such as copper, gold, lead and zinc in sulfidic ores. The main ores of arsenic are arsenopyrites (FeAsS), realagar (As2S2), orpiment (As2S3) and arsenolyte (As2O3). Arsenic is usually not mined but is recovered as a by-product from the smelting of copper, lead, zinc and other ores. Natural processes such as weathering, biological activity and volcanic eruption disturb its geochemical cycle and it is released into the environment. Anthropogenic activities such as combustion of fossil fuels, mining ore smelting and well drilling also mobilize and introduce arsenic into the environment.

Although, most typical environmental exposures to arsenic do not pose a health risk, several countries are known to suffer the risk of arsenic poisoning. Over 140 million people worldwide consume arsenic contaminated drinking water that exceeds the World Health Organization (WHO) limit of 10ppb [1]. Highest concentration of arsenic are known to occur in the ground water of Bangladesh and West Bengal in India [2]. Human population of other countries that are suffering from arsenic poisoning include Taiwan [3-5], Argentina [6,7], Chile [8,9], India [10,11], Bangladesh [12,13], China [14] and inner Mongolia [15]. WHO declared arsenic poisoning as a global emergency. A strong association between exposure to high concentration of arsenic and prevalence of cancer of skin, lung and bladder has also been established [16]. Agencies like International Agency for Research on Cancer [17] and European Food Safety Authorty [18], have declared it as a human carcinogen. Agency for Toxic Substance and Drug Registry (ATSDR), has registered it as number one substance in the Comprehensive Environmental Response Compensation and Liability Act (CERCLA) priority list of hazardous substances [19].

In environment, arsenic exists in inorganic as well as organic forms and also in different valence or oxidation states. Elemental arsenic has a valence state (o). Arsine and arsenides have a valence state (III). All arsenic compounds may be classified into inorganic, organic and gaseous forms. The most common inorganic trivalent arsenic compounds are arsenic trioxide, sodium arsenite and arsenic trichloride. Pentavalent compounds are arsenic pentoxide, arsenic acid, arsenate (e.g. lead arsenate, calcium arsenate). Common organic arsenic compounds are arsanilic acid, monomethylarsonic acid, dimethylarsinic acid (cacodylic acid) and arsenobetaine [20].

Absorption of arsenic may occur through inhalation, ingestion and contact by skin. After absorption, arsenic is transported by the blood to other parts of the body. Two basic processes are involved in its biotransformation, (i) oxidation and reduction reactions that intervert As III and As V, and (ii) methylation reactions which convert arsenite to Monomethyarsanalic Acid (MMA) and Dimethylarsenilic Acid (DMA).

Research on the mechanism of arsenic toxicity has been ongoing for many years, yet precise mode of action (MOA) for many disease end points after exposure to arsenic are not fully understood. Trivalent arsenicals have been found to be more potent toxicants than pentavalent arsenicals. Several review articles have been published on its MOA [21-23]. These reviews indicate involvement of several mechanisms viz: altered DNA methylation, signal transduction, cell proliferation, Reactive Oxygen Species (ROS), oxidative stress and genotoxicity in its toxicity. Several of these mechanisms may be interdependent. Based on its MOA, attempts have been made to find out suitable drugs/antidotes against arseniasis.

Arsenic as a Medicine

Documented evidence showing that arsenic was used as a therapeutic agent dates back to 2000 BCE [33,34]. Ancient pioneering physicians e.g. Aristotle and Paracelsus reportedly used arsenic as medicine [35,36]. Hippocrates, the Father of Medicine is thought to have used arsenic paste to treat ulcers and abscesses [37,38].

Fowler’s solution, that was discovered in 1786, is a 1% solution of potassium arsenite, used in the treatment of malaria, syphilis, asthma, cholera, eczema and psoriasis [39,40]. Paul Ehrlich discovered a new arsenic based drug called “salvarsan” which later became known as “magic bullet” for treating syphilis. It was used till penicillin became more popular in 1940s [38,41].

Pharmacological texts from 1880s described the use of arsenical pastes for the treatment of skin and breast cancer. It was found that Fowler’s solution could be effective in lowering the white blood cell count in leukemia patients [42]. Later on the use of Fowler’s solution declined due to its overt toxicity. More detailed understanding on the mechanisms of action of arsenic helped arsenic trioxide to emerge as an effective drug against Acute Promyelocytic Leukemia (APL) [43]. The treatment of other types of cancers with arsenic trioxide is still a matter of investigation [44,45].

Amelioration of Arsenic Toxicity

Sincere efforts have been made to develop methods to both enhance the efficacy of arsenic as well as to ameliorate the toxicity profile associated with different forms of arsenic. In recent past therapeutic efficacy of chelating agents, vitamins, nutrients, antioxidants and hormones has been investigated in many laboratories. Important developments are reviewed in the following paragraphs.

Chelation of Arsenic

Several metal binding substances function by chelation. A substance which binds metals is called a ligand. When a metal is gripped in a ligand between any two of the elements i.e. N, O, or S, a chelate ring is formed. This process is known as chelation. The term was coined by Morgan and Drew [46] and is derived from the Greek word khele meaning crab’s claw.

The first experimental use of a chelator against metal poisoning was made by Kety and Letonoff [41] to treat lead poisoning with sodium citrate. However, traditional chelating agents include calcium disodium ethylamine diamine tetra acetic acid (CaNa2EDTA), British Anti Lewisite (BAL), and meso-2,3-dimercapto succinic acid (DMSA). Recently mono and diesters of DMSA have been developed and tried against experimental heavy metal poisoning. Other chelating agents with established clinical use include D-penicillamine and desferrioxamine [48].

The therapeutic efficacy of chelation depends upon metal chelator and organism related factors e.g. ionic diameter, ring size and deformability, hardness/softness of electron donors and acceptors, route of administration, bioavailability, metabolism, intra/extra cellular compartmentalization and excretion. Hydrophilic chelating agents promote renal excretion of the metal while lipophilic chelators may deplete intracellular stores and may redistribute toxic metals. In long term therapy, side effects of the administered chelating agent may be limiting. The metal selectivity of chelator is important because of the risk of depletion of stores of essential metals.

Chelation therapy to prevent metal toxicity perhaps started 70 years ago with the development of British Anti Lewisite (BAL) or dimercaprol in Britain [49]. Later on DMPS (unithiol) and DMSA ( succimer) were developed in Soviet Union and China in late 1950s. These three agents have been extensively used to treat arsenic and mercury intoxication [50,51]. BAL possesses marked side effects and low safety ratio, however, DMPS and DMSA are non toxic. A comparative study on their efficacy in the liver and kidney of mice treated with arsenic by Tripathi and Flora [52] confirmed that DMSA was more effective than DMPS. Muckter et al., [53] suggested that BAL should be replaced with 2,3-Dimercaptopropane-Sulphonate Sodium (DMPS) and meso-2,3-Dimercaptosuccinic Acid (DMSA) due to their low toxicity. However, in case of severe poisoning by organic arsenicals, BAL remains to be a preferred antidote for arsenic. Another chelate-Monoisoamyl Dimercaptosuccinic Acid (MiADMSA) has also been found to elicit significant protection against arsenic induced oxidative stress and apoptotic cell death in human keritinocytes [54]. A concept of using chelation therapy with essential elements like calcium and zinc has also been suggested. Kadeyala et al., [55] reported that MiADMSA combined with calcium and zinc could be more effective in reducing arsenic toxicity. Recently Anderson and Aaseth [56] reviewed the shortcomings of chelation therapy. Chelation procedures should alleviate and not aggravate the clinical status of poisoned patients.

There are a few reports where combination therapy has been used against arseniasis. Co-administration of DMSA and MiADMSA at a concentration of 0.15mM/kg was found effective in reducing arsenic load from blood and soft tissues and also in reducing oxidative stress. DNA damage caused by As was also repaired [57]. Subsequent study showed that combination of DMSA with long chain carbon analogues like MiADMSA and monocyclohexyl DMSA (MchDMSA) significantly reduced arsenic burdeon and reversed altered biochemical variables indicative of oxidative stress and apoptosis [58]. Thus further attempts to use suitable combination(s) of chelating agents and essential element may be made to prevent arsenic toxicity.

Arsenic is known to cause reproductive toxicity also. Available literature shows that it could be prevented by DMSA and DMPS [59]. Flora and Mehta [60] has reported that MiADMSA protects against arsenic induced developmental toxicity in stem cell derived embryoid bodies.

Studies on the protective role of nanoparticles of chelating agents against arseniasis are also being undertaken in a few laboratories. Yadav et.al., [61] showed better efficacy of nano-MiADMSA (50nm) than bulk MiADMSA in reducing oxidative stress and efficient removal of arsenic from blood and tissues of sodium arsenite treated Swiss albino mice. Histopathological observations and urinary level of 8-OHdG also proved better therapeutic efficacy of nano- MiADMSA than bulk MiADMSA. Another report on the application of nanotechnology in the prevention of arsenic poisoning was published by Ghosh et al., [62] who nanoencapsulated quercetin and DMSA and tested against chronic arsenic toxicity in a rat model. Their combined treatment displayed a synergistic effect. It decreased arsenic burdeon, normalized mitochondrial function and reduced the formation of reactive oxygen species in liver. It was a novel approach of therapeutic intervention combining hydrophilic and hydrophobic drugs into a single delivery system. Earlier, Mishra and Flora [58] have also shown that combined administration of quercetin with MiADMSA decreased arsenic concentration in blood and soft tissues. Similar study was made with taurine and MiADMSA in rats treated with sodium arsenite for 24 hours. Co-administration of a higher dose of taurine (100mg/kg) and MiADMSA improved antioxidant status of liver and kidney and reduced arsenic burdeon compared to their individual treatment [63].

Protection by Antioxidants

It has been established now that arsenic toxicity is manifested through oxidative stress. Therefore, antioxidants have been at the forefront of chemotherapeutic intervention against arseniasis. Nonenzymatic antioxidants function as free radical scavengers and include ascorbic acid (vitamin C), alpha tocopherol (vitamin E), B-carotene, N-acetyl cysteine, alpha lipoic acid and selenium.

Ascorbic acid: L-ascorbic acid (C₆H₈O₆) is the trivial name of vitamin C that has been accepted by IUPAC-IUB commission on biological nomenclature [64]. The systemic chemical designation is 2-oxo-L threo-hexono-1,4 lactone-2,3-enediol. Vitamin C refers to compounds exhibiting full or partial biological activity of L-ascorbic acid. These include esters of ascorbic acid such as ascorbyl palmitate, 6-deoxy-L-ascorbic acid and primary oxidized form of ascorbic acid, dehydroascorbic acid.

The concept that arsenical toxicity could be modified by nutrients was initially proposed in early 1930’s by Mayer and Sulzberger [65] who suggested that adequate concentration of ascorbic acid in the diet prevented or reduced arsenic induced occurrence of anaphylaxix. Subsequently, a number of researchers confirmed this hypothesis on ascorbic acid-arsenic interaction [66-69].

Several workers like Tanaka [70]; Tabacova et al., [71]; Mc Call and Frei [72]; and Odunuga et al., [73] reported on free radical scavenging role of L-ascorbate as a major mechanism of protection against arsenic poisoning. Vitamin C in combination with methionine also reduced toxicity of arsenic [74,75]. [76] concluded in their studies in rat that L-ascorbate plays a pivotal role in maintaining normal ovarian activities and brain monoamines in arsenic treated rats. Anti myeloma effect of ascorbic acid has also been observed by Bahlis et al., [77]. Improvement in microsomal function by ascorbic acid in arsenic treated rat has also been observed [78]. It was also concluded that ascorbate overcomes drug resistance in myeloma and significantly increases the anti myeloma effects of arsenic trioxide in animal models.

A number of studies especially made in last decade attribute the protective effects of ascorbic acid to its antioxidative property. It was suggested that ascorbic acid forms first line of antioxidant defence [80,81]. Nandi and coworkers (2005) also observed that ascorbic acid reduces tissue burdeon of arsenic and reverses oxidative stress in rats. Studies made in our laboratory also suggested that it reduces oxidative stress [84]; improves mitochondrial function [83]; and reverses disturbances in the structure and function of liver and kidney of arsenic treated rats [84] Not only liver and kidney, protective effects of ascorbic acid have been observed in testis [86] and neural function of rats [87]. Combined treatments with vitamin E and vitamin C have also displayed protection against arseniasis in rats [88,89].

These properties make ascorbic acid a suitable antidote for arsenic poisoning even in human subjects.

Vitamin E (a-tocopherol): Vitamin E is a family of lipophilic antioxidants, termed tocopherols that contain a chromanol nucleus and isoprenoid side chain [90]. Individual tocopherols differ by the position and number of methyl substituents on the aromatic ring. Of these, the principal tocopherols found in human and animal diets are y-tocopherol and a-tocopherol. a-tocopherol from natural sources (R.R.R. a-tocopherol is the most potent form of vitamin E. Peroxyl radicals analogously oxidize a-tocopherol to the tocopheroxyl radical, an unusually stable phenoxyl radical that does not propagate the radical chain [91]. Recognizing these kinetics, several studies have been made using a-tocopherol as antidote for several xenobiotics.

A population based study was conducted in Bangladesh using vitamin E and selenium to protect against nonmelanoma skin cancer caused by arsenic amongst 7000 adults [12]. Vitamin E together with vitamin C and zinc was found to ameliorate hematological effects of arsenic in rats during pregnancy and lactation [92]. Plasma a-tocopherol might modify the risk of inorganic arsenic related urothelial carcinoma [93]. A few reports indicated the protective effects of vitamin C and E against arsenic induced teratogenicity [89]. Effects of vitamin E together with other nutrients like selenium have also been found protective against co-carcinogenicity induced by arsenite and solar UVR [94].

An excellent review by Liebler [95] on the role of metabolism in the antioxidant function of vitamin E concluded that a-tocopherol is the principal chain breaking antioxidant in biological membranes. It prevents toxicant/carcinogen induced oxidative damage by trapping reactive oxygen radicals.

β- carotene: Very few workers have studied the amelioration of arsenic poisoning by B carotene. It is a lipophilic antioxidant. Its protection against many xenobiotics has been attributed to its role in the prevention of oxidative DNA damage. It can induce GSH synthesis. An association between as induced skin cancer and B -carotene was first reported by Hsuch [96] in arseniasis affected villages of Taiwan. Skin cancer patients had significantly lower serum levels of B-carotene than matched healthy controls. The same group of workers recorded a reverse dose-response relationship with arsenic related Ischemic Heart Disease (ISHD) [97]. Another study from west Bengal (India) by Chung et al., [93] showed that arsenic toxicity could be influenced by micronutrients in particular, selenium, methionine and B-carotene. In a recent study made by Das et al., [98], B -carotene displayed ameliorative effect against arsenic induced toxicity in Swiss albino mice. They also attributed this effect to its antioxidative and antigenotoxic properties. In future, attempts can be made to introduce a combination therapy using B- carotene and chelating agents.

N-acetyl cysteine: N-Acetyl Cysteine (NAC), a synthetic aminothiol, possesses antioxidative and cytoprotective properties. L-cysteine is a precursor to the biological antioxidant glutathione. Hence, in principle, administration of NAC replinishes glutathione stores. Patrick [99] suggested mitigating role of NAC against arsenic and cadmium toxicity. In vitro and in vivo models have shown that NAC modulated cellular thiols for protection against reactive oxygen species [100]. In a recent study, da Silva [101] observed that co-administration of NAC and As₂O₃ in male mouse prevented the harmful effects of arsenic on male genital system. However, no protective effects were observed in the urinary bladder of rats treated with dimethylarsinic acid [102]. Reddy and coworkers [103] showed that treatment of arsenic exposed mice with NAC increased the weight of reproductive organs, reduced arsenic induced oxidative stress and impaired steroidogenesis indicating the beneficial role of NAC.

Pre-treatment of NAC to arsenic treated mice abrogated apoptosis in liver, as determined through TUNEL test, caspase assay and histology [104]. It was hypothesized that since these processes are GSH dependent, supplementation of NAC would display beneficial effects. Pal et al., [105] suggested that NAC prevented As induced hypoglycemia and glycogenetic effects. As induced changes in glucose-6-phosphatase activity in liver and kidney both were counteracted.

Another approach adopted by a few workers was to use NAC with another suitable therapeutic agent. Combined therapy of NAC and DMSA was tried against oxidative stress and hepatic dysfunction induced by sodium arsenite in male rats. Combined therapy was found to be superior than monotherapy in recovery of glutathione and structural changes [106]. Another group used NAC and zinc to combat As induced oxidative stress in male rats [107]. Concommitant administration of Zinc and NAC showed protection against delta amino levulinic acid dehydratase, oxidative stress and catalase activity in the liver of male rats. Combined therapy using NAC and suitable nutrient(s) or chelating agent(s) may be a good alternative to treat arsenicosis in humans.

Reduced glitathione(GSH): Arsenic and GSH relationship is as old as the discovery of this tripeptide (glutamyl cysteinyl glycine) by Hopkins and coworkers in 1922 [108]. There is a serene phrase coined by Kosower and Kosower [109],”Lest I forget thee glutathione”. This statement has now been replaced by “inevitable glutathione” by Rana et al., [110]. Cysteinyl moiety of GSH binds with trivalent arsenicals and thus offers protection against their toxicity. Investigations during 1920s and 1930s on GSH-As interactions laid the groundwork for development of an antidote for lewisite (chlorovinyl dichloroarsine). BAL (2,3-dimercaptopropanol) was the product of this early development at national drug design [111].

Molecular mechanisms involved in As-GSH interaction are associated with reduction reactions that convert pentavalent arsenic to trivalent arsenic [112,113]. Trivalent arsenic is complexed by GSH, hence GSH dependent reduction and complexation are inextricably linked in cells. These complexes have been detected in diverse biological systems [114,115]. These complexes inhibit Glutathione Reductase (GR) [116]. Regeneration of GSH from GSSG due to inhibition of GR may affect the intracellular GSH: GSSG ratio. The resulting shift in cellular redox status may contribute to its toxicity/ carcinogenesis.

There are a few reports that suggest that dietary GSH can modulate arsenic toxicity. Protective effects of GSH on sodium arsenite induced ovarian and uterine disorders in Wistar rats were observed by Chattopadhyay and Ghosh, [117]. Other compounds like resveratrol protect against As2O3 toxicity via cellular antioxidative pathway i.e. maintaining GSH homeostasis and suppressing apoptosis [118].

The formation of As-GSH complexes may also facilitate the efflux of arsenicals from cells. New findings suggest that glutathione-Stransferases especially glutathone transferase P₁ (GSTP₁) catalyzes the formation of As-GSH complexes which are preferred substrates for ATP binding cassette membrane transporters which mediate efflux from cells [119]. Nevertheless, there are no data concerning the kinetics of formation of As-GSH complexes in GSTP₁ catalyzed reactions [120]. However, this information favours the use of GSH as an antidote for arsenicosis.

Curcumin: Curcumin (CUR) is the active ingredient derived from the rhizome of turmeric, Curcuma longa. CUR is a good antioxidant but with limited clinical applications due to its hydrophilic nature and limited bioavailability. It is a naturally occurring polyphenolic compound with wide range of therapeutic and pharmacological properties. Garcia-Nino and Pedraza Chaveri [121] showed that curcumin reduces hepatotoxicity induced by several elements viz: arsenic, cadmium, chromium, copper, lead and mercury. Metal conjugation and free radical scavenging activities of CUR make it a safe antidote. Dutta et al., [122] showed that metal conjugates of CUR derivatives enhance its antioxidative activities. It has been observed that CUR counteracted DNA damage caused by arsenic. It decreased lipid peroxidation and increased the activities of Phase-II enzymes viz: catalase, superoxide dismutase and glutathione peroxidase in arsenic treated human lymphocytes [123]. These authors suggested that CUR can be an economic model for the mitigation of arsenic toxicity amongst rural population of West Bengal (India). Several reports support this proposition. Neurotoxicity of arsenic could be attentuated by CUR in rat [124]. They observed that strong antioxidant potential of CUR reduced genotoxicity of arsenic in Swiss albino mice. This activity was attributed to an increase in antioxidant enzymes viz: catalase, superoxide dismutase, glutathione peroxidase, glutathione transferase and glutathione itself [127]. In vitro studies on human peripheral lymphocytes have also confirmed that CUR mitigates genotoxic potential of arsenic and fluoride [126]. CUR treatment administered to arsenic exposed human population of West Bengal (India) enhanced DNA repair monitored through 8-OHdG. This study made on protein expression and genetic profile suggested protective effects of CUR both at protein and genetic levels [127].

Mechanism of chemoprevention expressed by CUR against arsenic toxicity was recently studied by Gao et al., [128]. They observed that it activates nuclear factor 2 (Nrf₂) and phase-II enzymes in the liver of mice. Further, it promoted arsenic methylation. Two Nrf₂ Downstream Genes NADP(H) Quinine Oxidoreductase I (NQO₁) and heme oxygenase-I (HO-I) were also upregulated after CUR treatment. Nrf₂ activation by CUR appears to be a valuable factor in chemoprevention of arsenic toxicity.

CUR could protect arsenic induced cholinergic deficits by modulating the expression of pro and anti apoptotic proteins in the brain of rats. It improved mitochondrial structure and function as well [129].

Recent observations show that Tetrahydrocurcumin (THC) a metabolite of CUR was found to possess greater antioxidant activity than CUR. Treatment of THC to arsenic treated rats reversed its hepato-toxicity. This effect was attributed to the presence of identical to B-diketone of 3rd and 5th substitution in hepatic moiety [130]. Recently, a group of workers from India used nanocurcumin to ameliorate arsenic toxicity in rat. It prevented genotoxicity, hepatotoxicity and reduced arsenic induced oxidative stress in brain and kidney of rats [131-134]. It could express immunomodulatory effects better than free curcumin [132-134]. CUR definitely offers advantages over other antioxidants.

Selenium: Selenium (Se) was discovered in 1817 by Swedish chemist Berzelius, who named it after the moon goddess, selene, in Greek language. Today, almost 200 years later, selenium is well established as an essential trace element of fundamental importance to human health. Se is primarily known for its antioxidative properties [135]. Keshan disease is a potentially fatal form of cardiomyopathy prevalent in children and endemic in parts of China with extremely low levels of Se in soil. Condition can be prevented completely by Se supplementation [136].

The incorporation of Se as selenocysteine in 25 proteins by a highly elaborate cotranslation mechanism has defined the human “selenoproteome”, in which the precise function of about half of the proteins is still unknown. Many of the proteins have functions ranging from antioxidants or oxidoreductases including Glutathione Peroxidases (GPxs) and Thioredoxin Reductases (TrxR). The enzyme glutathione peroxidase contains Se in the form of selenocysteine and catalyzes the oxidation of glutathione and reduction of organic hydroperoxides or H₂O₂ thereby protecting membrane lipids and other macromolecules from oxidative damage. Whereas, several studies demonstrate antioxidative properties of Se, there is no evidence in literature that Se exterts chemopreventive effects via such a mechanism [137,138]. However, inorganic Se salts i.e. selenite or dietary selenoamino acids lead to reductive metabolic pathway forming hydrogen sulfide (H₂Se). H2Se then acts as Se donor to the Se containing amino acids found in various selenoproteins or it may lead to the formation of methylselenide anion [139]. Nevertheless, transcription factor modulation by Se may be relevant to chemopreventive mechanism [140].

Despite versatile nature of Se, Se-As interactions have been poorly described. Biswas et al., [141] in their experiment on Swiss albino mice demonstrated that organoselenium protects against As+UVR induced carcinogenesis through the formation of a compound seleno-bis (S-glutathionyl) arsinium rather than its antioxidative effect. Contrarily, Messarah et al., [142] in their observations made in sodium selenite and sodium arsenite treated male rats suggested that Se co-administration protected liver against As intoxication probably owing to its antioxidant properties. Recent report from Dash et al., [143] suggest that chronic arsenicosis in cattle could be mitigated by Zn and Se. Recently Krohn et al., [144] have shown that high Se lentils from Canadian prairies protect against As triggered atherosclerosis in mice.

Thus, there is ample experimental evidence to suggest that Se treatment can protect against arsenicosis.

Hormones as Antidotes

Melatonin: Melatonin (N-acetyl-methoxytryptamine), a main product of pineal gland functions as a time giver (zeitgeber) in the regulation of circadian rhythms [145]. It synchronizes the reproductive cycle with appropriate season of the year in photoperiodic species [146]. In non-photoperiodic species such as humans, the actions of melatonin are restricted to other functions of circadian clock i.e. consolidation of sleep and core body temperature [147]. Since 1993, melatonin has been recognized as a free radical scavenger [148-150]. Its widespread sub cellular distribution enables it to interact with toxic molecules, thereby reducing oxidative damage to molecules in both aqueous and lipid environment of the cell. Melatonin acts as an indirect antioxidant through activation of major antioxidant enzymes including superoxide dismutase, catalase and glutathione peroxidase [151-154].

A few investigators have studied the protective effect of melatonin on arsenic toxicity. Pal and Chatterjee [155] showed that melatonin treatment reverses the inhibition of antioxidant enzyme caused by arsenic. Anti-genotoxic potential of melatonin in arsenic affected human population was established by Pant and Rao [156]. Melatonin could ameliorate testicular injury mediated by arsenic [157]. A recent report from Teng et al., [158] showed that melatonin protects against arsenic induced neurotoxicity. All these effects have been attributed to general antioxidant properties of melatonin.

Thyroid hormones: Much is not known on thyroid-arsenic interaction. Reciprocal interaction between thyroid activity and arsenic toxicity was studied in our laboratory. It was reported by Allen and Rana [159] that thyroxine treatment diminished oxidative stress caused by arsenic trioxide in the liver and kidney of rat. Hyperthyroidic conditions restricted the accumulation of arsenic in liver and kidney. However, histopathological observations indicated severe lesions in the kidney of arsenic and thyroxine treated rats [160]. Further studies are needed to establish arsenic -thyroid-parathyroid interaction.

Conclusion

Arsenicosis or arseniasis are the common terms used to designate arsenic poisoning. They represent disease endpoints viz: specific skin manifestations like pigmentation and keratosis, respiratory diseases, liver and kidney disorders, haematological effects, neuropathy, diabetes and cancer. Despite that mortality is high in severe cases, effective management of arsenicosis remains elusive. Is there any “magic bullet” to treat arsenicosis? Perhaps the answer is no. During recent years, therapeutic intervention using a variety of molecules i.e. chelating agents, antioxidants, nutrients and hormones has been studied in a number of laboratories. A novel approach was made using a combination of these agents. Efficacy of nanoparticles viz: nano MiADMSA has also been investigated. It is interesting to know that tetra-hydrocurcumin a metabolite of curcumin expressed greater antioxidant activity than curcumin. While curcumin promotes arsenic methylation, As-GSH complex facilitates the efflux of arsenicals from target cells. Protective effects of melatonin are attributed to its strong antioxidative and chelation properties. Perhaps a careful combination therpay may prove better than monotherapy. The studies reported so far have been mainly made in experimental animals and controlled conditions. Cohorts made in human population are insignificant. Suitable clinical trials using these therapeutic agents along with blind placebo controls, if made in future may lead to the discovery of magic bullet for arsenicosis.

Acknowledgement

The author is thankful to his colleagues- Dr Tanu Allen, Dr Sohini Singh, Dr Neetu Singh and Dr Seema Sharma for their valuable inputs and suggestions.

Conflict of Interest

The author declares no conflict of interest.

Acknowledgements

The financial support from Indian Science Congress Association (Kolkata) is gratefully acknowledged.

References

1. Ravenscroft P, Brammer H, Richards K. Arsenic Pollution: A Global Synthesis. 2009; 47: 47-0826-47-0826.
2. Rahman MM, Chowdhury UK, Mukherjee SC, Mondal BK, Paul K, Lodh D, et al. Chronic Arsenic Toxicity in Bangladesh and West Bengal, India—A Review and Commentary. Journal of Toxicology: Clinical Toxicology. 2001; 39: 683-700.
3. Chen CJ, Chuang YC, You SL, Lin TM, Wu HY. A retrospective study on malignant neoplasms of bladder, lung and liver in blackfoot disease endemic area in Taiwan. British Journal of Cancer. 1986; 53: 399-405.
4. Chen C, Chen C, Wu M, Kuo T. Cancer potential in liver, lung, bladder and kidney due to ingested inorganic arsenic in drinking water. British Journal of Cancer. 1992; 66: 888-892.
5. Chiou HY, Hsueh YM, Liaw KF, Horng SF, Chiang MH, et al. Incidence of internal cancers and ingested inorganic arsenic: a seven year follow up study in Taiwan. Cancer Res. 1995; 55: 1296-1300.
6. Hopenhayn-Rich C, Biggs ML, Fuchs A, Bergoglio R, Tello EE, Nicolli H, et al. Bladder Cancer Mortality Associated with Arsenic in Drinking Water in Argentina. Epidemiology. 1996; 7: 117-124.
7. Steinmaus C, Yuan Y, Kalman D, Rey OA, Skibola CF, Dauphine D, et al. Individual differences in arsenic metabolism and lung cancer in a casecontrol study in Cordoba, Argentina. Toxicology and applied pharmacology. 2010; 247: 138-145.
8. Smith AH, Marshall G, Yuan Y, Liaw J, Ferreccio C, Steinmaus C. Evidence from Chile that arsenic in drinking water may increase mortality from pulmonary tuberculosis. American journal of epidemiology. 2011; 173: 414- 420.
9. Smith AH, Goycolea M, Haque R, Biggs ML. Marked increase in bladder and lung cancer mortality in a region of Northern Chile due to arsenic in drinking water. American journal of epidemiology. 1998; 147: 660-669.
10. Chowdhury TR, Mandal BK, Samanta G, Basu GK, Chowdhury P, et al. In Arsenic Exposure and Health Effects. Abernathy CO, Calderon RL, Chappell WR eds. Chapman & Hall: London. 1997: 93.
11. Das D, Chatterjee A, Mandal BK, Samanta G, Chakraborti D, Chanda B. Arsenic in ground water in six districts of West bengal, India: the biggest arsenic calamity in the world. Part 2. Arsenic concentration in drinking water, hair, nails, urine, skin-scale and liver tissue (biopsy) of the affected people. The Analyst. 1995; 120: 917.
12. Argos M, Kalra T, Rathouz PJ, Chen Y, Pierce B, Parvez F, et al. Arsenic exposure from drinking water, and all-cause and chronic-disease mortalities in Bangladesh (HEALS): a prospective cohort study. The Lancet. 2010; 376: 252-258.
13. Sohel N, Persson LA, Rahman M, Streatfield PK, Yunus M, et al. Arsenic in drinking water and adult mortality: a population based cohort study in Bangladesh. Epidemiology. 2009; 20: 824-830.
14. Luo ZD, Zhang YM, Ma L, Zhang GY, He X, et al. In Arsenic Exposure and Health Effects, Abernathy CO, Calderon RL, Chappel WR Eds, Chapman and Hall, London. 1997: 55.
15. Mo J, Xia Y, Wade TJ, Schmitt M, Le XC, Dang R, et al. Chronic Arsenic Exposure and Oxidative Stress: OGG1 Expression and Arsenic Exposure, Nail Selenium, and Skin Hyperkeratosis in Inner Mongolia. Environmental Health Perspectives. 2006; 114: 835-841.
16. Mazumder DNG. Chronic arsenic toxicity & human health. The Indian journal of medical research. 2008; 128: 436-47.
17. IARC. Some Drinking -Water Disinfectants and Contaminants including Arsenic.IARC Monographs on the Evaluation of Carcinogenic Risks to Humans. International Agency for Research on Cancer. WHO, Lyon, France. 2004.
18. European Food Safety Authority (EFSA). Scientific opinion on arsenic in food. EFSA J. 2009; 7: 1351.
19. ATSDR. CERLA Priority List of Hazardous Substances for 2007. Agency for Toxic Substances and Disease Registry US. Department of Health and Human Services, Atlanta, GA. 2007a. Available at: http://www.atsdr.cdc.gov/ cercla/07list.html.
20. NRC. 1999. Arsenic in Drinking Water. National Research Council. 310. National Academy Press, Washington DC. 1999.
21. Druwe IL, Vaillancourt RR. Influence of arsenate and arsenite on signal transduction pathways: an update. Archives of Toxicology. 2010; 84: 585- 596.
22. Kitchin KT, Conolly R. Arsenic induced carcinogenesis- oxidative stress as a possible mode of action and future research needs for more biologically based risk assessment. Chem Res Toxicol. 2010; 23: 327-335.
23. Platanias LC. Biological Responses to Arsenic Compounds. Journal of Biological Chemistry. 2009; 284: 18583-18587.
24. Vaughan DJ, Polya DA. Arsenic-the great poisoner revisited. Elements. 2013; 9: 315-316.
25. Kelynack TN, Kirkly W, Delepine S, Tattersal CH. Arsenical poisoning from beer drinking. Lancet. 1900; 2: 1600-1602.
26. SATTERLEE HS. The arsenic-poisoning epidemic of 1900. Its relation to lung cancer in 1960 - an exercise in retrospective epidemiology. The New England journal of medicine. 1960; 263: 676-684.
27. Conley BE. Morbidity and mortality from economic poisons in the United States. Arch Ind Health. 1958; 18: 126-133.
28. Amarasingham RD, Lee H. A review of poisoning cases examined by the Department of Chemistry, Malaysia, from 1963 to 1967. The Medical journal of Malaya. 1969; 23: 220-7.
29. Tokanehara S, Akao S, Tagaya S. Blood findings in infantlile arsenic toxicosis caused by powdered milk. Shonika rinsho. 1956; 9: 1078-1084. (EPA translation No. TR 110-74).
30. Terada H, Katsuta K, Sasakawa T, Saito H, Shrota H, et al. Clinical observations of chronic toxicosis by arsenic. Nihon rinsho. 1960; 18: 2394- 2403. (EPA translation No.TR 106-74).
31. Fowler BA, Weissberg JB. Arsine poisoning. New Eng J Med. 1974; 291: 1171-1174.
32. Peters RA. Biochemistry of some toxic agents. I Bull Johns Hopkins Hosp. 1955; 97: 1-20.
33. Antman KH. Introduction: the history of arsenic trioxide in cancer therapy. The oncologist. 2001; 6: 1-2.
34. Hyson JM. 2007. A history of arsenic in dentistry. J Calif Dent Assoc. 2007; 35: 135-139.
35. Cullen WR. Is Arsenic an Aphrodisiac. 2008.
36. Jolliffe DM. A history of the use of arsenicals in man. J R Soc Med. 1995; 86: 287-289.
37. Waxman S, Anderson KC. History of the development of arsenic derivatives in cancer therapy. The oncologist. 2001; 6: 3-10.
38. Riethmiller S. From Atoxyl to Salvarsan: Searching for the Magic Bullet. Chemotherapy. 2005; 51: 234-242.
39. Roche GH. Arsenic In Reference Book of Practical Therapeutics. (F.P.Foster. Ed). vol.1. Appleton Company, New York. 1896: 142-146.
40. Scheindlin S. The duplicitous nature of inorganic arsenic. Molecular interventions. 2005; 5: 60-64.
41. YARNELL A. SALVARSAN. Chemical & Engineering News Archive. 2005; 83: 116.
42. Antman KH. Introduction, The history of arsenic trioxide in cancer therapy. Oncologist. 2001; 6: 1-2.
43. Zhang TD, Chen CQ, Wang ZG, Wang ZY, Chen SJ, et al. Arsenic trioxide a therapeutic agent for APL. Oncogene. 2001; 20: 7146-7153.
44. Murgo AJ. Clinical trials of arsenic trioxide in haematologic and solid tumors: overview of the National Cancer Institute Cooperative Research and Development Studies. Oncologist. 2001; 6: 22-28.
45. Sekeres MA. New data with arsenic trioxide in leukemias and myelodysplastic syndromes. Clinical lymphoma & myeloma. 2007; 8: S7-S12.
46. Morgan and Drew. In Selective Toxicity, Adrien Albert. Chapman and Hall London and New York. 1920: 430.
47. Kety SS, Letonoff TV. Treatment of Lead Poisoning with Sodium Citrate. Proceedings of the Society for Experimental Biology and Medicine. 1941; 46: 476-477.
48. Aaseth J. Recent advances in the therapy of metal poisonings with chelating agents. Hum Toxico. 1983; 2: 257-272.
49. Carleton AB, Peters RA, Stocken LA, Thompson RHS, Williams DI, Storey IDE, et al. Clinical Uses of 2,3-Dimercaptopropanol (Bal). VI. The Treatment of Complications of Arseno-Therapy with Bal (British Anti-Lewisite) 1. Journal of Clinical Investigation. 1946; 25: 497-527.
50. Inns RH, Rice P, Bright JE, Marrs TC. Evaluation of the Efficacy of Dimercapto Chelating Agents for the Treatment of Systemic Organic Arsenic Poisoning in Rabbits. Human & Experimental Toxicology. 1990; 9: 215-220.
51. Kosnett MJ. The Role of Chelation in the Treatment of Arsenic and Mercury Poisoning. Journal of Medical Toxicology. 2013; 9: 347-354.
52. Tripathi N, Flora SJS. Effects of some thiol chelators on enzymatic activities in blood, liver and kidneys of acute arsenic (III) exposed mice. Biomed Env Sci. 1998; 110: 38-45.
53. Mückter H, Lieb B, Reich F, Hunder G, Walther U, Fichtl B. Are we ready to replace dimercaprol (BAL) as an arsenic antidote?. Human & Experimental Toxicology. 1997; 16: 460-465.
54. Pachauri V, Mehta A, Mishra D, Flora SJS. Arsenic induced neuronal apoptosis in guinea pigs is Ca2+ dependent and abrogated by chelation therapy: role of voltage gated calcium channels. Neurotoxicology. 2013; 35: 137-145.
55. Kadeyala PK, Sannadi S, Gottipolu RR. Alterations in apoptotic caspases and antioxidant enzymes in arsenic exposed rat brain regions: reversal effect of essential metals and a chelating agent. Environmental toxicology and pharmacology. 2013; 36: 1150-1166.
56. Andersen O, Aaseth J. A review of pitfalls and progress in chelation treatment of metal poisonings. Journal of Trace Elements in Medicine and Biology. 2016; 38: 74-80.
57. Bhadauria S, Flora SJS. Response of arsenic-induced oxidative stress, DNA damage, and metal imbalance to combined administration of DMSA and monoisoamyl-DMSA during chronic arsenic poisoning in rats. Cell Biology and Toxicology. 2006; 23: 91-104.
58. Mishra D, Mehta A, Flora SJS. Reversal of arsenic-induced hepatic apoptosis with combined administration of DMSA and its analogues in guinea pigs: role of glutathione and linked enzymes. Chemical research in toxicology. 2008; 21: 400-407.
59. Domingo JL. Prevention by chelating agents of metal-induced developmental toxicity. Reproductive toxicology. 1995; 9: 105-113.
60. Flora SJS, Mehta A. Monoisoamyl dimercaptosuccinic acid abrogates arsenic-induced developmental toxicity in human embryonic stem cellderived embryoid bodies: comparison with in vivo studies. Biochemical pharmacology. 2009; 78: 1340-1349.
61. Yadav A, Mathur R, Samim M, Lomash V, Kushwaha P, Pathak U, et al. Nanoencapsulation of DMSA monoester for better therapeutic efficacy of the chelating agent against arsenic toxicity. Nanomedicine. 2014; 9: 465-481.
62. Ghosh S, Dungdung SR, Chowdhury ST, Mandal AK, Sarkar S, Ghosh D, et al. Encapsulation of the flavonoid quercetin with an arsenic chelator into nanocapsules enables the simultaneous delivery of hydrophobic and hydrophilic drugs with a synergistic effect against chronic arsenic accumulation and oxidative stress. Free radical biology & medicine. 2011; 51: 1893-1902.
63. Zheng Y, Qu H, Wang D, Li S, Zhang C, Piao F. Protection of taurine against arsenic induced DNA damage of mice kidneys. Adv Exp Med Biol. 2017; 975: 917-927.
64. Moser U, Bendich A. Vitamin C. In Handbook of vitamins. Machlin, L.J.(ed). Marcell Dekker, New York. 1990: 195-232.
65. Mayer RL, Sulzberger MB. Zur Frug der janreszeilichen schwankungen experimentalle seneepilisierungen. Archiv Fuer Dermat Und syph. 1931; 163: 245.
66. Cormia FE. Experimental Arsphenamine Dermatitis: the Influence of Vitamin C in the Production of Arsphenamine Sensitiveness. Canadian Medical Association journal. 1937; 9: 201.
67. Dainow I. Intarance aux arsenobenzenes et vitamin C. Presse Med. 1937; 45: 1670-1676.
68. Bise E. Grave erythroderma due to arsphenamine, case by ceratamic acid. Rev Med De la Suisse Rom. 1938; 58: 603.
69. Abt AF. The human skin as an indicator of vitamin C (ascorbic acid) in the reactions due to arsenicals used in anti syphilitic therapy. U.S. Naval Med Bull. 1942; 40: 291-303.
70. Tanaka I. Arsenic metabolism. (17) Studies of placental transfer of arsenic and the effects of antidotes and diet]. Nihon yakurigaku zasshi. Folia pharmacologica Japonica. 1976; 72: 673-687.
71. Tabacova S, Hunter ES, Balabaeva L. Potential role of oxidative damage in developmental toxicity of arsenic. In Arsenic exposure and Health Effects. Abernathy CO, Colderm RL, Chappell WR. (eds). Chapman and Hall, London. 1992: 135-144.
72. McCall MR, Frei B. Can antioxidant vitamins materially reduce oxidative damage in humans?. Free radical biology & medicine. 1999; 26: 1034-1053.
73. Odunuga OO, Okunade GW, Oloruhsogo OO. Reversal of sodium arsenate inhibition of rat liver microsomal Ca2 pumping by ATPase by vitamin C. Biosci Rep. 1999; 19: 11-15.
74. Hsueh YM, Huang YL, Huang CC, Wu WL, Chen HM, Yang MH, et al. Urinary levels of inorganic and organic arsenic metabolites among residents in an arseniasis-hyperendemic area in Taiwan. Journal of toxicology and environmental health. Part A. 1998; 54: 431-444.
75. Hsueh YM, Cheng GS, Wu MM, Yu HS, Kuo TL, Chen CJ. Multiple risk factors associated with arsenic-induced skin cancer: effects of chronic liver disease and malnutritional status. British Journal of Cancer. 1995; 71: 109- 114.
76. Chattopadhyay S, Ghosh S, Debnath J, Ghosh D. Protection of sodium arsenate induced ovarian toxicity by co-administration of L-ascorbate (vitamin-C) in mature Wistar strain rat. Arch Environ Cont Toxicol. 2001; 41: 83-89.
77. Bahlis NJ, Mc Cafferty Grad J, Jordan Mc Murry I, Neil J, Goodman M, Fernandez HF, et al. Feasibility and correlates of arsenic trioxide combined with ascorbic acid mediated depletion of intracellular glutathione for the treatment of relapsed, refractory multiple myeloma. Clin Cancer Res. 2002; 8: 3658-3668.
78. Ramanathan K, Shila S, Kumaran S, Paneerselvam C. Protective role of ascorbic acid and alpha tocopherol on arsenic induced microsomal function. Hum Exp Toxicol. 2003; 22: 129-136.
79. Campbell RA, Chen H, Zhu D, Santos CJ, Bonavida V, et al. Ascorbic acid overcomes drug resistance in myeloma and significantly increases the antimyeloma effects of both arsenic trioxide and melphalan in vitro and in vivo. Blood. 2004; 104: 678a.
80. Frei B. On the role of vitamin C and other antioxidants in atherogenesis and vascular dysfunction. Proceedings of the Society for Experimental Biology and Medicine. Society for Experimental Biology and Medicine. 1999; 222: 196-204.
81. Carr A, Frei B. The role of natural antioxidants in preserving the biological activity of endothelium-derived nitric oxide. Free radical biology & medicine. 2000; 28: 1806-1814.
82. Nandi D, Patra RC, Swarup D. Effect of cysteine, methionine, ascorbic acid and thiamine on arsenic-induced oxidative stress and biochemical alterations in rats. Toxicology. 2005; 211: 26-35.
83. Singh S, Rana SVS. Ascorbic acid improves mitochondrial function in liver of arsenic-treated rat. Toxicology and Industrial Health. 2010; 26: 265-272.
84. Singh S, Rana SVS. Amelioration of arsenic toxicity by L-Ascorbic acid in laboratory rat. Journal of environmental biology. 2007; 28: 377-84.
85. Singh N, Rana SVS. Effect of Insulin on Arsenic Toxicity in Diabetic Rats— Liver Function Studies. Biological Trace Element Research. 2009; 132: 215- 226.
86. Chang SI, Jin B, Youn P, Park C, Park J, Ryu D. Arsenic-induced toxicity and the protective role of ascorbic acid in mouse testis. Toxicology and applied pharmacology. 2007; 218: 196-203.
87. Sarkozi K, Papp A, Horvath E, Mate Z, Ferencz A, et al. Green tea and vitamin C ameliorate some neurofunctional and biogeochemical signs of arsenic toxicity in rats. Nutr Neurosci. 2016; 19: 102-109.
88. Kadrivel R, Sundaram K, Mani S, Samuel S, Elango N, et al. Supplementation of ascorbic acid and alpha tocopherol prevents arsenic induced protein oxidation and DNA damage induced by arsenic in rats. Hum Exp Toxicol. 2007; 26: 939-946.
89. Qureshi F, Tahir M, Saini W. Protective role of vitamin C and vitamin E against sodium arsenate induced changes in developind kidney of mice. J Ayub Med Coll Abbottebad. 2009; 21: 63-69.
90. Machlin LJ. Vitamin E. In Handbook of vitamins, 2nd Ed.(Machlin LJ. ed). Marcell and Dekker, New York. 1991: 99.
91. Burton GW, Ingold KU. Autoxidation of biological molecules. 1. Antioxidant activity of vitamin E and related chain-breaking phenolic antioxidants in vitro. Journal of the American Chemical Society. 1981; 103: 6472-6477.
92. Antonio Gracia MT, Herrera Ducnas A, Pineda Pampliega J. Haematological Effects of arsenic in rats after subchronical exposure during pregnancy and lactation, the protective role of antioxidants. Exp Toxicol Pathol. 2013; 65: 609-614.
93. Chung JS, Haque R, Mazumder DNG, Moore LE, Ghosh N, Samanta S, et al. Blood concentrations of methionine, selenium, beta-carotene, and other micronutrients in a case-control study of arsenic-induced skin lesions in West Bengal, India. Environmental research. 2006; 101: 230-237.
94. Uddin AN, Burns FJ, Rossman TG. Vitamin E and organoselenium prevent the cocarcinogenic activity of arsenite with solar UVR in mouse skin. Carcinogenesis. 2005; 26: 2179-2186.
95. Liebler DC. The role of metabolism in the antioxidant function of vitamin E. Crit Rev Toxicol. 1993; 23: 147-169.
96. Hsueh YM, Chiou HY, Huang YL, Wu WL, Huang CC, Yang MH, et al. Serum beta-carotene level, arsenic methylation capability, and incidence of skin cancer. Cancer epidemiology, biomarkers & prevention: a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology. 1997; 6: 589-96.
97. Hsueh YM, Wu WL, Huang YL, Chiou HY, Tseng CH, Chen CJ. Low serum carotene level and increased risk of ischemic heart disease related to longterm arsenic exposure. Atherosclerosis. 1998; 141: 249-257.
98. Das R, Das A, Roy A, Kumari U, Bhattachrya S, Haldar PK. B-carotene ameliorates arsenic induced toxicity in albino mice. Biol Trace Elem Res. 2015; 164: 226-233.
99. Patrick L. Toxic metals and antioxidants: Part II. The role of antioxidants in arsenic and cadmium toxicity. Altern Med Rev. 2003; 8: 106-128.
100. Flora SJS. Arsenic-induced oxidative stress and its reversibility. Free radical biology & medicine. 2011; 51: 257-281.
101. Da Silva RF, Borges Cdos S, Villela E Silva P, Missassi G, Kiguti LR, et al. The co-administration of N-actylcysteine ameliorates the effects of arsenic trioxide on the male mouse genid tal system. Oxid Med Longev. 2016; 2016: 4257498.
102. Takahashi N, Yoshida T, Ohnuma A, Horiuchi H, Ishitsuka K, Kashimoto Y, et al. The Enhancing Effect of the Antioxidant N-Acetylcysteine on Urinary Bladder Injury Induced by Dimethylarsinic Acid. Toxicologic Pathology. 2011; 39: 1107-1114.
103. Reddy PS, Rani GP, Sainath SB, Meena R, Supriya Ch. Protective effects of N-acetylcysteine against arsenic induced oxidative stress and reprotoxicity in male mice. J Trace Element Med Biol. 2011; 25: 247-253.
104. Santra A, Chowdhury A, Ghatak S, Biswas A, Dhali GK. Arsenic induced apoptosis in mouse liver is mitochondria dependent and is abrogated by N-acetyl cysteine. Toxicol Appl Pharmacol. 2007; 220: 146-155.
105. Pal S, Chatterjee AK. Possible Beneficial Effects of Melatonin Supplementation on Arsenic-Induced Oxidative Stress in Wistar Rats. Drug and Chemical Toxicology. 2006; 29: 423-433.
106. Abu-El-Saad AM, Al-Kahtani MA, Abdel-Moneim AM. N-acetylcysteine and meso-2,3-dimercaptosuccinic acid alleviate oxidative stress and hepatic dysfunction induced by sodium arsenite in male rats. Drug Des Devel Ther. 2016; 20: 3425-3434.
107. Modi M, Kaul RK, Kannan GM, Flora SJS. Co-administration of zinc and n-acetylcysteine prevents arsenic-induced tissue oxidative stress in male rats. Journal of trace elements in medicine and biology: organ of the Society for Minerals and Trace Elements. 2006; 20: 197-204.
108. Hopkins FG. Glutathione: Its Influence in the Oxidation of Fats and Proteins. The Biochemical journal. 1925; 19: 787-819.
109. KOSOWER EM, KOSOWER NS. Lest I Forget Thee, Glutathione. Nature. 1969; 224: 117-120.
110. Rana SVS, Allent T, Singh R. Inevitable glutathione,then and now. Indian J Exp Biol. 2002; 40: 706-716.
111. Ord MG, Stocken LA. A contribution to chemical defence in World War II. Trends in Biochemical Sciences. 2000; 25: 253-256.
112. Delnomdedieu M, Basti MM, Styblo M, Otvos JD, Thomas DJ. Complexation of arsenic species in rabbit erythrocytes. Chemical research in toxicology. 1994; 7: 621-627.
113. Scott N, Hatlelid KM, Mackenzie NE, Carter DE. Reactions of arsenic(III) and arsenic(V)species with glutathione. Chem Res Toxicol. 1993; 6: 102-106.
114. Kala SV, Kala G, Prater CI, Sartorelli AC, Liberman MW. Formation and urinary excretion of arsenic triglutathione and methylarsine diglutathione. Chem Res Toxicol. 2004; 17: 243-249.
115. Suzuki KT, Tomita T, Ogra Y, Ohmichi M. Glutathione-conjugated arsenics in the potential hepato-enteric circulation in rats. Chemical research in toxicology. 2001; 14: 1604-1611.
116. Styblo M, Serves SV, Cullen WR, Thomes DJ. Comparative inhibition of yeast glutathione reductase by arsenicals arsenothiols. Chem Res Toxicol. 1997; 10: 27-33.
117. Chattopadhyay S, Ghosh D. Role of dietary GSH in the amelioration of sodium arsenite-induced ovarian and uterine disorders. Reproductive toxicology. 2010; 30: 481-488.
118. Chen C, Jiang X, Lai Y, Liu Y, Zhang Z. Resveratrol protects against arsenic trioxide-induced oxidative damage through maintenance of glutathione homeostasis and inhibition of apoptotic progression. Environmental and Molecular Mutagenesis. 2014; 56: 333-346.
119. Leslie EM, Haimeur A, Waalkes MP. Arsenic Transport by the Human Multidrug Resistance Protein 1 (MRP1/ABCC1). Journal of Biological Chemistry. 2004; 279: 32700-32708.
120. Thomas DT. Unraveling arsenic-glutathione connections. Toxicological Sciences. 2009; 107: 309-311.
121. Garcia-Nino WR, Pedraza-Chaverri J. Protective effects of curcumin against heavy metals -induced liver damage. Food Chemical Toxicol. 2014; 69: 182- 201.
122. Dutta S, Murugkar A, Gandhe N, Padhye S. Enhanced Antioxidant Activities of Metal Conjugates of Curcumin Derivatives. Metal-Based Drugs. 2001; 8: 183-188.
123. Mukherjee S, Roy M, Dey S, Bhattacharya RK. A Mechanistic Approach for Modulation of Arsenic Toxicity in Human Lymphocytes by Curcumin, an Active Constituent of Medicinal Herb Curcuma longa Linn. Journal of Clinical Biochemistry and Nutrition. 2007; 41: 32-42.
124. Yadav RS, Sankhwar ML, Shukla RK, Chandra R, Pant AB, Islam F, et al. Attenuation of arsenic neurotoxicity by curcumin in rats. Toxicology and applied pharmacology. 2009; 240: 367-376.
125. Deedwania PC. The need for a cost-effective strategy to detect ambulatory silent ischemia. The American Journal of Cardiology. 1994; 74: 1061-1062.
126. Tiwari H, Rao MV. Curcumin supplementation protects from genotoxic effect of arsenic and fluoride. Food Chem Toxicol. 2010; 48: 1234-1238.
127. Roy M, Sinha D, Mukherjee S, Biswas J. Curcumin prevents DNA damage and enhances the repair potential in chronically arsenic exposed human population in west Bengal, India. 2011; 20: 123-131.
128. Gao S, Duan X, Wang X, Dong D, Liu D, Li X, et al. Curcumin attenuates arsenic-induced hepatic injuries and oxidative stress in experimental mice through activation of Nrf2 pathway, promotion of arsenic methylation and urinary excretion. Food and chemical toxicology: an international journal published for the British Industrial Biological Research Association. 2013; 59: 739-747.
129. Srivastava P, Yadav RS, Chandravanshi LP, Shukla RK, Dhuriya YK, Chauhan LK, et al. Unraveling the mechanism of neuroprotection of curcumin in arsenic induced cholinergic dysfunctions in rats. Toxicology and applied pharmacology. 2014; 279: 428-440.
130. Muthumani M, Miltonprabu S. Ameliorative efficacy of tetrahydrocurcumin against arsenic induced oxidative damage, dyslipidemia and hepatic mitochondrial toxicity in rats. Chemico-biological interactions. 2015; 235: 95-105.
131. Sankar P, Telang AG, Ramya K, Vijayakaran K, Kesavan M, Sarkar SN. Protective action of curcumin and nano-curcumin against arsenic-induced genotoxicity in rats in vivo. Molecular Biology Reports. 2014; 41: 7413-7422.
132. Sankar P, Telang AG, Kalaivanan R, Karunakaran V, Manikam K, Sarkar SN. Effects of nanoparticle-encapsulated curcumin on arsenic-induced liver toxicity in rats. Environmental Toxicology. 2013; 30: 628-637.
133. Sankar P, Telang AG, Kalaivanan R, Karunakaran V, Manikam K, Sarkar SN. Effects of nanoparticle-encapsulated curcumin on arsenic-induced liver toxicity in rats. Environmental Toxicology. 2013; 30: 628-637.
134. Sankar P, Telang AG, Kalaivanan R, Karunakaran V, Suresh S, Keasavan M. Oral nanoparticulate curcumin combating arsenic induced oxidative damage in kidney and brain of rats. Toxicol Ind Health. 2013; 32: 410-421.
135. Rayman MP. The importance of selenium to human health. The Lancet. 2000; 356: 233-241.
136. Xia Y, Hill KE, Byrne DW, Xu J, Burk RF. Effectiveness of selenium supplements in a low-selenium area of China. The American journal of clinical nutrition. 2005; 81: 829-834.
137. Horvath PM, Ip C. Synergistic effect of vitamin E and selenium in the chemoprevention of mammary carcinogenesis in rats. Cancer research. 1983; 43: 5335-41.
138. Lane HW, Medina D. Mode of action of selenium inhibition of 7,12-dimethylbenz[a]anthracene-induced mouse mammary tumorigenesis. Journal of the National Cancer Institute. 1985; 75: 675-9.
139. Ganther HE, Lawrence JR. Chemical transformations of selenium in living organisms. Improved forms of selenium for cancer prevention. Tetrahedron. 1997; 53: 12299-12310.
140. Spyrou G, Bjornstedt M, Kumar S, Holmgren A. AP-1 DNA binding activity is inhibited by selenite and selenodiglutathione, 59 FEBS Lett. 1995; 368: 59-63.
141. Biswas S, Talukder G, Sharma A. Prevention of cytotoxic effects of arsenic by short term dietary supplementationwith selenium in mice in vivo. Mutat Res. 1999; 441: 155-160.
142. Messarah M, Klibet F, Boumendjel A, Abdennour C, Bouzerna N, Boulakoud MS, et al. Hepatoprotective role and antioxidant capacity of selenium on arsenic-induced liver injury in rats. Experimental and toxicologic pathology: official journal of the Gesellschaft fur Toxikologische Pathologie. 2012; 64: 167-174.
143. Dash JR, Datta BK, Sarkar S, Mandal TK. Chronic arsenicosis in cattle: Possible mitigation with Zn and Se. Ecotoxicology and Environmental Safety. 2013; 92: 119-122.
144. Krohn RM, Lemaire M, Negro Silva LF, Lemarie C, Bolt A, et al. High selenium lentil diet protects against arsenic induced atherosclerosis in a mouse model. J Nutr Biochem. 2016; 27: 9-15.
145. Arendt J. Importance and Relevance of Melatonin to Human Biological Rhythms. Journal of Neuroendocrinology. 2003; 15: 427-431.
146. Reiter RJ. The pineal and its hormones in the control of reproduction in mammals. Endocrine reviews. 1980; 1: 109-131.
147. Turek FW, Gillette MU. Melatonin, sleep, and circadian rhythms: rationale for development of specific melatonin agonists. Sleep medicine. 2004; 5: 523-532.
148. Tan DX, Chen LD, Poeggeler B, Manchester LC, Reiter RJ. Melatonin: a potent endogenous hydroxyl radical scavenger. Endocr J. 1993; 1: 57-60.
149. Tan DX, Reiter RJ, Manchester LC, Yan MT, ElSawi M, et al. Chemical and physical properties and potential mechanisms: melatonin as a broad spectrum antioxidant and free radical scavenger. Curr Top Med Chem. 2002; 2: 181-198.
150. Allegra M, Reiter RJ, Tan DX, Gentile C, Tesorure L, et al. The chemistry of melatonins’ interaction with reactive species. J Pineal Res. 2003; 34: 1-10.
151. Barlow-Walden LR, Reiter RJ, Abe M, Pablos M, Menendez-Pelaez A, Chen L, et al. Melatonin stimulates brain glutathione peroxidase activity. Neurochemistry International. 1995; 26: 497-502.
152. Pablos MI, Reiter RJ, Ortiz GG, Guerrero JM, Agapito MT, Chuang J, et al. Rhythms of glutathione peroxidase and glutathione reductase in brain of chick and their inhibition by light. Neurochemistry International. 1998; 32: 69-75.
153. Antolin I, Rodriguez C, Sainz RM, Mayo JC, Uria H, et al. Neurohormone melatonin prevents cell damage: effect on gene expression for antioxidant enzymes. FASEB J. 1996; 10: 882-890.
154. Tomas-Zapico C, Boga JA, Caballero B, Vega-Naredo I, Sierra V, Alvarez- Garcia O, et al. Coexpression of MT1 and RORalpha1 melatonin receptors in the Syrian hamster Harderian gland. Journal of Pineal Research. 2005; 39: 21-26.
155. Pal S, Chatterjee AK. Possible Beneficial Effects of Melatonin Supplementation on Arsenic-Induced Oxidative Stress in Wistar Rats. Drug and Chemical Toxicology. 2006; 29: 423-433.
156. Pant HH, Rao MV. Evaluation of in vitro anti-genotoxic potential of melatonin against arsenic and fluoride in human blood cultures. Ecotoxicology and environmental safety. 2010; 73: 1333-1337.
157. Uygur R, Aktas C, Caglar V, Uygur E, Erdogan H, et al. Protective effects of melatonin against arsenic induced apoptosis and oxidative stress in rat testes. Toxicol Ind Health. 2016; 32: 848-859.
158. Teng YC, Tai YI, Huang HJ, Lin AMY. Melatonin Ameliorates Arsenite- Induced Neurotoxicity: Involvement of Autophagy and Mitochondria. Molecular Neurobiology. 2015; 52: 1015-1022.
159. Allen T, Rana SVS. Oxidative stress by inorganic arsenic: modulation by thyroid hormones in rat. Comp Biochem Physiol (Part-C). 2003; 135: 157- 162.
160. Rana SVS, Allen T. Influence of thyroxine and n-propylthiouracil on nephrotoxicity of arsenic in rat. Toxicol Indus Health. 2006; 22: 137-145.
161. Mishra D, Mehta A, Flora SJS. Reversal of arsenic inducedhepatic apoptosis with combined administration of DMSA and its analogues in guinea pigs: role of glutathione and linked enzymes. Chem Res Toxicol. 2008; 21: 400-407.
162. Morgan and Drew. In Selective Toxicity. Adrien Albert. Chapman and Hall. London & New York. 1920: pp430.
163. Mückter H, Lieb B, Reich F, Hunder G, Walther U, Fichtl B. Are we ready to replace dimercaprol (BAL) as an arsenic antidote?. Human & Experimental Toxicology. 1997; 16: 460-465.
164. Tripathi N, Flora SJS. Effect of some thiol chelators on enzymatic activities in blood, liver and kidneys of acute arsenic (III)exposed mice. Biomed Env Sci. 1998; 110: 38-45.
165. Inns RH, Rice P, Bright JE, Marrs TC. Evaluation of the efficacy of dimercapto chelating agents for the treatment of systemic organic arsenic poisoning in rabbits. Hum Exp Toxicol. 1990; 9: 215-220.
166. Sankar P, Telang AG, Suresh S, Kesavan M, Kannan K, et al. Immunomodulatory effects of nanocurcumin in arsenic exposed rats. Int Immunopharmacol. 2013; 17: 65-70.
167. Chen C, Jiang X, Lai Y, Liu Y, Zhang Z. Resveratrol protects against arsenic trioxide-induced oxidative damage through maintenance of glutathione homeostasis and inhibition of apoptotic progression. Environmental and Molecular Mutagenesis. 2014; 56: 333-346.
168. Burns FJ, Rossman T, Vega K, Uddin A, Vogt S, Lai B, et al. Mechanism of Selenium-Induced Inhibition of Arsenic-Enhanced UVR Carcinogenesis in Mice. Environmental Health Perspectives. 2008; 116: 703-708.
169. Brigelius-Flohé R, Sies H. Diversity of Selenium Functions in Health and Disease. 2015: 31-54.
170. Garla R, Ganger R, Mohanty BP, Verma S, Bansal MP, Garg ML. Metallothionein does not sequester arsenic(III) ions in condition of acute arsenic toxicity. Toxicology. 2016; 366-367: 68-73.
171. Miao X, Tang Z, Wang Y, Su G, Sun W, Wei W, et al. Metallothionein prevention of arsenic trioxide-induced cardiac cell death is associated with its inhibition of mitogen-activated protein kinases activation in vitro and in vivo. Toxicology letters. 2013; 220: 277-285.