Arsenic toxicity
Encyclopedia
Arsenic
and many of its compounds are especially potent poisons. Arsenic disrupts ATP
production through several mechanisms. At the level of the citric acid cycle
, arsenic inhibits pyruvate dehydrogenase
and by competing with phosphate it uncouples oxidative phosphorylation
, thus inhibiting energy-linked reduction of NAD+
, mitochondrial respiration, and ATP synthesis. Hydrogen peroxide production is also increased, which might form reactive oxygen species and oxidative stress. These metabolic interferences lead to death from multi-system organ failure
(see arsenic poisoning
) probably from necrotic cell death, not apoptosis
. A post mortem reveals brick red colored mucosa, due to severe hemorrhage. Although arsenic causes toxicity, it can also play a protective role.
Inorganic arsenic trioxide
is a component of geologic formations and can be washed out into the ground water. Arsenic poisoning
can be related to human activities such as mining and ore smelting but is more often associated with dissolved solids naturally endemic in the aquifer environment. Unlike the organic form, inorganic arsenic is quite harmful even in minute quantities.
and was used as herbicide in the American war in the South-East Asian country of Viet Nam.
In humans inorganic arsenic is reduced nonenzymatically from pentoxide to trioxide, using glutathione (GSH) or it is mediated by enzymes. Reduction of arsenic pentoxide to arsenic trioxide increases its toxicity and bio availability, . Methylation occurs through methyltransferase enzymes. S-adenosylmethionine (SAM) may serve as methyl donor. Various pathways are used, the principal route being dependent on the current environment of the cell. Resulting metabolites are monomethylarsonous acid (MMA(III)) and dimethylarsinous acid (DMA(III)).
Methylation had been regarded as a detoxification process. While in fact reduction from +5 As to +3 As may be considered as a bioactivation instead. Another suggestion is that methylation might be a detoxification if "As[III] intermediates are not permitted to accumulate" because the pentavalent organoarsenics have a lower affinity to thiol groups than inorganic pentavalent arsenics. Gebel (2002) stated that methylation is a detoxification through accelerated excretion. With regard to carcinogenicity it has been suggested that methylation should be regarded as a toxification.
Arsenic, especially +3 As, binds to single, but with higher affinity to vicinal sulfhydryl groups, thus reacts with a variety of proteins and inhibits their activity. It was also proposed that binding of arsenite at nonessential sites might contribute to detoxification. Arsenite inhibits members of the disulfide oxidoreductase family like glutathione reductase and thioredoxin reductase.
The remaining unbound arsenic (≤ 10%) accumulates in cells, which over time may lead to skin, bladder, kidney, liver, lung, and prostate cancers. Other forms of arsenic toxicity in humans have been observed in blood, bone marrow, cardiac, central nervous system, gastrointestinal, gonadal, kidney, liver, pancreatic, and skin tissues.
Experiments demonstrated enhanced arterial thrombosis in a rat animal model, elevations of serotonin levels, thromboxane A[2] and adhesion proteins in platelets, while human platelets showed similar responses. The effect on vascular endothelium may eventually be mediated by the arsenic-induced formation of nitric oxide.
It was demonstrated that +3 As concentrations substantially lower than concentrations required for inhibition of the lysosomal protease cathepsin L in B cell line TA3 were sufficient to trigger apoptosis in the same B cell line, while the latter could be a mechanism mediating immunosuppressive effects.
However, in vitro, most purified DNA repair enzymes are rather insensitive to As, but in cell culture, As produces a dose-dependant decrease of DNA ligase activity. This might indicate that inhibition of DNA repair is an indirect effect due to changes in cellular redox levels or alterated signal transduction and consequent gene expression. In spite of its carcinogenicity, the potential of arsenic to induce point mutations is weak. If administered with point mutagens it enhances the frequency of mutations in a syngergistic way.
Its comoutagenic effects may be explained by interference with base and nucleotide excision repair, eventually through interaction with zinc finger structures. DMA showed to effectuate DNA single stand breaks resulting from inhibition of repair enzymes at levels of 5 to 100 mM in human epithelial type II cells.
+3 MMA and +3 DMA were also shown to be directly genotoxic by effectuating scissions in supercoiled ΦX174 DNA. Increased arsenic exposure is associated with an increased frequency of chromosomal aberrations, micronuclei and sister-chromatid exchanges. An explanation for chromosomal aberrations is the sensitivity of the protein tubulin and the mitotic spindle to arsenic. Histological observations confirm effects on cellular integrity, shape and locomotion.
+3 DMA is able to form reactive oxygen species (ROS) by reaction with molecular oxygen. Resulting metabolites are the dimethylarsenic radical and the dimethylarsenic peroxyl radical.
Both +5 DMA and +3 DMA were shown to release iron from horse spleen as well as from human liver ferritin if ascorbic acid was administered simultaneously. Thus, formation of ROS can be promoted.
Moreover, Arsenic could cause oxidative stress by depleting the cell’s antioxidants, especially the ones containing thiol groups. The accumulation of ROS like the cited above and hydroxyl radicals, superoxide radicals and hydrogen peroxides causes aberrant gene expression at low concentrations and lesions of lipids, proteins and DNA in higher concentrations which eventually lead to cellular death.
In a rat animal model, urine levels of 8-hydroxy-2’-desoxyguanosine (as a biomarker of ROS DNA damage) were measured after treatment with DMA. In comparison to control levels, they turned out to be significantly increased. This theory is further supported by a cross-sectional study which found elevated mean serum lipid peroxides (LPO) in the As exposed individuals which correlated with blood levels of inorganic arsenic and methylated metabolites and inversely correlated with nonprotein sulfhydryl (NPSH) levels in whole blood. Another study found an association of As levels in whole blood with the level of reactive oxidants in plasma and an inverse relationship with plasma antioxidants. A finding of the latter study indicates that methylation might in fact be a detoxification pathway with regard to oxidative stress: the results showed that the lower the As methylation capacity was, the lower the level of plasma antioxidant capacity. As reviewed by Kitchin (2001), the oxidative stress theory provides an explanation for the preferred tumor sites connected with arsenic exposure. Considering that a high partial pressure of oxygen is present in lungs and +3 DMA is excreted in gaseous state via the lungs this seems to be a plausible mechanism for special vulnerability. The fact that DMA is produced by methylation in the liver, excreted via the kidneys and latter on stored in the bladder accounts for the other tumor localizations.
Regarding DNA methylation, some studies suggest interaction of As with methyltransferases which leads to an inactivation of tumor suppressor genes through hypermethylation, others state that hypomethylation might occur due to a lack of SAM resulting in aberrant gene activation. An experiment by Zhong et al. (2001) with arsenite-exposed human lung A549, kidney UOK123, UOK109 and UOK121 cells isolated eight different DNA fragments by methylation-sensitive arbitrarily primed PCR. It turned out that six of the fragments were hyper- and two of them were hypomethylated. Higher levels of DNA methltransferase mRNA and enzyme activity were found.
Kitchin (2001) proposed a model of altered growth factors which lead to cell proliferation and thus to carcinogenesis. From observations it is known that chronic low-dose arsenic poisoning can lead to increased tolerance to its acute toxicity. MRP1-overexpressing lung tumor GLC4/Sb30 cells poorly accumulate arsenite and arsenate. This is mediated through MRP-1 dependent efflux. The efflux requires GSH, but no As-GSH complex formation.
Although a lot of mechanisms have been proposed, no definite model can be given for the mechanisms of chronic arsenic poisoning. The prevailing events of toxicity and carcinogenicity might be quite tissue-specific. Current consensus on the mode of carcinogenesis is that it acts primarily as a tumor promoter. Its co-carcinogenicity has been demonstrated in several models. However, the finding of several studies that chronically arsenic-exposed Andean populations (as most extremely exposed to UV-light) do not develop skin cancer with chronic arsenic exposure, is puzzling.
Via JNK and p38 it activates c-fos, c-jun and egr-1 which are usually activated by growth factors and cytokines The effects are largely dependant on the dosing regime and may be as well inversed.
As shown by some experiments reviewed by Del Razo (2001), ROS induced by low levels of inorganic arsenic increase the transcription and the activity of the activator protein 1 (AP-1) and the nuclear factor-κB (NF-κB) (maybe enhanced by elevated MAPK levels), which results in c-fos/c-jun activation, over-secretion of pro-inflammatory and growth promoting cytokines stimulating cell proliferation. Germolec et al. (1996) found an increased cytokine expression and cell proliferation in skin biopsies from individuals chronically exposed to arsenic-contaminated drinking water.
Increased AP-1 and NF-κB obviously also result in an up-regulation of mdm2 protein, which decreases p53 protein levels. Thus, taking into account p53’s function, a lack of it could cause a faster accumulation of mutations contributing to carcinogenesis. However, high levels of inorganic arsenic inhibit NF-κB activation and cell proliferation. An experiment of Hu et al. (2002) demonstrated increased binding activity of AP-1 and NF-κB after acute (24 h) exposure to +3 sodium arsenite, whereas long-term exposure (10–12 weeks) yielded the opposite result. The authors conclude that the former may be interpreted as a defense response while the latter could lead to carcinogenesis. As the contradicting findings and connected mechanistic hypotheses indicate, there is a difference in acute and chronic effects of arsenic on signal transduction which is not clearly understood yet.
Epidemiological studies have suggested a correlation between chronic consumption of drinking water contaminated with arsenic and the incidence of Type 2-diabetes. The human liver after exposure to therapeutic drugs may exhibit hepatic non-cirrhotic portal hypertension, fibrosis, and cirrhosis. However, the literature provides insufficient scientific evidence to show cause and effect between arsenic and the onset of diabetes mellitus Type 2.
Arsenic
Arsenic is a chemical element with the symbol As, atomic number 33 and relative atomic mass 74.92. Arsenic occurs in many minerals, usually in conjunction with sulfur and metals, and also as a pure elemental crystal. It was first documented by Albertus Magnus in 1250.Arsenic is a metalloid...
and many of its compounds are especially potent poisons. Arsenic disrupts ATP
Adenosine triphosphate
Adenosine-5'-triphosphate is a multifunctional nucleoside triphosphate used in cells as a coenzyme. It is often called the "molecular unit of currency" of intracellular energy transfer. ATP transports chemical energy within cells for metabolism...
production through several mechanisms. At the level of the citric acid cycle
Citric acid cycle
The citric acid cycle — also known as the tricarboxylic acid cycle , the Krebs cycle, or the Szent-Györgyi-Krebs cycle — is a series of chemical reactions which is used by all aerobic living organisms to generate energy through the oxidization of acetate derived from carbohydrates, fats and...
, arsenic inhibits pyruvate dehydrogenase
Pyruvate dehydrogenase
Pyruvate dehydrogenase complex is a complex of three enzymes that transform pyruvate into acetyl-CoA by a process called pyruvate decarboxylation. Acetyl-CoA may then be used in the citric acid cycle to carry out cellular respiration, and this complex links the glycolysis metabolic pathway to the...
and by competing with phosphate it uncouples oxidative phosphorylation
Oxidative phosphorylation
Oxidative phosphorylation is a metabolic pathway that uses energy released by the oxidation of nutrients to produce adenosine triphosphate . Although the many forms of life on earth use a range of different nutrients, almost all aerobic organisms carry out oxidative phosphorylation to produce ATP,...
, thus inhibiting energy-linked reduction of NAD+
Nicotinamide adenine dinucleotide
Nicotinamide adenine dinucleotide, abbreviated NAD, is a coenzyme found in all living cells. The compound is a dinucleotide, since it consists of two nucleotides joined through their phosphate groups. One nucleotide contains an adenine base and the other nicotinamide.In metabolism, NAD is involved...
, mitochondrial respiration, and ATP synthesis. Hydrogen peroxide production is also increased, which might form reactive oxygen species and oxidative stress. These metabolic interferences lead to death from multi-system organ failure
Organ failure
Organ dysfunction is a condition where an organ does not perform its expected function. Organ failure is organ dysfunction to such a degree that normal homeostasis cannot be maintained without external clinical intervention.It is not a diagnosis...
(see arsenic poisoning
Arsenic poisoning
Arsenic poisoning is a medical condition caused by increased levels of the element arsenic in the body. Arsenic interferes with cellular longevity by allosteric inhibition of an essential metabolic enzyme...
) probably from necrotic cell death, not apoptosis
Apoptosis
Apoptosis is the process of programmed cell death that may occur in multicellular organisms. Biochemical events lead to characteristic cell changes and death. These changes include blebbing, cell shrinkage, nuclear fragmentation, chromatin condensation, and chromosomal DNA fragmentation...
. A post mortem reveals brick red colored mucosa, due to severe hemorrhage. Although arsenic causes toxicity, it can also play a protective role.
Exposure
Organic arsenic exposure can occur by eating food. Organic arsenic is 500 times less harmful than inorganic arsenic. Food is a source of the less toxic organic arsenic, with the predominant source being seafood.Inorganic arsenic trioxide
Arsenic trioxide
Arsenic trioxide is the inorganic compound with the formula As2O3. This commercially important oxide of arsenic is the main precursor to other arsenic compounds, including organoarsenic compounds. Approximately 50,000 tonnes are produced annually...
is a component of geologic formations and can be washed out into the ground water. Arsenic poisoning
Arsenic poisoning
Arsenic poisoning is a medical condition caused by increased levels of the element arsenic in the body. Arsenic interferes with cellular longevity by allosteric inhibition of an essential metabolic enzyme...
can be related to human activities such as mining and ore smelting but is more often associated with dissolved solids naturally endemic in the aquifer environment. Unlike the organic form, inorganic arsenic is quite harmful even in minute quantities.
Kinetics
The two forms of inorganic arsenic, reduced (trivalent As (III)) and oxidized (pentavalent As(V)), can be absorbed, and accumulated in tissues and body fluids. In the liver, the metabolism of arsenic involves enzymatic and non-enzymatic methylation, the most frequently excreted metabolite (≥ 90%) in the urine of mammals is dimethylarsinic acid(or Cacodylic acid) (DMA(V)). Dimethylarsenic acid is also known as Agent BlueAgent Blue
Agent Blue is one of the "rainbow herbicides" that is known for its use by the United States during the Vietnam War. It was sprayed on rice paddies and other crops in an attempt to deprive the Viet Cong of valuable crops. Agent Blue is a mixture of two arsenic-containing compounds, sodium...
and was used as herbicide in the American war in the South-East Asian country of Viet Nam.
In humans inorganic arsenic is reduced nonenzymatically from pentoxide to trioxide, using glutathione (GSH) or it is mediated by enzymes. Reduction of arsenic pentoxide to arsenic trioxide increases its toxicity and bio availability, . Methylation occurs through methyltransferase enzymes. S-adenosylmethionine (SAM) may serve as methyl donor. Various pathways are used, the principal route being dependent on the current environment of the cell. Resulting metabolites are monomethylarsonous acid (MMA(III)) and dimethylarsinous acid (DMA(III)).
Methylation had been regarded as a detoxification process. While in fact reduction from +5 As to +3 As may be considered as a bioactivation instead. Another suggestion is that methylation might be a detoxification if "As[III] intermediates are not permitted to accumulate" because the pentavalent organoarsenics have a lower affinity to thiol groups than inorganic pentavalent arsenics. Gebel (2002) stated that methylation is a detoxification through accelerated excretion. With regard to carcinogenicity it has been suggested that methylation should be regarded as a toxification.
Arsenic, especially +3 As, binds to single, but with higher affinity to vicinal sulfhydryl groups, thus reacts with a variety of proteins and inhibits their activity. It was also proposed that binding of arsenite at nonessential sites might contribute to detoxification. Arsenite inhibits members of the disulfide oxidoreductase family like glutathione reductase and thioredoxin reductase.
The remaining unbound arsenic (≤ 10%) accumulates in cells, which over time may lead to skin, bladder, kidney, liver, lung, and prostate cancers. Other forms of arsenic toxicity in humans have been observed in blood, bone marrow, cardiac, central nervous system, gastrointestinal, gonadal, kidney, liver, pancreatic, and skin tissues.
Mechanism
Arsenite inhibits not only the formation of Acetyl-CoA but also the enzyme succinic dehydrogenase. Arsenate can replace phosphate in many reactions. It is able to form Glc-6-Arsenate in vitro; therefore it has been argued that hexokinase could be inhibited. (Eventually this may be a mechanism leading to muscle weakness in chronic arsenic poisoning.) In the glyceraldehyde-3-P-dehydrogenase reaction arsenate attacks the enzyme-bound thioester. The formed 1-arseno-3-phosphoglycerate is unstable and hydrolyzes spontaneously. Thus, ATP formation in Glycolysis is inhibited while bypassing the phosphoglycerate kinase reaction. (Moreover, the formation of 2,3-bisphosphoglycerate in erythrocytes might be affected, followed by a higher oxygen affinity of hemoglobin and subsequently enhanced cyanosis) As shown by Gresser (1981), submitochondrial particles synthesize Adenosine-5’-diphosphate-arsenate from ADP and arsenate in presence of succinate. Thus, by a variety of mechanisms arsenate leads to an impairment of cell respiration and subsequently diminished ATP formation. This is consistent with observed ATP depletion of exposed cells and histopathological findings of mitochondrial and cell swelling, glycogen depletion in liver cells and fatty change in liver, heart and kidney.Experiments demonstrated enhanced arterial thrombosis in a rat animal model, elevations of serotonin levels, thromboxane A[2] and adhesion proteins in platelets, while human platelets showed similar responses. The effect on vascular endothelium may eventually be mediated by the arsenic-induced formation of nitric oxide.
It was demonstrated that +3 As concentrations substantially lower than concentrations required for inhibition of the lysosomal protease cathepsin L in B cell line TA3 were sufficient to trigger apoptosis in the same B cell line, while the latter could be a mechanism mediating immunosuppressive effects.
Carcinogenicity
It is still a matter of debate whether DNA repair inhibition or alterations in the status of DNA methylation are responsible for the carcinogenic potential of As. As vicinal sulfhydryl groups are frequently found in DNA-binding proteins, transcription factors and DNA-repair proteins, interaction of arsenic with these molecules appears to be likely.However, in vitro, most purified DNA repair enzymes are rather insensitive to As, but in cell culture, As produces a dose-dependant decrease of DNA ligase activity. This might indicate that inhibition of DNA repair is an indirect effect due to changes in cellular redox levels or alterated signal transduction and consequent gene expression. In spite of its carcinogenicity, the potential of arsenic to induce point mutations is weak. If administered with point mutagens it enhances the frequency of mutations in a syngergistic way.
Its comoutagenic effects may be explained by interference with base and nucleotide excision repair, eventually through interaction with zinc finger structures. DMA showed to effectuate DNA single stand breaks resulting from inhibition of repair enzymes at levels of 5 to 100 mM in human epithelial type II cells.
+3 MMA and +3 DMA were also shown to be directly genotoxic by effectuating scissions in supercoiled ΦX174 DNA. Increased arsenic exposure is associated with an increased frequency of chromosomal aberrations, micronuclei and sister-chromatid exchanges. An explanation for chromosomal aberrations is the sensitivity of the protein tubulin and the mitotic spindle to arsenic. Histological observations confirm effects on cellular integrity, shape and locomotion.
+3 DMA is able to form reactive oxygen species (ROS) by reaction with molecular oxygen. Resulting metabolites are the dimethylarsenic radical and the dimethylarsenic peroxyl radical.
Both +5 DMA and +3 DMA were shown to release iron from horse spleen as well as from human liver ferritin if ascorbic acid was administered simultaneously. Thus, formation of ROS can be promoted.
Moreover, Arsenic could cause oxidative stress by depleting the cell’s antioxidants, especially the ones containing thiol groups. The accumulation of ROS like the cited above and hydroxyl radicals, superoxide radicals and hydrogen peroxides causes aberrant gene expression at low concentrations and lesions of lipids, proteins and DNA in higher concentrations which eventually lead to cellular death.
In a rat animal model, urine levels of 8-hydroxy-2’-desoxyguanosine (as a biomarker of ROS DNA damage) were measured after treatment with DMA. In comparison to control levels, they turned out to be significantly increased. This theory is further supported by a cross-sectional study which found elevated mean serum lipid peroxides (LPO) in the As exposed individuals which correlated with blood levels of inorganic arsenic and methylated metabolites and inversely correlated with nonprotein sulfhydryl (NPSH) levels in whole blood. Another study found an association of As levels in whole blood with the level of reactive oxidants in plasma and an inverse relationship with plasma antioxidants. A finding of the latter study indicates that methylation might in fact be a detoxification pathway with regard to oxidative stress: the results showed that the lower the As methylation capacity was, the lower the level of plasma antioxidant capacity. As reviewed by Kitchin (2001), the oxidative stress theory provides an explanation for the preferred tumor sites connected with arsenic exposure. Considering that a high partial pressure of oxygen is present in lungs and +3 DMA is excreted in gaseous state via the lungs this seems to be a plausible mechanism for special vulnerability. The fact that DMA is produced by methylation in the liver, excreted via the kidneys and latter on stored in the bladder accounts for the other tumor localizations.
Regarding DNA methylation, some studies suggest interaction of As with methyltransferases which leads to an inactivation of tumor suppressor genes through hypermethylation, others state that hypomethylation might occur due to a lack of SAM resulting in aberrant gene activation. An experiment by Zhong et al. (2001) with arsenite-exposed human lung A549, kidney UOK123, UOK109 and UOK121 cells isolated eight different DNA fragments by methylation-sensitive arbitrarily primed PCR. It turned out that six of the fragments were hyper- and two of them were hypomethylated. Higher levels of DNA methltransferase mRNA and enzyme activity were found.
Kitchin (2001) proposed a model of altered growth factors which lead to cell proliferation and thus to carcinogenesis. From observations it is known that chronic low-dose arsenic poisoning can lead to increased tolerance to its acute toxicity. MRP1-overexpressing lung tumor GLC4/Sb30 cells poorly accumulate arsenite and arsenate. This is mediated through MRP-1 dependent efflux. The efflux requires GSH, but no As-GSH complex formation.
Although a lot of mechanisms have been proposed, no definite model can be given for the mechanisms of chronic arsenic poisoning. The prevailing events of toxicity and carcinogenicity might be quite tissue-specific. Current consensus on the mode of carcinogenesis is that it acts primarily as a tumor promoter. Its co-carcinogenicity has been demonstrated in several models. However, the finding of several studies that chronically arsenic-exposed Andean populations (as most extremely exposed to UV-light) do not develop skin cancer with chronic arsenic exposure, is puzzling.
Heat shock response
Another aspect is the similarity of arsenic effects to the heat shock response. Short-term arsenic exposure has effects on signal transduction inducing heat shock proteins with masses of 27,60,70,72,90,110 kDa as well as metallotionein, ubiquitin, mitogen-activated [MAP] kinases, extracellular regulated kinase [ERK], c-jun terminal kinases [JNK] and p38.Via JNK and p38 it activates c-fos, c-jun and egr-1 which are usually activated by growth factors and cytokines The effects are largely dependant on the dosing regime and may be as well inversed.
As shown by some experiments reviewed by Del Razo (2001), ROS induced by low levels of inorganic arsenic increase the transcription and the activity of the activator protein 1 (AP-1) and the nuclear factor-κB (NF-κB) (maybe enhanced by elevated MAPK levels), which results in c-fos/c-jun activation, over-secretion of pro-inflammatory and growth promoting cytokines stimulating cell proliferation. Germolec et al. (1996) found an increased cytokine expression and cell proliferation in skin biopsies from individuals chronically exposed to arsenic-contaminated drinking water.
Increased AP-1 and NF-κB obviously also result in an up-regulation of mdm2 protein, which decreases p53 protein levels. Thus, taking into account p53’s function, a lack of it could cause a faster accumulation of mutations contributing to carcinogenesis. However, high levels of inorganic arsenic inhibit NF-κB activation and cell proliferation. An experiment of Hu et al. (2002) demonstrated increased binding activity of AP-1 and NF-κB after acute (24 h) exposure to +3 sodium arsenite, whereas long-term exposure (10–12 weeks) yielded the opposite result. The authors conclude that the former may be interpreted as a defense response while the latter could lead to carcinogenesis. As the contradicting findings and connected mechanistic hypotheses indicate, there is a difference in acute and chronic effects of arsenic on signal transduction which is not clearly understood yet.
Oxidative stress
Studies have demonstrated that the oxidative stress generated by arsenic may disrupt the signal transduction pathways of the nuclear transcriptional factors PPAR’s, AP-1, and NF-κB, as well as the pro-inflammatory cytokines IL-8 and TNF-α. The interference of oxidative stress with signal transduction pathways may affect physiological processes associated with cell growth, metabolic syndrome X, glucose homeostasis, lipid metabolism, obesity, insulin resistance, inflammation, and diabetes-2. Recent scientific evidence has elucidated the physiological roles of the PPAR’s in the ω- hydroxylation of fatty acids and the inhibition of pro-inflammatory transcription factors (NF-κB and AP-1), pro-inflammatory cytokines (IL-1, -6, -8, -12, and TNF-α), cell4 adhesion molecules (ICAM-1 and VCAM-1), inducible nitric oxide synthase, proinflammatory nitric oxide (NO), and anti-apoptotic factors.Epidemiological studies have suggested a correlation between chronic consumption of drinking water contaminated with arsenic and the incidence of Type 2-diabetes. The human liver after exposure to therapeutic drugs may exhibit hepatic non-cirrhotic portal hypertension, fibrosis, and cirrhosis. However, the literature provides insufficient scientific evidence to show cause and effect between arsenic and the onset of diabetes mellitus Type 2.