<unk>  interferes with cellular longevity by allosteric inhibition of an essential metabolic enzyme pyruvate dehydrogenase complex, which catalyzes the oxidation of pyruvate to acetyl-CoA by NAD+. With the enzyme inhibited, the energy system of the cell is disrupted resulting in cellular apoptosis. Biochemically,<unk>  prevents use of thiamine resulting in a clinical picture resembling thiamine deficiency. Poisoning with<unk>  can raise lactate levels and lead to lactic acidosis. Low potassium levels in the cells increases the risk of experiencing a life-threatening heart rhythm problem from<unk>  trioxide.<unk>  in cells clearly stimulates the production of hydrogen peroxide (H2O2). When the H2O2 reacts with certain metals such as iron or manganese it produces a highly reactive hydroxyl radical. Inorganic<unk>  trioxide found in ground water particularly affects voltage-gated potassium channels, disrupting cellular electrolytic function resulting in neurological disturbances, cardiovascular episodes such as prolonged QT interval, neutropenia, high blood pressure, central nervous system dysfunction, anemia, and death.<unk>  has also been shown to induce cardiac hypertrophy by activating certain transcription factors involved in pathologically remodeling the heart. Tissue culture studies have shown that<unk>  compounds block both IKr and Iks channels and, at the same time, activate IK-ATP channels.<unk>  compounds also disrupt ATP production through several mechanisms. At the level of the citric acid cycle,<unk>  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, probably from necrotic cell death, not apoptosis. A post mortem reveals brick red colored mucosa, due to severe hemorrhage. Although<unk>  causes toxicity, it can also play a protective role. Mechanism<unk> e 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<unk> .) In the glyceraldehyde 3-phosphate 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 A2 and adhesion proteins in platelets, while human platelets showed similar responses. The effect on vascular endothelium may eventually be mediated by the<unk> -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. Kinetics The two forms of inorganic<unk> , 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<unk>  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 Blue and was used as herbicide in the American war in Vietnam. In humans inorganic<unk>  is reduced nonenzymatically from pentoxide to trioxide, using glutathione or it is mediated by enzymes. Reduction of<unk>  pentoxide to<unk>  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, but reduction from +5 As to +3 As may be considered as a bioactivation instead. Another suggestion is that methylation might be a detoxification if "AsIII intermediates are not permitted to accumulate" because the pentavalent organoarsenics have a lower affinity to thiol groups than inorganic pentavalent<unk> s. 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.<unk> , 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<unk> e at nonessential sites might contribute to detoxification.<unk> e inhibits members of the disulfide oxidoreductase family like glutathione reductase and thioredoxin reductase. The remaining unbound<unk>  (≤ 10%) accumulates in cells, which over time may lead to skin, bladder, kidney, liver, lung, and prostate cancers. Other forms of<unk>  toxicity in humans have been observed in blood, bone marrow, cardiac, central nervous system, gastrointestinal, gonadal, kidney, liver, pancreatic, and skin tissues. Heat shock response Another aspect is the similarity of<unk>  effects to the heat shock response. Short-term<unk>  exposure has effects on signal transduction inducing heat shock proteins with masses of 27, 60, 70, 72, 90, and 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 dependent on the dosing regime and may be as well inversed. As shown by some experiments reviewed by Del Razo (2001), reactive oxygen species induced by low levels of inorganic<unk>  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<unk> -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<unk>  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<unk> e, 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<unk>  on signal transduction which is not clearly understood yet. Oxidative stress Studies have demonstrated that the oxidative stress generated by<unk>  may disrupt the signal transduction pathways of the nuclear transcriptional factors PPARs, 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 PPARs 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<unk>  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<unk>  and the onset of diabetes mellitus Type 2.
Arsenic poisoning
Mercury poisoning
Cadmium poisoning
Chlorine gas poisoning
Salicylate poisoning
Mercury Poisoning
Tin poisoning
Cobalt poisoning