Definition
A shiny gray element with atomic symbol As, atomic number 33, and atomic weight 75. It occurs throughout the universe, mostly in the form of metallic arsenides. Most forms are toxic. According to the Fourth Annual Report on Carcinogens (NTP 85-002, 1985), arsenic and certain arsenic compounds have been listed as known carcinogens. (From Merck Index, 11th ed)
Description
Arsenic(As) is a ubiquitous metalloid found in several forms in food and the environment, such as the soil, air and water. Physiologically, it exists as an ion in the body. The predominant form is inorganic arsenic in drinking water, which is both highly toxic and carcinogenic and rapidly bioavailable. Arsenic is currently one of the most important environmental global contaminants and toxicants, particularly in the developing countries. For decades, very large populations have been and are currently still exposed to inorganic Arsenic through geogenically contaminated drinking water. An increased incidence of disease mediated by this toxicant is the consequence of long-term exposure. In human's chronic ingestion of inorganic arsenic (> 500 mg/L As) has been associated with cardiovascular, nervous, hepatic and renal diseases and diabetes mellitus as well as cancer of the skin, bladder, lung, liver and prostate. Contrary to the earlier view that methylated compounds are innocuous, the methylated metabolites are now recognized to be both toxic and carcinogenic, possibly due to genotoxicity, inhibition of antioxidative enzyme functions, or other mechanisms. Arsenic inhibits indirectly sulfhydryl containing enzymes and interferes with cellular metabolism. Effects involve such phenomena as cytotoxicity, genotoxicity and inhibition of enzymes with antioxidant function. These are all related to nutritional factors directly or indirectly. Nutritional studies both in experimental and epidemiological studies provide convincing evidence that nutritional intervention, including chemoprevention, offers a pragmatic approach to mitigate the health effects of arsenic exposure, particularly cancer, in the relatively resource-poor developing countries. Nutritional intervention, especially with micronutrients, many of which are antioxidants and share the same pathway with Arsenic , appears a host defence against the health effects of arsenic contamination in developing countries and should be embraced as it is pragmatic and inexpensive. (A7664, A7665).
Top Gene Interactions
Related Pathways
General Information
- Metabolism: Arsenic is absorbed mainly by inhalation or ingestion, as to a lesser extent, dermal exposure. It is then distributed throughout the body, where it is reduced into arsenite if necessary, then methylated into monomethylarsenic (MMA) and dimethylarsenic acid (DMA) by arsenite methyltransferase. Arsenic and its metabolites are primarily excreted in the urine. Arsenic is known to induce the metal-binding protein metallothionein, which decreases the toxic effects of arsenic and other metals by binding them and making them biologically inactive, as well as acting as an antioxidant. (L20)
- Uses/Sources: Arsenic is used in pesticides, wood preservatives, paints/pigments, and various metal alloys (electronics). Small amounts of arensic can be found in contaminated air, water, and some meat products, especially seafood. (L2)
- Health Effects: Arsenic poisoning can lead to death from multi-system organ failure, probably from necrotic cell death, not apoptosis. Arsenic is also a known carcinogen, especially in skin, liver, bladder and lung cancers. (T1, L20) Arsenic poisoning is has also been associated with heart disease, (hypertension related cardiovascular), stroke (cerebrovascular diseases), chronic lower respiratory diseases and diabetes. Chronic exposure to arsenic can lead to a vitamin A deficiency which is related to heart disease and night blindness.
- Symptoms: Exposure to lower levels of arsenic can cause nausea and vomiting, decreased production of red and white blood cells, abnormal heart rhythm, damage to blood vessels, and a sensation of “pins and needles” in hands and feet. Breathing high levels of inorganic arsenic can give you a sore throat or irritated lungs. Arsenic also affects the brain, causing neurological disturbances such as headaches, confusion, and drowsiness. (A1)
- Treatment: Arsenic poisoning can be treated by chelation therapy, using chelating agents such as dimercaprol, EDTA or DMSA. Charcoal tablets may also be used for less severe cases. In addition, maintaining a diet high in sulfur helps eliminate arsenic from the body. (L20)
- Route of Exposure: Oral (L2); inhalation (L2); dermal (L2)
Toxicity
- Carcinogenicity: 1, carcinogenic to humans. (L135)
- Toxicity: LD50: 763 mg/kg (Oral, Rat) (T14) LD50: 13.4 ug/kg (Intraperitoneal, Rat) (T14)
- Lethal Dose: 130 mg for an adult human. (T15)
- Minimum Risk Level: Acute Oral: 0.005 mg/kg/day (L134) Chronic Oral: 0.0003 mg/kg/day (L134) Chronic Inhalation: 0.01 mg/m3 (L134) The World Health Organization asserts that a level of 0.01 mg/L in drinking water poses a risk of 1/1600 chance of lifetime skin cancer risk.
Mechanism of Action
| Target Name | Mechanism of Action | References |
|---|---|---|
|
Pyruvate kinase PKM Metallothionein-1A |
16984198 17499915 |
|
| Poly [ADP-ribose] polymerase 1 | Arsenic binding of PARP-1 is believed to induce carcinogenesis by affecting DNA repair. (A17) |
18164070 |
| Kelch-like ECH-associated protein 1 | Arsenic binds to kelch-like ECH-associated protein 1. (A17) |
18164070 |
| DNA repair protein complementing XP-A cells | Arsenic binding of XPA is believed to induce carcinogenesis by affecting DNA repair. (A17) |
18164070 |
|
Hemoglobin subunit beta Hemoglobin subunit alpha |
Arsenic binds to hemoglobin. (A15) |
18247522 |
| Estrogen receptor | Arsenic binds to the estrogen receptor. (A17) |
18164070 |
|
Thioredoxin reductase 1, cytoplasmic Thioredoxin reductase 2, mitochondrial Thioredoxin reductase 3 |
Arsenic binds thioredoxin reductase, which results in the inhibition of essential biochemical reactions, alteration of cellular redox status, and eventual cytotoxicity. (L2) |
2007 |
|
Actin, cytoplasmic 1 Actin, cytoplasmic 2 Actin, alpha cardiac muscle 1 Actin, alpha skeletal muscle Actin, aortic smooth muscle Actin, gamma-enteric smooth muscle |
Arsenic binds to actin. (A16) |
10221271 |
| Glucocorticoid receptor | Arsenic binds to the glucocorticoid receptor. (A17) |
18164070 |
|
Pyruvate dehydrogenase E1 component subunit alpha, testis-specific form, mitochondrial Dihydrolipoyllysine-residue acetyltransferase component of pyruvate dehydrogenase complex, mitochondrial Pyruvate dehydrogenase E1 component subunit alpha, somatic form, mitochondrial Pyruvate dehydrogenase E1 component subunit beta, mitochondrial Pyruvate dehydrogenase protein X component, mitochondrial |
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. (T1) |
2003 |
|
Tubulin beta chain Tubulin alpha-1B chain Tubulin alpha-3C/D chain Tubulin alpha-4A chain Tubulin beta-2A chain Tubulin beta-4B chain Tubulin beta-3 chain Tubulin beta-4A chain Tubulin alpha-1A chain Tubulin alpha-1C chain Tubulin alpha-3E chain Tubulin beta-1 chain Tubulin beta-2B chain Tubulin alpha-8 chain Tubulin beta-8 chain Tubulin beta-6 chain Tubulin alpha chain-like 3 Tubulin beta-8 chain-like protein LOC260334 Putative tubulin beta chain-like protein ENSP00000290377 Putative tubulin beta-4q chain Putative tubulin-like protein alpha-4B |
Arsenic's carginogenicity is believed to be caused by the arsenical binding of tubulin, which results in aneuploidy, polyploidy and mitotic arrests. (A17) |
17499915 18164070 |
| Glutathione reductase, mitochondrial | Arsenic binds glutathione reductase, which results in the inhibition of essential biochemical reactions, alteration of cellular redox status, and eventual cytotoxicity. (L2) |
2007 |
| Haptoglobin | Arsenic binds to haptoglobin. (A15) |
18247522 |