Arsenic trioxide is a chemotheraputic agent of idiopathic function used to treat leukemia that is unresponsive to first line agents. It is suspected that arsenic trisulfide induces cancer cells to undergo apoptosis. Due to the toxic nature of arsenic, this drug carries significant health risks. The enzyme thioredoxin reductase has recently been identified as a target for arsenic trioxide.
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- Metabolism: Arsenic is mainly absorbed by inhalation or ingestion, and to a lesser extent by 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) The metabolism of arsenic trioxide involves reduction of pentavalent arsenic to trivalent arsenic by arsenate reductase and methylation of trivalent arsenic to monomethylarsonic acid and monomethylarsonic acid to dimethylarsinic acid by methyltransferases. The main site of methylation reactions appears to be the liver. Arsenic is stored mainly in liver, kidney, heart, lung, hair and nails. Route of Elimination: Trivalent arsenic is mostly methylated in humans and excreted in urine.
- Uses/Sources: Arsenic trioxide is a byproduct of certain kinds of ore processing. It is the starting point for the manufacture of many arsenic-based products, including pesticides, pharamaceuticals, alloys, and semiconductors. It is also used as a wood preservative and decolorizing agent. (L718) It is also use for induction of remission and consolidation in patients with acute promyelocytic leukemia (APL), and whose APL is characterized by the presence of the t(15;17) translocation or PML/RAR-alpha gene expression.
- 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)
- Symptoms: Symptoms of overdose include convulsions, muscle weakness and confusion. Exposure to lower levels of arsenic can cause nausea and vomiting, decreased production of red and white blood cells, abnormal heart rhythm, and damage to blood vessels.
- 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)
- Carcinogenicity: 1, carcinogenic to humans. (L135)
- Toxicity: LD50: 871 mg/kg (Intraperitoneal, Rat) (T14) LD50: 31 500 ug/kg (Oral, Mouse) (T14) LD50: 9800 ug/kg (Subcutaneous, Mouse) (T14) LD50: 10 700 ug/kg (Intravenous, Mouse) (T14)
- Lethal Dose: 200 mg for an adult human. (T17)
- 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)