225
T3D0224
Arsenic trioxide
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.
1327-53-3
518740
As2O3
197.827940
White powder.
465°C
1.7E+004 mg/L (at 16°C)
Oral (L2) ; inhalation (L2) ; dermal (L2)
Pyruvate Dehydrogenase (P29803)
Hemoglobin subunit beta (P68871)
Hemoglobin subunit alpha (P69905)
Haptoglobin (P00738)
Estrogen receptor (P03372)
Glucocorticoid receptor (P04150)
Glutathione reductase (P00390)
Kelch-like ECH-associated protein 1 (Q14145)
Poly [ADP-ribose] polymerase 1 (P09874)
Thioredoxin (P10599)
Tubulin beta chain (P07437)
Actin, cytoplasmic 1 (P60709)
Actin, cytoplasmic 2 (P63261)
Arsenite methyltransferase (Q9HBK9)
Thioredoxin reductase 1 (Q16881)
Thioredoxin reductase 2 (Q9NNW7)
Thioredoxin reductase 3 (Q86VQ6)
(A15, A16, A17)
The mechanism of action of Arsenic Trioxide is not completely understood. Arsenic trioxide causes morphological changes and DNA fragmentation characteristic of apoptosis in NB4 human promyelocytic leukemia cells <i>in vitro</i>. Arsenic trioxide also causes damage or degradation of the fusion protein PML/RAR-alpha. It is suspected that arsenic trioxide induces cancer cells to undergo apoptosis. Arsenic and its metabolites disrupt 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. Arsenic's carginogenicity is influenced by the arsenical binding of tubulin, which results in aneuploidy, polyploidy and mitotic arrests. The binding of other arsenic protein targets may also cause altered DNA repair enzyme activity, altered DNA methylation patterns and cell proliferation. (T1, A17)
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.
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)
200 mg for an adult human. (T17)
1, carcinogenic to humans. (L135)
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.
Acute Oral: 0.005 mg/kg/day (L134)
Chronic Oral: 0.0003 mg/kg/day (L134)
Chronic Inhalation: 0.01 mg/m3 (L134)
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 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.
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)
2009-03-06T18:58:19Z
2016-11-09T01:08:11Z
Metallothionein-2 (P02795)
Metallothionein-1G (P13640)
Metallothionein-1H (P80294)
Metallothionein-3 (P25713)
Metallothionein-1F (P04733)
Metallothionein-1E (P04732)
Metallothionein-1X (P80297)
Metallothionein-1A (P04731)
Metallothionein-1B (P07438)
Metallothionein-1M (Q8N339)
Metallothionein-4 (P47944)
Metallothionein-1L (Q93083)
Arsenite methyltransferase (Q9HBK9)
(L92)
Arsenic_trioxide
30621
CPD-763
C006632
Arsenic trioxide
DB01169
104
true
Arsenite methyltransferase (Q9HBK9)
(L92)
Metallothionein-2 (P02795)
Metallothionein-1G (P13640)
Metallothionein-1H (P80294)
Metallothionein-3 (P25713)
Metallothionein-1F (P04733)
Metallothionein-1E (P04732)
Metallothionein-1X (P80297)
Metallothionein-1A (P04731)
Metallothionein-1B (P07438)
Metallothionein-1M (Q8N339)
Metallothionein-4 (P47944)
Metallothionein-1L (Q93083)
(L92)
O1[As]2O[As]1O2
As2O3
InChI=1S/As2O3/c3-1-4-2(3)5-1
GOLCXWYRSKYTSP-UHFFFAOYSA-N
197.8414
197.8279367
Exogenous
Solid
HMDB15300
CHEMBL1200978
452539
CHEM000196