Arsenic biochemistry is the set of biochemical processes that can use arsenic or its compounds, such as arsenate. Arsenic is a moderately abundant element in Earth's crust, and although many arsenic compounds are often considered highly toxic to most life, a wide variety of organoarsenic compounds are produced biologically and various organic and inorganic arsenic compounds are metabolized by numerous organisms. This pattern is general for other related elements, including selenium, which can exhibit both beneficial and deleterious effects. Arsenic biochemistry has become topical since many toxic arsenic compounds are found in some aquifers, potentially affecting many millions of people via biochemical processes.Elke Dopp, Andrew D. Kligerman and Roland A. Diaz-Bone Organoarsenicals. Uptake, Metabolism, and Toxicity 2010, Royal Society of Chemistry. .
Sources of arsenic
Organoarsenic compounds in nature
The evidence that arsenic may be a beneficial nutrient at trace levels below the background to which living organisms are normally exposed has been reviewed. Some organoarsenic compounds found in nature are arsenobetaine and arsenocholine,Arsenocholine - Structure and Data both being found in many marine organisms. Some As-containing nucleosides (sugar derivatives) are also known. Several of these organoarsenic compounds arise via methylation processes. For example, the mold Scopulariopsis brevicaulis produces significant amounts of trimethylarsine if inorganic arsenic is present. The organic compound arsenobetaine is found in some marine foods such as fish and algae, and also in mushrooms in larger concentrations. In clean environments, the edible mushroom species Cyanoboletus pulverulentus hyperaccumulates arsenic compounds in concentrations reaching 1,300 mg/kg (dry weight). A very unusual set of organoarsenic compounds was found in deer truffles (Elaphomyces spp.). The average person's intake is about 10–50 μg/day. Values about 1000 μg are not unusual following consumption of fish or mushrooms; however, there is little danger in eating fish since this arsenic compound is nearly non-toxic.
A topical source of arsenic are the green pigments once popular in wallpapers, e.g. Paris green. A variety of illness have been blamed on this compound, although toxicity has been exaggerated.
Trimethylarsine, once known as Gosio's gas, is an intensely malodorous organoarsenic compound that is produced by microbial action on inorganic arsenic minerals.
Arsenic(V) compounds are easily reduced to arsenic(III) and could have served as an electron acceptor on the early Earth. Lakes that contain a substantial amount of dissolved inorganic arsenic, harbor arsenic-tolerant biota.
Incorrect claims of arsenic incorporation into DNA and RNA Although phosphate and arsenate are structurally similar, there is no evidence that arsenic can be incorporated into DNA or RNA. In 2010, Felisa Wolfe-Simon published a paper claiming that the bacterium GFAJ-1 could incorporate arsenic into its DNA; other researchers vigorously refuted this claim, leading Science to retract the paper in 2025.
Anthropogenic arsenic compounds Anthropogenic (man-made) sources of arsenic, like the natural sources, are mainly arsenic oxides and the associated anions. Man-made sources of arsenic, include wastes from mineral processing, swine and poultry farms. For example, many ores, especially sulfide minerals, are contaminated with arsenic, which is released in roasting (burning in air). In such processing, arsenide is converted to arsenic trioxide, which is volatile at high temperatures and is released into the atmosphere. Poultry and swine farms make heavy use of the organoarsenic compound roxarsone as an antibiotic in feed. Some wood is treated with copper arsenates as a preservative. The mechanisms by which these sources affect "downstream" living organisms remains uncertain but are probably diverse. One commonly cited pathway involves methylation.
The monomethylated acid, methanearsonic acid (CH3AsO(OH)2), is a precursor to fungicides (tradename Neoasozin) in the cultivation of rice and cotton. Derivatives of phenylarsonic acid (C6H5AsO(OH)2) are used as feed additives for livestock, including 4-hydroxy-3-nitrobenzenearsonic acid (3-NHPAA or Roxarsone), ureidophenylarsonic acid, and p-arsanilic acid. These applications are controversial as they introduce soluble forms of arsenic into the environment.
Arsenic-based drugs Despite, or possibly because of, its long-known toxicity, arsenic-containing potions and drugs have a history in medicine and quackery that continues into the 21st century. Starting in the early 19th century and continuing into the 20th century, Fowler's solution, a toxic concoction of sodium arsenite, was sold. The organoarsenic compound Salvarsan was the first synthetic chemotherapeutic agent, discovered by Paul Ehrlich. The treatment, however, led to many problems causing long lasting health complications.Elschenbroich, C. "Organometallics" (2006) Wiley-VCH: Weinheim. Around 1943 it was finally superseded by penicillin. The related drug Melarsoprol is still in use against late-state African trypanosomiasis (sleeping sickness), despite the substance's possibly fatal side effects.
Arsenic trioxide (As2O3) inhibits cell growth and induces apoptosis (programmed cell death) in certain types of cancer cells, which are normally immortal and can multiply without limit. Arsenic trioxide-induced necrosis has been shown to provoke immune activation through release of damage-associated molecular patterns (DAMPs). In combination with all-trans retinoic acid, it is FDA-approved as first-line treatment for promyelocytic leukemia.
Methylation of arsenic Inorganic arsenic and its compounds, upon entering the food chain, are progressively metabolised (detoxified) through a process of methylation. The methylation occurs through alternating reductive and oxidative methylation reactions, that is, reduction of pentavalent to trivalent arsenic followed by addition of a methyl group (CH3).
In mammals, methylation occurs in the liver by methyltransferases, the products being the dimethylarsinous acid ((CH3)2AsOH) and dimethylarsinic acid ((CH3)2As(O)OH), which have the oxidation states As(III) and As(V), respectively. Although the mechanism of methylation of arsenic in humans has not been elucidated, the source of methyl is methionine, which suggests a role of S-adenosyl methionine. Exposure to toxic doses begin when the liver's methylation capacity is exceeded or inhibited.
There are two major forms of arsenic that can enter the body, arsenic (III) and arsenic (V). Arsenic (III) enters the cells though aquaporins 7 and 9, which is a type of aquaglyceroporin. Arsenic (V) compounds use phosphate transporters to enter cells. The arsenic (V) can be converted to arsenic (III) by the enzyme purine nucleoside phosphorylase. This is classified as a bioactivation step, as although arsenic (III) is more toxic, it is more readily methylated.
There are two routes by which inorganic arsenic compounds are methylated. The first route uses Cyt19 arsenic methyltransferase to methylate arsenic (III) to a mono-methylated arsenic (V) compound. This compound is then converted to a mono-methylated arsenic (III) compound using Glutathione S-Transferase Omega-1 (GSTO1). The mono-methylated arsenic (V) compound can then be methylated again by Cyt19 arsenic methyltransferase, which forms a dimethyl arsenic (V) compound, which can be converted to a dimethyl arsenic (III) compound by Glutathione S-Transferase Omega-1 (GTSO1). The other route uses glutathione (GSH) to conjugate with arsenic (III) to form an arsenic (GS) 3 complex. This complex can form a monomethylated arsenic (III) GS complex, using Cyt19 arsenic methyltransferase, and this monomethylated GS complex is in equilibrium with the monomethylated arsenic (III). Cyt19 arsenic methyltransferase can methylate the complex one more time, and this forms a dimethylated arsenic GS complex, which is in equilibrium with a dimethyl arsenic (III) complex. Both of the mono-methylated and di-methylated arsenic compounds can readily be excreted in urine. However, the monomethylated compound was shown to be more reactive and more toxic than the inorganic arsenic compounds to human hepatocytes (liver), keratinocytes in the skin, and bronchial epithelial cells (lungs).
Studies in experimental animals and humans show that both inorganic arsenic and methylated metabolites cross the placenta to the fetus, however, there is evidence that methylation is increased during pregnancy and that it could be highly protective for the developing organism.
Enzymatic methylation of arsenic is a detoxification process; it can be methylated to methylarsenite, dimethylarsenite or trimethylarsenite, all of which are trivalent. The methylation is catalyzed by arsenic methyltransferase (AS3MT) in mammals, which transfers a methyl group on the cofactor S-adenomethionine (SAM) to arsenic (III). An orthologue of AS3MT is found in bacteria and is called CmArsM. This enzyme was tested in three states (ligand free, arsenic (III) bound and SAM bound). Arsenic (III) binding sites usually use thiol groups of cysteine residues. The catalysis involves thiolates of Cys72, Cys174, and Cys224. In an SN2 reaction, the positive charge on the SAM sulfur atom pulls the bonding electron from the carbon of the methyl group, which interacts with the arsenic lone pair to form an As−C bond, leaving SAH.
Excretion In humans, the major route of excretion of most arsenic compounds is via the urine. The biological half-life of inorganic arsenic is about 4 days, but is slightly shorter following exposure to arsenate than to arsenite. The main metabolites excreted in the urine of humans exposed to inorganic arsenic are mono- and dimethylated arsenic acids, together with some unmetabolized inorganic arsenic.
The biotransformation of arsenic for excretion is primarily done through the nuclear factor erythroid 2 related factor 2 (Nrf2) pathway. Under normal conditions the Nrf2 is bound to Kelch-like ECH associated protein 1 (Keap1) in its inactive form. With the uptake of arsenic within cells and the subsequent reactions that result in the production of reactive oxygen species (ROS), the Nrf2 unbinds and becomes active. Keap1 has reactive thiol moieties that bind ROS or electrophilic arsenic species such as monomethylted arsenic (III) and induces the release of Nrf2 which then travels through the cytoplasm to the nucleus. The Nrf2 then activates antioxidant responsive element (ARE) as well as electrophilic responsive element (EpRE) both of which contribute in the increase of antioxidant proteins. Of particular note in these antioxidant proteins is heme oxygenase 1 (HO-1), NAD(P)H-quinone oxidoreductase 1 (NQO1), and γ-glutamylcysteine synthase (γGCS) which work in conjunction to reduce the oxidative species such as hydrogen peroxide to decrease the oxidative stress upon the cell. The increase in γGCS causes an increased production of arsenite triglutathionine (As(SG)3) an important adduct that is taken up by either multidrug associated protein 1 (MRP1) or MRP2 which remove the arsenic out of the cell and into bile for excretion. This adduct can also decompose back into inorganic arsenic.
Of particular note in the excretion of arsenic is the multiple methylation steps that take place which may increase the toxicity of arsenic due to MMeAsIII being a potent inhibitor of glutathione peroxidase, glutathione reductase, pyruvate dehydrogenase, and thioredoxin reductase.
Arsenic toxicity
Arsenic is a cause of mortality throughout the world; associated problems include heart, respiratory, gastrointestinal, liver, nervous and kidney diseases.