This article has been reviewed and edited. Elemental Arsenic Review
Arsenic, atomic element number 33, is a semi-metal/metalloid and occurs naturally in two different solid forms; yellow and gray/metallic, gray arsenic being the stable form. It has an atomic mass of 74.92 and was first documented in 1250 by Albert Magnus1). Isotope 75 is the naturally occurring form of arsenic, but over 33 isotopes have been created, with isotope 73 being the most stable2)). Although arsenic is a chemical analog of phosphorus, it more commonly exists in the -3 or +3 oxidation states, unlike phosphorus which commonly exists in the +5 oxidation state. Arsenic tends to cause skin discoloration, and in victorian times was mixed with vinegar and chalk to be eaten by women to lighten their complexion3).
Arsenic is often used as a wood preservative and a pesticide, but can contaminate air, water, and soil. Arsenic generally enters the biosphere due to leaching from geological formations. High levels of arsenic exposure can cause death4). Arsenic is a notorious poison, and while excess arsenic affects the health of the heart, nervous system, skin and lungs, the toxic effects of elemental arsenic have to some extent been historically exaggerated. Arsenic derivatives have at times been used as deliberate poisons, and death from arsenic poisoning is slow and painful. The symptoms of arsenic poisoning have not been well documented, so it was a commonly used poison before the discovery of the Marsh test, which is a sensitive chemical test for the presence of arsenic. Pure elemental arsenic, however, is not toxic, even when consumed in large quantities but arsenic derivatives such as arsenic trioxide are very dangerous5).
The proposed reason for the biochemical toxicity of arsenic(III) oxides is their high affinity for thiols. Since cysteine residues form thiols, they are often located at important enzymatic active sites. Arsenic binding to these active sites contributes to its toxic cellular effect6). Arsenic is a pervasive element in daily life due to its environmental presence. When exposed environmentally, the most dangerous forms are the trivalent and pentavalent oxidation states, which can cause acute toxicity. Chronic exposure to inorganic forms of arsenic can cause skin lesions, hyperpigmentation, hypopigmentation and hyperkeratosis in the skin. Chronic exposure can also affect the cardiovascular, nervous, hepatic, endocrine and renal systems7). Pentavalent arsenic is toxic due to its chemical similarity to phosphate. Arsenate can replace phosphate in many biochemical reactions, including reacting with glucose and gluconate to make glucose-6-arsenate and 6-arsenogluconate, which interfere with the production of glucose-6-phosphate and 6-phosphogluconate. These compounds then act as substrates for glucose-6-phosphate dehydrogenase, inhibiting hexokinase. Arsenate can also interfere with the sodium pump of red blood cells, replacing phosphate. Arsenate also interferes with the formation of ATP by through arsenolysis, which can occur during glycolysis. ATP is generated under normal conditions during glycolysis, but in the presence of arsenate and not phosphate, ATP isn't generated. This is due to the instability of adenosine-5′-diphosphate–arsenate, the compound formed under arsenate rich conditions. ADP-arsenate, unlike ATP, is very easily hydrolyzed and it reduces the production of more useful ATP. This depletion of ATP in vitro only occurs under arsenate rich conditions, arsenite and other oxidation states of arsenic don't have this effect on cells8).
Recent research has found that some species of photosynthetic bacteria can grow utilizing Arsenic (III) as the only electron acceptor. These bacteria were found in Mono Lake, California and were able to photosynthesize by converting Arsenic (III) to Arsenic (V), in the absence of oxygen. The results of this research are significant in that they propose a mechanism that explains the arsenic cycle, especially as it relates to ancient Earth and ancient bacteria9). Other forms of bacteria utilize arsenic by reducing arsenite to arsenate to fuel their metabolism. These bacteria contain specific enzymes known as arsenic reductases that function to facilitate the metabolism of arsenic containing compounds10). It is hypothesized that these two strains of bacteria support each other's growth.
There are three recognized families of arsenic reductase enzymes. The first involves the arsC gene, found on both plasmids and chromosomes. E coli bacteria have three separate forms of this family of enzymes. The second family of enzymes has the same name, but uses thioredoxin as a reducing potential source. The final family is a protein tyrosine phosphate phosphatase. There are no known instances of functioning mammalian arsenic reductases thus far, but there have been some identified in human liver extracts11).
Arsenic has been investigated as a potential epigenetic factor in human and animal subjects. Epigenetics entails the study of changes in gene expression that occur without corresponding changes in DNA sequences. There are several mechanisms for epigenetic changes, that include DNA methylation, modification of histones, and alterations in microRNA. Arsenic, along with several other metals, can play a role as environmental chemicals that can modify gene expression. There is an association between DNA methylation and exposure to environmental metals - arsenic in particular, but also nickel, cadmium and lead. It has been hypothesized that this is due to metal-induced oxidative stress, as metals increase the production of reactive oxygen species. Arsenic exposure has specifically been shown to produce DNA hypermethylation, particularly on p53 and p16 promoter regions in humans12).
Inorganic arsenic is a carcinogen and toxic to humans. When consumed, it is metabolized by progressive methylation, which forms compounds like pentavalent dimethyarsinic acid. These compounds cause cell death, which may in turn act as a protective detoxifying mechanism by destroying the abnormal cells caused by the arsenic exposure13). Most organisms have a method for detoxifying arsenic. Arsenic is commonly taken up by organisms as arsenic(V) in the form of arsenate by phosphate transporters, and then converted to arsenic(III) which is sequestered and removed. Arsenic can also be taken up by organisms in the form of arsenic(III) by aguaglyceroporins14).
Arsenic is a known carcinogen, with animal studies confirming its carcinogenity. The exact mechanism of its carcinogenic effect is unknown, but there are several possibilities that have been evaluated. These includes genotoxicity, cell proliferation, altered DNA repair and DNA methylated oxidative stress, co-carcinogenesis, and tumor promotion mechanisms. Further studies are being conducted to elucidate the mechanism of arsenic's carcinogenity15).