Arsenic biochemistry refers to 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, 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.
Arsenic is a cause of mortality throughout the world; associated problems include heart, respiratory, gastrointestinal, liver, nervous and kidney diseases. Genotoxicity involves inhibition of DNA repair and DNA methylation. The carcinogenic effect of arsenic arises from the oxidative stress induced by arsenic. Arsenic's high toxicity naturally led to the development of a variety of arsenic compounds as chemical weapons, e.g. dimethylarsenic chloride. Some were employed as chemical warfare agents, especially in World War I. This threat led to many studies on antidotes and an expanded knowledge of the interaction of arsenic compounds with living organisms. One result was the development of antidotes such as British anti-Lewisite. Many such antidotes exploit the affinity of As(III) for thiolate ligands, which convert highly toxic organoarsenicals to less toxic derivatives. It is generally assumed that arsenates bind to cysteine residues in proteins.
Organoarsenic compounds in nature
Trimethylarsine, once known as Gosio's gas is an intensely malodorous organoarsenic compound that is commonly produced by microbial action on inorganic arsenic substrates. A topical source of this compound are the green pigments once popular in wallpapers, e.g. Paris green. A variety of illness have been blamed on this compound, although its toxicity has been exaggerated.
Other organoarsenic compounds found in nature are arsenobetaine and arsenocholine, 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. 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.
Arsenobetaine, one of the most common arsenic compound in nature. Also common is arsenocholine, which has CH2OH in place of CO2H).
Arsenic-containing ribose derivatives (R = several groups)
Cacodylic acid, formed in the liver after ingestion of arsenic
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 biomethylation.
Biomethylation 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 (CH3)2AsOH (dimethylarsinous acid) and (CH3)2As(O)OH (dimethylarsinic acid), 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.
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.
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.
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. Around 1943 it was finally superseded by penicillin.
In vitro studies suggest that arsenic trioxide (As2O3) inhibits the proliferation of myeloma cells via cell cycle arrest as well as triggering cell death. These results suggest that arsenic trioxide may be a clinically useful treatment in patients with multiple myeloma or leukemia.
Arsenic(V) as an electron acceptor
Arsenic (V) compounds are easily reduced to arsenic (III) and could have served as an electron acceptor on primordial Earth. Lakes that contain a substantial amount of dissolved inorganic arsenic, harbor arsenic-tolerant biota. Although phosphate and arsenate are structurally similar, there is no evidence that arsenic replaces phosphorus in DNA or RNA.
Arsenic(V) compounds typically feature the functional groups RAsO(OH)2 or R2AsO(OH) (R = alkyl or aryl). Cacodylic acid, with the formula (CH3)2AsO2H, figures prominently throughout the chemistry of organoarsenic compounds. In contrast, the dimethylphosphonic acid is less significant in the corresponding chemistry of phosphorus. Cacodylic acid arises from the methylation of arsenic(III) oxide. Phenylarsonic acids can be accessed by the reaction of arsenic acid with anilines, the so-called Bechamp reaction.
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.
Compounds of arsenic(V) containing only organic ligands are rare, the pre-eminent member being the pentaphenyl derivative As(C6H5)5.
- Arsenic compounds
- Hypothetical types of biochemistry
- Organoarsenic chemistry
- Pearce, Fred (2006). When the Rivers Run Dry: Journeys Into the Heart of the World's Water Crisis. Toronto: Key Porter. ISBN 978-1-55263-741-8.
- Elke Dopp, Andrew D. Kligerman and Roland A. Diaz-Bone Organoarsenicals. Uptake, Metabolism, and Toxicity 2010, Royal Society of Chemistry. ISBN 978-1-84973-082-2. doi:10.1039/9781849730822-00231
- "Arsenic in Drinking Water - Review article". IARC Monographs - World Health Organization 84. Retrieved 2011-01-10.
- William R. Cullen, Kenneth J. Reimer "Arsenic speciation in the environment" Chemical Reviews, 1989, volume 89, pp 713–764. doi:10.1021/cr00094a002
- Ronald Bentley and Thomas G. Chasteen (2002). "Microbial Methylation of Metalloids: Arsenic, Antimony, and Bismuth". Microbiology and Molecular Biology Reviews 66 (2): 250–271. doi:10.1128/MMBR.66.2.250-271.2002. PMC 120786. PMID 12040126.
- Arsenocholine - Structure and Data
- Kevin A. Francesconi, John S. Edmonds, Robert V. Stick "Arsenic Compounds from the Kidney of the Giant Clam Tridacna maxima: Isolation and Identification of an Arsenic-containing Nucleoside" J. Chem. Soc. Perkin Trans. 1 1992 1349.
- Bentley, Ronald; Chasteen, TG (2002). "Microbial Methylation of Metalloids: Arsenic, Antimony, and Bismuth". Microbiology and Molecular Biology Reviews 66 (2): 250–271. doi:10.1128/MMBR.66.2.250-271.2002. PMC 120786. PMID 12040126.
- Cullen, William R; Reimer, Kenneth J. (1989). "Arsenic speciation in the environment". Chemical Reviews 89 (4): 713–764. doi:10.1021/cr00094a002.
- Nordstrom DK (2002). "Worldwide occurrences of arsenic in ground water". Science 296 (5576): 2143. doi:10.1126/science.1072375.
- Hileman, B (9 April 2007). "Arsenic in Chicken Production". Chemical and Engineering News. pp. 34–35.
- Bottemiller, Helena (26 September 2009). "Bill Introduced to Ban Arsenic Antibiotics in Feed". Food Safety News. Retrieved 2011-01-10.
- Sakurai T (2003). "Biomethylation of Arsenic is Essentially Detoxicating Event". Journal of Health Science 49 (3): 171–178. doi:10.1248/jhs.49.171. Retrieved 2011-01-10.
- "Arsenic in Drinking Water - Review article". IARC Monographs - World Health Organization 84: 133–135. Retrieved 2011-01-10.
- "Arsenic in Drinking Water - Review article". IARC Monographs - World Health Organization 84: 138. Retrieved 2011-01-10.
- Jun Zhu; Zhu Chen; Valérie Lallemand-Breitenbach; Hugues de Thé (2002). "How Acute Promyelocytic Leukaemia Revived Arsenic". Nature Reviews Cancer 2 (9): 705–714. doi:10.1038/nrc887. PMID 12209159. Retrieved 2013-09-27.
- Gibaud, Stéphane; Jaouen, Gérard (2010). "Arsenic - based drugs: from Fowler's solution to modern anticancer chemotherapy". Topics in Organometallic Chemistry. Topics in Organometallic Chemistry 32: 1–20. doi:10.1007/978-3-642-13185-1_1. ISBN 978-3-642-13184-4.
- Elschenbroich, C. ”Organometallics” (2006) Wiley-VCH: Weinheim. ISBN 978-3-527-29390-2
- Park, Woo H. Park; Jae G. Seol, Eun S. Kim, Jung M. Hyun, Chul W. Jung, Chung C. Lee, Byoung K. Kim, and Young Y. Lee (June 6, 2000). "Arsenic Trioxide-mediated Growth Inhibition in MC/CAR Myeloma Cells via Cell Cycle Arrest in Association with Induction of Cyclin-dependent Kinase Inhibitor, p21, and Apoptosis". Cancer Research 60 (3065): 3065–71. PMID 10850458. Retrieved 2010-12-15.
- Lunghi, Paolo Lunghi; Antonio Costanzo, Massimo Levrero, and Antonio Bonati (15 July 2004). "Treatment with arsenic trioxide (ATO) and MEK1 inhibitor activates the p73-p53AIP1 apoptotic pathway in leukemia cells". Blood 104 (2): 519–525. doi:10.1182/blood-2003-08-2743. PMID 15031205. Retrieved 2010-12-15.
- Oremland, Ronald S., Chad W. Saltikov, Felisa Wolfe-Simon, and John F. Stolz. "Arsenic in the Evolution of Earth and Extraterrestrial Ecosystems." Geomicrobiology Journal 26 (2009): 522-36.
- T. J. Erb, P. Kiefer, B. Hattendorf, D. Günther and J. A. Vorholt, "GFAJ-1 Is an Arsenate-Resistant, Phosphate-Dependent Organism", Science 2012 doi:10.1126/science.1218455; M. L. Reaves, S. Sinha, J. D. Rabinowitz, L. Kruglyak and R. J. Redfield, "Absence of Detectable Arsenate in DNA from Arsenate-Grown GFAJ-1 Cells", Science 2012 doi:10.1126/science.1219861
- Westheimer, F.H. (6 June 1987). "Why nature chose phosphates". Science 235 (4793): 1173–1178 (see pp. 1175–1176). doi:10.1126/science.2434996.