Archives of Toxicology

, Volume 87, Issue 6, pp 969–979 | Cite as

Metabolism of arsenic and its toxicological relevance

  • Takayuki Watanabe
  • Seishiro HiranoEmail author
Review Article


Arsenic is a worldwide environmental pollutant and a human carcinogen. It is well recognized that the toxicity of arsenicals largely depends on the oxidoreduction states (trivalent or pentavalent) and methylation levels (monomethyl, dimethyl, and trimethyl) that are present during the process of metabolism in mammals. However, presently, the specifics of the metabolic pathway of inorganic arsenicals have yet to be confirmed. In mammals, there are two possible mechanisms that have been proposed for the metabolic pathway of inorganic arsenicals, oxidative methylation, and glutathione conjugation. Oxidative methylation, which was originally proposed in fungi, is based on findings that arsenite (iAsIII) is sequentially converted to monomethylarsonic acid (MMAV) and dimethylarsinic acid (DMAV) in both humans and in laboratory animals such as mice and rats. However, recent in vitro observations have demonstrated that arsenic is only methylated in the presence of glutathione (GSH) or other thiol compounds, which strongly suggests that arsenic is methylated in trivalent forms. The glutathione conjugation mechanism is supported by findings that have shown that most intracellular arsenicals are trivalent and excreted from cells as GSH conjugates. Since non-conjugated trivalent arsenicals are highly reactive with thiol compounds and are easily converted to less toxic corresponding pentavalent arsenicals, the arsenic–glutathione conjugate stability may be the most important factor for determining the toxicity of arsenicals. In addition, “being a non-anionic form” also appears to be a determinant of the toxicity of oxo-arsenicals or thioarsenicals. The present review discusses both the metabolism of arsenic and the toxicity of arsenic metabolites.


Arsenic (+3 oxidation state) methyltransferase Glutathione Multidrug resistance-associated protein Thioarsenical Oxidoreduction 



This work was partially supported by Grant-in-Aid from Ministry of Education, Culture, Sports, Science, and Technology (23390167-002).

Conflict of interest

The authors declare no conflict of interest.


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Copyright information

© Springer-Verlag 2012

Authors and Affiliations

  1. 1.Graduate School of Pharmaceutical SciencesChiba UniversityChuoJapan
  2. 2.Research Center for Environmental RiskNational Institute for Environmental StudiesTsukubaJapan

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