Biotransformation of arsenic and toxicological implication of arsenic metabolites
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REVIEW ARTICLE
Biotransformation of arsenic and toxicological implication of arsenic metabolites Seishiro Hirano1 Received: 25 February 2020 / Accepted: 4 May 2020 © Springer-Verlag GmbH Germany, part of Springer Nature 2020
Abstract Arsenic is a well-known environmental carcinogen and chronic exposure to arsenic through drinking water has been reported to cause skin, bladder and lung cancers, with arsenic metabolites being implicated in the pathogenesis. In contrast, arsenic trioxide (As2O3) is an effective therapeutic agent for the treatment of acute promyelocytic leukemia, in which the binding of arsenite (iAsIII) to promyelocytic leukemia (PML) protein is the proposed initial step. These findings on the two-edged sword characteristics of arsenic suggest that after entry into cells, arsenic reaches the nucleus and triggers various nuclear events. Arsenic is reduced, conjugated with glutathione, and methylated in the cytosol. These biotransformations, including the production of reactive metabolic intermediates, appear to determine the intracellular dynamics, target organs, and biological functions of arsenic. Keywords Arsenic · Metalloid · Methylation · Reduction · Arsine · Glutathione · Promyelocytic leukemia
Introduction There are several ways to differentially indicate trivalent and pentavalent inorganic arsenic; As3+ vs As5+, As(III) vs As(V), and iAsIII vs iAsV, where ‘i’ signifies ‘inorganic’. In this article, superscripted III and V are used because inorganic arsenite (trivalent) is neutral and arsenate (pentavalent) is a negatively charged oxyanion at physiological pH. Arsenic trioxide ( As2O3) and m-arsenite (AsO2−) are hydrolyzed and generates arsenous acid (As(OH)3) in aqueous solution and are also referred to as iAsIII in this article. The abbreviations shown in Table 1 are used for common arsenicals and related compounds hereafter in the text; however, chemical formulas are also used as necessary to clarify the arsenic species. Arsenic has an interesting history in toxicology, probably because this metalloid element is methylated and its oxidation state changes during the metabolic process. The acute toxicity of arsenic has been known since antiquity and curiosity regarding its toxicity arose following the discovery * Seishiro Hirano [email protected] 1
Center for Health and Environmental Risk Research, National Institute for Environmental Studies, 16‑2 Onogawa, Tsukuba, Ibaraki 305‑8506, Japan
that Gosio gas ((CH3)3As) is generated by molds in wall paper (Bentley and Chasteen 2002; Challenger 1945). Most mammals methylate arsenic; however, New World animals such as the guinea pig, tamarin, and marmoset, and the chimpanzee (an Old World animal) do not (Healy et al. 1998, 1999). Methylation and rapid excretion of arsenic are not apparently favorable for survival where trypanosomal diseases are endemic because trypanothione, an important glutathione-containing protein for trypanosomes, reacts with arsenic (Aposhian 1997; Mukhopadhyay et al. 1996). The question of whether the methy
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