Abstract
Arsenic occurs naturally in the environment, and exists predominantly as inorganic arsenite (As (III) and arsenate As (V)). Arsenic contamination of drinking water has long been recognized as a major global health concern. Arsenic exposure causes changes in skin color and lesions, and more severe health conditions such as black foot disease as well as various cancers originating in the lungs, skin, and bladder. In order to efficiently metabolize and excrete arsenic, it is methylated to monomethylarsonic and dimethylarsinic acid. One single enzyme, arsenic methyltransferase (AS3MT) is responsible for generating both metabolites. AS3MT has been purified from several mammalian and nonmammalian species, and its mRNA sequences were determined from amino acid sequences. With the advent of genome technology, mRNA sequences of AS3MT have been predicted from many species throughout the animal kingdom. Horizontal gene transfer had been postulated for this gene through phylogenetic studies, which suggests the importance of this gene in appropriately handling arsenic exposures in various organisms. An altered ability to methylate arsenic is dependent on specific single nucleotide polymorphisms (SNPs) in AS3MT. Reduced AS3MT activity resulting in poor metabolism of iAs has been shown to reduce expression of the tumor suppressor gene, p16, which is a potential pathway in arsenic carcinogenesis. Arsenic is also known to induce oxidative stress in cells. However, the presence of antioxidant response elements (AREs) in the promoter sequences of AS3MT in several species does not correlate with the ability to methylate arsenic. ARE elements are known to bind NRF2 and induce antioxidant enzymes to combat oxidative stress. NRF2 may be partly responsible for the biotransformation of iAs and the generation of methylated arsenic species via AS3MT. In this article, arsenic metabolism, excretion, and toxicity, a discussion of the AS3MT gene and its evolutionary history, and DNA methylation resulting from arsenic exposure have been reviewed.
Highlights
Arsenic is a metalloid found naturally in rocks and soil and is one of the major world-wide contaminants of drinking water
Methylated product of inorganic arsenic (iAs), monomethylarsonic acid (MMA) is generally considered more toxic than dimethylarsinic acid (DMA)
Namely MMAIII and DMAIII, are more toxic compared to pentavalent species
Summary
Arsenic is a metalloid found naturally in rocks and soil and is one of the major world-wide contaminants of drinking water. Arsenic partially exerts its toxicity by inactivating over 200 enzymes, predominantly involved in DNA metabolism and repair [7] Based on both human exposure potential and associated health risks, the WHO established a drinking water standard of 10 μg/L [4]. It is likely that mammals have evolved to metabolize inorganic arsenic to its relatively non-cytotoxic pentavalent forms, but encounter high cytotoxicity due to intermediate metabolites, namely MMAIII and DMAIII. The cytotoxicity and genotoxicity of inorganic arsenic and its methylated species including methyloxoarsine (CH3AsIIIO), iododimethylarsine (CH3AsIIII), monomethylarsonic acid (MMAV), dimethylarsinic acid (DMAV), monomethylarsonous acid (MMAIII), and dimethylarsinous acid (DMAIII) differ significantly [33]. While there may be slight discrepancies in the reported cytotoxicities between MMAIII and DMAIII, inorganic and organic trivalent arsenic species are certainly more cytotoxic compared to pentavalent forms [21]
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