Arsenic Methyltransferase and Methylation of Inorganic Arsenic

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.

Arsenic Speciation and Metallomics Profiling of Human Toenails as a Biomarker to Assess Prostate Cancer Cases: Atlantic PATH Cohort Study

“…Urine is a well-established biomarker and represents an accurate representation of acute As exposure, with approximately 75% of absorbed As excreted through urine (41). Similar to urine, metal concentration in nails has also been shown to be a proxy for exposure (42)(43)(44)(45).…”

Transcriptomic Diversity in the Livers of South African Sardines Participating in the Annual Sardine Run

“…Among the highly polymorphic genes in the South African sardines’ liver transcriptome ( Supplementary Table S4 ), the product of the arsenic (+3 oxidation state) methyltransferase gene ( AS3MT ) metabolizes naturally-occurring or xenobiotic arsenic compounds into the easily-excretable monomethylarsonic and dimethylarsonic products [ 52 ]. Similarly, glutathione S-transferase pi 1 ( GSTP1 ) and glutathione S-transferase pi 2 ( GSTP2 ) genes catalyse glutathione into electrophilic compounds, which are essential in the detoxification process [ 53 ].…”

A

“…AsV is usually reduced to AsIII in the cells of plants and further forms less toxic inorganic AsIII via methylation; e.g. dimethylarsenate (DMAsV) and trimethykarsenic oxide (TMAs) (Zhu et al 2017;Alam et al 2019;Roy et al 2020). Arsenic only AsIII can bind to PCs and activate phytochelatin synthase, the reduction of AsV to AsIII is the first step in the detoxification of As, and As(V) reductase (AR) and its activity are therefore critical for As tolerance in plants (Li et al 2016).…”