# Arsenic: A Review on a Great Health Issue Worldwide
## 5 Metabolic Pathways and Toxicity of Arsenic  
In living organisms, arsenic is present in both inorganic and organic form and in trivalent and pentavalent oxidation states. The inorganic As (III; arsenic) is more toxic than As (V; arsenate) and inorganic arsenicals are more toxic than organic arsenicals. Arsenous  
\begin{table}
\begin{tabular}{c c} \hline \hline
**Structure** & **Compound** \\ \hline \(\text{OH}\) & \(\text{As}_{\text{As}}\) & \(  
acid enters the cells of kidney, testis, and liver through aquaglyceroporins and glucose transporters (GLUT1, GLUT4), while arsenic acid crosses the cellular membranes via phosphate transporters, given the extreme similarity between arsenate (AsO\({}_{4}\)\({}^{3-}\)) and phosphate (PO\({}_{4}\)\({}^{3-}\)) anions. Inorganic arsenic metabolites are exported through the multidrug resistance proteins (MRP1, MRP2, or MRP4). The metabolic pathway of arsenic is depicted in Figure 1. Inorganic arsenic (V, in the form of arsenic acid) is reduced to arsenic (III, in the form of arsenous acid) in the presence of the enzyme arsenate reductase mediated by glutathione. Furthermore, the enzyme arsenic methyltransferase, in the presence of S-adenosyl methionine (SAM) as methyl-donor, allows oxidative methylation reaction of the arsenous acid (As III) to form monomethylarsenic acid (MMA-V) and dimethylarsenic acid (DMA-V) through the reduction of pentavalent arsenic acids to trivalent arsenic acids, ultimately producing dimethylarsenuos acid (DMA-III) [50]. Inorganic and organic arsenic compounds are bound tightly to thiol groups (-SH) and vicinal dithiols, as for example the dihydroplopic acid. As (III) reacts with the sulfhydryl groups of enzymes and proteins. The affinity between As (III) and sulfhydryl groups is responsible for its accumulation in keratin rich-tissue such as skin, hair, and nails [51]. Furthermore, organic arsenic compounds also show high affinity to selenol groups (-SeH) present in thioredoxin reductase and glutathione peroxidase enzymes. Inorganic arsenic and its metabolites are eliminated through the urine and feces; however, high quantities of these compounds are accumulated in different tissues, such as lung, heart, and brain. Arsenic metabolites easily cross the blood-brain barrier accumulating in different regions of the brain, such as the striatum, hypothalamus, and hippocampus [52]. Arsenosugars and arsenobetaine, present in algae and seafood, are excreted in urine. Arsenic level in urine is an excellent marker of arsenic intoxication and has been used to identify the exposure in the population living close arsenic sources [53].  
Figure 1: Metabolic pathways of arsenic. As (V) is reduced to As (III) by GSH (as electron donor) in the presence of arsenate reductase; As(III) undergoes sequential methylation with SAM (methyl donor) in the presence of methyl transferase and reduction with GSH to generate MMA(V), MMA(III), DMA(V) and DMA(III). GSH: reduced glutathione; GS-SG: oxidized glutathione; SAM: S-adenosyl methionine; SAH: S-adenosyl homocysteine; MMA(V): monomethyl arsenic acid; MMA(III): mono methyl arsenous acid; DMA(V): dimethyl arsenic acid; DMA(III): dimethyl arsenous acid). This figure is an elaboration based on information retrieved from ref. [54; 55].  
The main and most abundant urinary metabolite found in human urine is DMA-V (60-80%). [PERSON] and coauthors (2005) [56] demonstrated that the urinary arsenic concentration at level higher than 50 \(\upmu\)g/g creatinine can be associated to the development of different diseases.