Genetic Variations Associated with Interindividual Sensitivity in the Response to Arsenic Exposure

Abstract

People are exposed to arsenic compounds environmentally, occupationally or therapeutically. In some areas, where arsenic is present in high proportions in the drinking water, this exposure represents an important health concern. Chronic exposure to arsenic leads to hyperkeratosis and loss of skin pigmentation, as well as to significant increases of different types of cancer in skin, lung, bladder and liver; in addition, other pathologies, such as vascular diseases, hepatotoxicity and diabetes, have also been related to arsenic exposure. Since high interindividual variability is observed among people exposed to equivalent doses, genetic susceptibility factors have been postulated to be involved. When inorganic arsenic enters into the body it undergoes metabolic conversion, in a process where methylation plays a crucial role. Trivalent forms, both inorganic and organic, are the most toxic and genotoxic and, for this reason, metabolic variations owing to variant alleles in genes involved in such a process have been the aim of several studies. Genes involved in other mechanisms, such as antioxidant defense and DNA-repair lesions, among others, have also been the subject of association studies. A survey of those studies related to individual susceptibility is summarized here. Results with genes involved in folate one-carbon metabolism and in arsenic transport across the cell membrane provide promising data for future studies.

Monomethylarsenic Diglutathione Transport by the Human Multidrug Resistance Protein 1 (MRP1/ABCC1)

“…MRP1 could be essential for preventing toxicity after acute arsenic exposure as well as arsenic carcinogenesis during chronic exposure through the efflux MMA III (GS) 2 . MRP1 is highly polymorphic, and genetic variants could account for some of the well established but poorly understood interindividual susceptibility to arsenic-induced carcinogenesis (Conseil et al, 2005;Hernández and Marcos, 2008).…”

Scientific Opinion on Arsenic in Food

“…Both arsenite and arsenate are readily transported to the cell, the former by aquaglycoporins 7 and 9, which normally transport water and glycerol, and the latter by phosphate transporters (Liu et al, 2002, Villa-Bellosta andSorribas, 2008;Schuhmacher-Wolz, 2009). Hexose permease transporters are another pathway for influx of arsenite (Hernandez and Marcos, 2008). In most species, after the administration of arsenicals, residue levels are elevated in liver, kidney, spleen and lung.…”

“…Similarly, Marcos et al (2006) found that the polymorphic expression of several genes of GST isoforms only partially explained the variations in the urinary profile of arsenic metabolites. In a recent review on genetic variations associated with interindividual sensitivity in the response to arsenic, Hernandez and Marcos (2008) concluded that, despite the large number of genes included in association studies with respect to the adverse effects of arsenic exposure, no clear results have been obtained until now, except for arsenic-methyltransferase.…”

Low 8-oxo-7,8-dihydro-2′-deoxyguanosine levels and influence of genetic background in an Andean population exposed to high levels of arsenic

“…The variation in As metabolite pattern is partly due to genetic polymorphisms, especially in As(+III)methyltransferase (AS3MT) [22][23][24][25][26][27]. Other polymorphisms that may 4 influence the 8-OxodG levels include genes involved in ROS detoxification and resistance.…”