Pathways of Arsenic Uptake and Efflux

Abstract

Arsenic is the most prevalent environmental toxic substance and ranks first on the U.S. Environmental Protection Agency’s Superfund List. Arsenic is a carcinogen and a causative agent of numerous human diseases. Paradoxically arsenic is used as a chemotherapeutic agent for treatment of acute promyelocytic leukemia. Inorganic arsenic has two biological important oxidation states: As(V) (arsenate) and As(III) (arsenite). Arsenic uptake is adventitious because the arsenate and arsenite are chemically similar to required nutrients. Arsenate resembles phosphate and is a competitive inhibitor of many phosphate-utilizing enzymes. Arsenate is taken up by phosphate transport systems. In contrast, at physiological pH, the form of arsenite is As(OH)3, which resembles organic molecules such as glycerol. Consequently, arsenite is taken into cells by aquaglyceroporin channels. Arsenic efflux systems are found in nearly every organism and evolved to rid cells of this toxic metalloid. These efflux systems include members of the multidrug resistance protein family and the bacterial exchangers Acr3 and ArsB. ArsB can also be a subunit of the ArsAB As(III)-translocating ATPase, an ATP-driven efflux pump. The ArsD metallochaperone binds cytosolic As(III) and transfers it to the ArsA subunit of the efflux pump. Knowledge of the pathways and transporters for arsenic uptake and efflux is essential for understanding its toxicity and carcinogenicity and for rational design of cancer chemotherapeutic drugs.

A Novel Pathway for Arsenic Elimination: Human Multidrug Resistance Protein 4 (MRP4/ABCC4) Mediates Cellular Export of Dimethylarsinic Acid (DMAV) and the Diglutathione Conjugate of Monomethylarsonous Acid (MMAIII)

“…This observation was consistent with a previous report that MRP4 expressed in NIH3T3 cells did not confer resistance to As III (Lee et al, 2000) and our finding that As III (6 GSH) and As(GS) 3 were not substrates for MRP4. As III is more toxic to cells than As V (Tables 1-4) (Yang et al, 2012). Cellular uptake of As III occurs at a faster rate than As V (Yang et al, 2012), and this potentially results in the saturation of methylation pathways, impeding the formation of MMA(GS) 2 and DMA V and preventing MRP4 from playing a protective role.…”

“…As III is more toxic to cells than As V (Tables 1-4) (Yang et al, 2012). Cellular uptake of As III occurs at a faster rate than As V (Yang et al, 2012), and this potentially results in the saturation of methylation pathways, impeding the formation of MMA(GS) 2 and DMA V and preventing MRP4 from playing a protective role.…”

“…As V is chemically similar to inorganic phosphate and enters cells through the sodium/ phosphate cotransporter type IIb (SLC34A2) (Villa-Bellosta and Sorribas, 2010). In solution, As III and As 2 O 3 exist as the neutral As(OH) 3 , which passively enters cells through aquaglyceroporins (Yang et al, 2012). Arsenic is methylated within most mammalian cells.…”

The Effect of Chronic Arsenic Exposure in Zebrafish

“…16 The human liver is the primary organ of arsenic accumulation through aquaglyceroporins, where these inorganic arsenicals can be further metabolized into a profile of methylated organic arsenic, including MAs(V) and DMAs(V). 17 Recent studies reveal that humans, rodents, and zebrafish share a high degree of evolutionary conservation in arsenic metabolism. [18][19][20] These findings validated that zebrafish can be a convenient aquatic vertebrate model closer to human conditions in the studies of arsenic metabolism and toxic effects.…”

When are metal complexes bioavailable?

“…[38,39] Similarly, owing to its structural similarities to phosphate, As V , in the form of AsO 4 3À , is known to be accumulated through phosphate transporters in E. coli, yeast and mammals. [40,41] Owing to this dependency on transporters that are designed for nutrients, the toxicity induced by the metalloids is highly dependent on nutrient exposure concentrations and conditions (Box 2).…”