Transport pathways for arsenic and selenium: A minireview
Introduction
Arsenic is one of the most common poisons found in the environment, introduced from both geochemical and anthropogenic sources, and is acted on biologically, creating an arsenic biogeocycle (Fig. 1) (Bhattacharjee and Rosen, 2007). The environmental prevalence of arsenic presents a health hazard in human populations world-wide. For example, arsenic in the water supply in Bangladesh and West Bengal is considered to be a health catastrophe (http://bicn.com/acic/infobank/bgs-mmi/risumm.htm). Because of its ubiquity, toxicity and exposure to humans, arsenic ranks first on the Superfund List of Hazardous Substances <http://www.atsdr.cdc.gov/cercla/05list.html>. Exposure to arsenic is associated with cardiovascular and peripheral vascular disease, neurological disorders, diabetes mellitus and various forms of cancer (Abernathy et al., 2003, Beane Freeman et al., 2004). Anthropogenic sources of arsenic include herbicides and pesticides, wood preservatives, animal feeds and semiconductors. Some contain inorganic arsenic such as chromated copper arsenate (CCA), which has been used for many decades to treat wood against attack by fungi and insects. If the wood is not sealed, the arsenic can find its way into human water and food supply. Both inorganic and organic arsenicals are used for agriculture and animal husbandry. During the last century, arsenic acid (H3AsO4), sold as Desiccant L-10 by Atochem/Elf Aquitaine, was euphemistically called “harvest aid for cotton” because it was used to defoliate cotton to allow planting of the next cotton crop. While it is no longer used agriculturally, the inorganic arsenic remains in fields throughout the southern United States. That land is now used for planting rice, and grocery store rice from those states constitutes the largest non-seafood source of arsenic in the American diet (Williams et al., 2007). The sodium and calcium salts of monomethylarsenate (MMA) and dimethylarsenate (DMA) are currently widely used as herbicides and pesticides. For example, the active ingredient in Weed-B-Gone Crabgrass Killer is calcium MMA. DMA and MMA are also widely used as a fungicide on golf courses in Florida, and the resulting arsenic enters the water supply of Florida municipalities. DMA, also known as cacodylic acid, is also used as a defoliant of cotton fields. Organic arsenicals such as Roxarsone (4-hydroxy-3-nitrophenylarsonic acid) are also used as growth enhancers and feed supplements in animal husbandry.
As a consequence of its pervasiveness, nearly every organism, from E. coli to humans, has mechanisms for arsenic detoxification, most of which involve transport systems that catalyze extrusion from the cytosol (Bhattacharjee and Rosen, 2007). In bacteria, the genes for arsenic detoxification are usually encoded by arsenic resistance (ars) operons. Many ars operons have only three genes, arsRBC, where ArsR is an As(III)-responsive transcriptional repressor (Xu and Rosen, 1999), ArsB is an As(OH)3/H+ antiporter that extrudes As(III), conferring resistance (Meng et al., 2004), and ArsC is an arsenate reductase that converts As(V) to As(III), the substrate of ArsB, hence extending the range of resistance to include As(V) (Mukhopadhyay and Rosen, 2002). Some ars operons have two additional genes, arsD and arsA, such as the arsRDABC operon in E. coli plasmid R773. In these cells ArsA forms a complex with ArsB that catalyzes ATP-driven As(III)/Sb(III) efflux and hence are more resistant to As(V) and As(III) than those without ArsA (Dey and Rosen, 1995). ArsD is an arsenic metallochaperone that transfers As(III) to ArsA, increasing its ability to extrude arsenite (Lin et al., 2006). Arsenicals and antimonials are also used as chemotherapeutic drugs for the treatment of parasitic diseases and cancer, and resistance to these drugs is commonplace. Thus, knowledge of the pathways, enzymes and transporters for metalloid uptake and detoxification is necessary for understanding their toxicity, for rational design of metallodrugs and for treating drug-resistant microorganisms and tumor cells.
Selenium is an environmental pollutant and ranks 147th on the Superfund Priority List of Hazardous Substances of the U.S. Comprehensive Environmental Response, Compensation, and Liability Act (CERCLA) (http://www.atsdr.cdc.gov/cercla/05list.html). The maximum allowable concentration (MCL) of selenium by the World Health Organization (WHO) in drinking water is 10 ppb (approximately 10− 7 M) (http://www.atsdr.cdc.gov/toxprofiles/tp92.html). Selenium has chemical properties similar to those of arsenic such a valence shells, electronic structures and atomic radii. Selenium enters the environment from both geochemical and anthropogenic sources. Much of selenium in the environment comes from selenium dioxide produced by burning of coal and other fossil fuels. Inhalation of selenide and selenium dioxide can produce serious injury to the respiratory tract, the cardiovascular and peripheral vascular systems, brain, muscle, kidney and liver (http://www.atsdr.cdc.gov/toxprofiles/tp92.pdf). The soluble forms of selenium are selenite (Se(IV)) and selenate (Se(VI)), which are more mobile and more toxic than elemental selenium.
While toxic at high concentrations, selenium is a required micronutrient, with a recommended dietary allowance of approximately 0.9 µg/kg of body weight, depending on age and sex. In China acute selenium deficiency results in Keshan Disease, which is characterized by an enlarged heart and impaired cardiac function (Li et al., 1985, Lu and Wang, 1964). Dietary supplementation with selenium alleviates Keshan Disease (Cheng and Qian, 1990). Selenium is also required for production of thyroid hormone, and deficiency affects thyroid function (Behne et al., 1990, Kohrle, 1992). Selenium deficiency has also been linked to neurodegenerative and cardiovascular diseases, as well as to an increased risk of cancer (Yan and Barrett, 1998, Chen and Berry, 2003, Combs, 2001, Clark et al., 1996). At least 25 selenoproteins in which selenocysteine substitutes for cysteine, have been identified (Stadtman, 1991). These are mainly antioxidant enzymes such as peroxidases and oxyreductases that protect from oxidative stress. For example, human erythrocytes have a selenocycteine-containing glutathione peroxidase (GPx) that catalyzes glutathione-coupled reduction of and protection from hydroxyperoxides (Rotruck et al., 1973, Wang et al., 2003). Clinical trials showed that selenium may also protect from prostate cancer (Colditz, 1996, Foster, 1988, Nelson et al., 1999, Rayman, 2005).
Selenium also protects against the toxic effects of toxic metal and organic compounds, including lead, cadmium, arsenic, mercury, and paraquat (Junod et al., 1987, Nehru and Bansal, 1997, Whanger, 1985) Antagonistic effects or mutual detoxification between As and Se have been reported in humans and other animals (Levander, 1977, Moxon, 1938, Schrauzer, 1992, Zeng, 2001). What is the physical basis for their interactions? Selenium and arsenic probably interact during their cellular metabolism, including uptake, reduction, methylation, conjugation with glutathione (GSH) and excretion, as discussed below.
Section snippets
Pathways of uptake of As(V) and As(III)
Arsenic is a toxic element with no known nutritional or metabolic roles. Since cells would have no reason to evolve uptake systems for toxic elements, both trivalent arsenite and pentavalent arsenate are taken up adventitiously by existing transport systems. Arsenate is a phosphate analogue and takes up arsenate by phosphate transporters in both prokaryotes and eukaryotes. In E. coli, both phosphate transporters, Pit and Pst, take up arsenate (Rosenberg et al., 1977), with the Pit system being
Pathways of uptake of Se(VI) and Se(IV)
Little is known about selenium transport, which is the first step in selenium metabolism that includes reduction, methylation, and incorporation into selenoenzymes. Selenate (Se(VI)) is less toxic than selenite (Se(IV)), just as arsenate (As(V)) is less toxic than arsenite (As(III)). Like the uptake of arsenate by the phosphate ABC transporter, in E. coli selenate uptake is via the sulfate ABC transporter complex encoded by the cysAWTP operon (Sirko et al., 1990, Turner et al., 1998). The
Acknowledgements
This work was supported by the United States Public Health Service Grants GM52216 to B.P.R and American Heart Association Postdoctoral Fellowship 0520014Z to Z.L.
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