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Final Progress Reports: New York University School of Medicine: Identification and Genetic Analysis of the Human Arsenite Efflux Pump

Superfund Research Program

Identification and Genetic Analysis of the Human Arsenite Efflux Pump

Project Leader: Toby G. Rossman
Grant Number: P42ES010344
Funding Period: 2000 - 2006

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Final Progress Reports

Year:   2005 

Not all individuals exposed to arsenic in drinking water show symptoms of arsenicosis. A possible source of this variability might be accumulation of arsenic in cells.  Dr. Rossman and his research team’s earlier work established that trivalent arsenic [As(III)] enters cells by the aquaglyceroporin (AQP) channels that facilitate movement of water, glycerol and other small neutral molecules. Arsenite in solution is arsenic trioxide [As(OH)3], a molecular mimic of glycerol. Cells take up much more arsenite in the absence of glucose than in its presence.  They found that hexose permeases are the major pathway for arsenite uptake in yeast. They constructed a yeast strain lacking all 20 genes for hexose permeases. This strain exhibits very low arsenite transport. When HXT1, HXT3, HXT4, HXT5, HXT7 or HXT9 were individually expressed in that strain, hexose-inhibited As(III) uptake is restored. These results demonstrate that hexose permeases catalyze the majority of transport of As(III).  The researchers next expressed rat and human GLUT1 and GLUT4, two mammalian glucose permeases, in the multiply disrupted yeast strain and found that they likewise restore growth on glucose and transport As(III).  Even though the predominate As(III) species in solution is As(OH)3, another form is a trimer of arsenic trioxide, a six-membered oxo-bridged ring (AsO)3(OH)3, which can mimic hexoses.


Skin is a major target for arsenic. Project researchers found that arsenite requires a partner in order to cause skin cancer.  Mice given solar UV and arsenite in drinking water had increased skin cancers compared with mice given solar UV alone.  In some parts of the world with high arsenic in the drinking water, low dietary selenium levels may exacerbate the arsenic toxicity and carcinogenicity.  The researchers showed that selenium compounds block-delayed mutations induced by arsenite in human osteosarcoma (HOS) cells.  These experiments are being repeated in a human keratinocyte cell line.  Selenium prevented arsenite’s enhancement of solar UV- induced skin cancer in mice.  They suggest that the antimutagenic effects of selenium may occur via the antioxidant action of selenoproteins.  The anticarcinogenic effect may have additional mechanisms that are specific to arsenic-selenium interactions, such as stimulation by selenium of arsenic excretion or other affects on arsenic metabolism.


Project researchers believe that arsenic uptake is linked to nutrition.  In countries such as Bangladesh, the effects of arsenic in drinking water are exacerbated by malnutrition.  AQP9 expression in rats is elevated 20-fold by starvation. If the same is true in humans, then poor nutrition could bring so much arsenic into the liver that it overwhelms our intrinsic detoxification mechanisms.  Low blood glucose would also be expected to increase arsenite uptake into cells.  Conversely, improving the nutritional status of affected individuals could ameliorate the effects of arsenic in drinking water.  Genetic variability in hexose transporters and selenium metabolism could also play roles in genetic susceptibility to arsenic.

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