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Glutathione Synthetase Linked to Arsenic Susceptibility in Fruit Fly Model

By Brian Chorley
March 2009

Iain Cartwright, Ph.D. and Jorge Muñiz Ortiz, Ph.D.
First author Muñiz Ortiz, left, posed with Cartwright, his mentor and the principal investigator on the study. Muñiz Ortiz now works with the EPA. (Photo courtesy of Iain Cartwright and the University of Cincinnati)

NIEHS grantee Iain Cartwright, Ph.D., an associate professor at the University of Cincinnati College of Medicine, his former student, Jorge Muñiz Ortiz, Ph.D., and two co-authors recently reported a surprising genetic twist regarding arsenic susceptibility in the February 2009 issue of Toxicological Sciences. He and his research team discovered evidence that gene sequence variation of Drosophila glutathione synthetase (GS), which encodes an enzyme responsible for the final step in gluthathione synthesis, may be a more likely explanation for differential arsenic sensitivity and exposure risk than previously thought.

In an editorial appearing in the same issue, Environmental Protection Agency (EPA) Research Toxicologist David Thomas, Ph.D., lauded the study's ( Exit NIEHS significant contribution to unraveling the arsenic-glutathione connection. "Additional information [of this kind] on the relation between the GS genotype and the phenotype for response to As may help to reduce some of the uncertainties in the risk assessment for this metalloid and assist regulators in their task of protecting public health."

Arsenic is a metalloid that forms various compounds readily in nature. At high dosage, arsenic is extremely toxic to many organisms and has been used as an active ingredient in insecticides and herbicides. For example chromated copper arsenate (CCA), an arsenic compound, was once heavily used as a wood preserver because of its toxicity to insects, bacteria, and fungi. Subsequently, due to potential environmental and human health impact concerns, CCA has been banned from use in the U.S. and other countries.

Naturally occurring arsenic contamination in well water used by Bangladesh and neighboring countries is a current health concern that has the potential to affect tens of millions of people. Chronic ingestion of arsenic has been linked to numerous diseases such as cancer, diabetes, and respiratory ailments; however, epidemiological evidence has demonstrated that arsenic sensitivity varies from individual to individual and population to population. This variation suggests there may be a strong genetic component to arsenic toxicity.

Drosophila, or the fruit fly, is a common model for genetic research for which Cartwright is certainly an advocate. "The use of simpler, but genetically highly amenable, model eukaryotic systems in toxicology has much to recommend it, both from a cost-effective and time-critical perspective," he explained.

By measuring egg-hatching rates in progeny of two different Drosophila strains that were respectively resistant and sensitive to arsenic and using a combination of genetic analysis techniques, Cartwright's team narrowed their focus to a region in the X-chromosome. This region of the X-chromosome coded a gene of particular interest, glutathione synthetase - an enzyme involved in glutathione biosynthesis. It has been known since the beginning of the early 1920's that glutathione could protect from arsenic toxicity, and it was used as an antidote to the arsenical war gas Lewisite. Since these initial observations, several studies have demonstrated that glutathione protects by facilitating both breakdown and transport of arsenic out of the cell.

What is surprising about Cartwright's finding is that glutathione synthetase is not considered the rate-limiting step for gluthathione biosynthesis and that partial deficiency in this enzyme is not thought to compromise gluthathione production. The research team used an RNA interference technique to demonstrate, however, that flies exhibiting partial reduction of this enzyme, showed significantly increased arsenic susceptibility. A possible explanation, suggested by the researchers, is that a stressed system may struggle to meet the demand of glutathione, thereby allowing other points of control, such as glutathione synthetase, to potentially limit overall biosynthesis rates.

"Given the intense interest in inter-individual variability in response to arsenic in studied human populations exposed to arsenic-laden water," Cartwright commented, "this work adds an additional dimension to the metabolic and biosynthetic pathways deserving scrutiny as potential arbiters of differential susceptibility based on genetic polymorphism."

(Brian Chorley, Ph.D., is a postdoctoral fellow in the NIEHS Laboratory of Molecular Genetics Environmental Genomics Group.)

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