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Fruit Flies on Phenobarbital? Sedative Studies Shed Light on How Insects, People Defend Themselves Against Environmental Toxins

July 5, 2006 — Give them a little Phenobarbital and fruit flies just drop like – well, like flies.

University of Utah researchers gave fruit flies, also called Drosophila, tiny sips of water laced with Phenobarbital and found that the sedative causes hundreds of genes involved in detoxification to switch on and off. They also identified a protein that plays an essential role in this insect detoxification response.

Led by Carl S. Thummel, Ph.D., professor of human genetics at the University’s School of Medicine and an investigator with the Howard Hughes Medical Institute, the researchers were able to identify genes the fruit fly uses to resist pesticides, poisons, and other toxins. These genes metabolize the myriad of toxins or xenobiotics that fruit flies-and people-encounter on a daily basis, eliminating those toxins from the body.

The study, published online in the July edition of the journal Cell Metabolism, presents important implications for global public health and for finding ways to control insects that rapidly build resistance to pesticides and destroy billions of dollars in agricultural crops every year.

Understanding how Drosophila detoxifies its body can also help explain how humans do it, according to Thummel. As medical scientists learn the biological mechanisms of how Drosophila and humans detoxify, it can have a worldwide impact on health, from stopping the spread of insect-borne diseases such as malaria to protecting people against the ill-effects of air pollution.

“Environmental toxins are a major public health issue, and that”s what interests us,” he said.

Whether it’s from pesticides sprayed on fruit and vegetables, noxious emissions from cars and power plants or the potentially harmful substances made by charring chicken on the barbecue, humans, insects, and all higher organisms live in a world with lots of toxins. Fortunately, evolution has allowed people and other creatures to develop biological mechanisms that detoxify these xenobiotics.

People and Drosophila share similar biological responses to detect toxins in their bodies, switching certain genes on and off. These genes encode enzymes that metabolize xenobiotics into less harmful substances that can be eliminated from the body. Humans and insects share four major classes of enzymes needed for detoxification.

To identify genes turned on and off when Drosophila ingested Phenobarbital, Thummel and co-workers used a microarray, a process that allows thousands of genes to be monitored at the same time. After the fruit flies drank the sedative in water, Thummel and his co-researchers identified approximately 1,000 genes that switched on or off in response to the drug. The affected genes encode many enzymes related to detoxification.

“This method gives us a genomewide view of how insects respond to xenobiotics,” he said. “We need to find the factors that regulate this massive detoxification response.”

He then focused on identifying a nuclear receptor-a molecular switch that turns genes on and off-that seemed a likely candidate to regulate genes in Drosophila detoxification.

Other labs had identified nuclear receptors that sense and detoxify xenobiotics in mammals. Drosophila carries a nuclear receptor, called DHR96, similar to the ones mammals use in detoxification.

To test whether DHR96 has a role in detoxification in Drosophila, Thummel and colleagues created a mutant form of the receptor and observed how fruit flies carrying the mutation reacted to Phenobarbital. Flies with the mutant DHR96 showed increased sensitivity to the sedative effects of Phenobarbital and the toxic effects of the pesticide DDT. They also showed improper regulation of some genes that are controlled by the sedative, indicating that the receptor plays a role in detoxification.

The studies establish Drosophila as a valid genetic model for understanding the detoxification response because the fruit flies are much easier to study than more complex organisms such as humans and mice, Thummel said.

Thummel believes other factors in the detoxification response remain to be identified and understood-and that the fruit fly provides a way to find these factors.

“This has relevance in day-to-day human life,” Thummel said. “If we didn’t have these genetic pathways, we wouldn’t live very long.”

The study’s other authors were University postdoctoral researcher Kirst King-Jones and research associates Michael A. Horner and Geanette Lam.

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The University of Utah Health Sciences Center is internationally regarded for its research and clinical expertise in the health sciences. Through its School of Medicine, College of Pharmacy, College of Nursing, College of Health, and Eccles Institute of Human Genetics, the Health Sciences Center conducts pioneering research in human genetics, pharmaceutical drugs, cancer, and numerous other areas of medicine. The Health Sciences Center also is the major training ground for Utah’s physicians, pharmacists, nurses, therapists, and other health-care professionals.