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Taking the Bitter out of Bittersweet

Of the five tastes—sweet, sour, salty, bitter, and savory—bitter has the hardest time pleasing our palates. Although the ability to taste bitterness has been conserved over eons of human development to protect us from eating toxic substances that could sicken or kill us, many good-for-you foods, such as leafy greens, contain bitter components that can make them less than appealing. This can have a negative impact on food choices, nutrition, and even drug compliance when oral medications are too bitter to swallow.

Scientists have been trying for years to come up with ways to eliminate bitter tastes in foods and drugs. Mostly they’ve resorted to disguising bitterness with sweetness or strong flavors, such as the fruit flavors that are added to children’s medicines to make them more palatable. But the recent discovery, by a team of NIDCD-funded researchers, of a substance that appears to block bitter taste may finally offer a way to effectively control bitterness. The finding was published in the May 24, 2011, issue of PLoS ONE.

Bitterness is detected by taste receptor cells on the tongue, palate, and throat that are activated by a large family of genes called TAS2R genes, which make the receptor proteins that are key to bitter perception. The compound the scientists have found appears to inhibit bitterness in a small subset of TAS2R receptors by reducing their ability to interact with bitter molecules.

The finding came as a serendipitous discovery in the course of a collaboration among scientists at the Monell Chemical Senses Center, Integral Molecular, Inc. (both in Philadelphia), and Rutgers University in New Brunswick, N.J. Since relatively little is known about the structure and function of the TAS2R receptors, the researchers were trying to identify the places on the receptors where bitter molecules attach and bind, as well as the places that activate the receptor and send bitter signals to the brain.

Joseph Rucker, Ph.D., was working with a number of TAS2R receptors in his lab at Integral Molecular as was another colleague, Tiffani Greene, Ph.D.. Both assumed they were using the same protocol to test the cellular response of the TAS2R proteins to PTC (a commonly used bitter tastant), and salicin (a bitter compound derived from poplar and willow trees) but they kept getting different results on some of their assays. As it turned out, Dr. Greene’s protocol differed in one important way from Dr. Rucker’s. She was using probenecid, a compound that keeps the fluorescent dye markers that reveal receptor activity from escaping too quickly out of the cells. Once the two researchers discovered the discrepancy, they could see how the addition of probenecid inhibited the activation of three different TAS2R receptors.

Further testing to discover how probenecid did its job showed that it wasn’t blocking the site where salicin binds to its receptor, nor was it globally inhibiting the cell’s ability to signal. It was attaching to the cell at another location and modifying the receptor function, almost as if it were a volume control turning down the bitter signal to a whisper. According to the researchers, this is the first published finding that shows a bitter receptor being modulated in this way.

Paul Breslin, Ph.D., from Monell and Rutgers, continued Drs. Greene and Rucker’s work with the TAS2R receptors, devising a series of perceptual studies to see if probenecid would act the same way in human mouths as it did in the lab, which it did. The team is now working with another researcher to create computer-generated molecular models of the TAS2R receptors. This will allow them to look for ways to design new and better receptor inhibitors that could potentially bind more strongly to the receptor or even interact with the receptor in unusual ways.

The search for bitter inhibitors is something that interests more than just nutritionists eager to find ways to get children to eat their vegetables. The bitter taste of medicines that can only be dissolved in liquids and administered by mouth poses real problems with drug compliance—especially in children who either can’t or won’t swallow pills.

Finding a way to block unpleasant bitter tastes is especially urgent for HIV-positive children taking anti-viral drug cocktails, which is currently the only way for them to keep AIDS from progressing. According to Dr. Breslin, there are some children who dislike the taste of the medicine so much that they end up not taking all of their doses. Missing doses gives the HIV virus the opportunity to mutate and become drug-resistant.

“This is truly a case in which bitterness can threaten lives if it’s not held in check,” says Dr. Breslin.