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Bitter taste blockers for drug and food industries
[Bloqueantes del gusto amargo para las industrias alimentaria y farmacéutica]
Montserrat Daban
Rubes Editorial

Biotech firm Linguagen of New York has succeed in blocking the taste of bitter substances by natural compounds. The company, founded by Robert F. Margolskee (an Associate Investigator of the Howard Hughes Medical Institute and Professor of Physiology & Biophysics and Pharmacology at the Mount Sinai School of Medicine), has received last February formal allowance from the U.S. Patent and Trademark Office for its patent on compounds that inhibit the bitter taste response. This is the first time a molecular biology approach allows to decrease the perception of bitterness caused by bitter tasting molecules, which constitutes a significant step towards the production of compounds that could help drug companies make bitter-tasting medicines more palatable and food manufacturers reduce the amounts of sugar, salt and fat that need to be added to most food processes.

Researchers at the Mount Sinai School of Medicine announced in November 2002 the identification of Trpm5, a protein present in taste cells and the gut that plays a determinant role in the delivery of bitter taste messages to the brain. Their results, published in Nature Neuroscience, made finally real the expectations of the industry of finding a way to eliminate the bitter taste that often accompanies medications and foods. Prior to that, in October, Linguagen founder Margolskee affirmed that they were testing compounds to block the bitter taste found in a long list of pharmaceuticals, foods and beverages. The answer to those needs came from findigas such as the above mentioned discovery of Trpm5, the transient receptor potential channel expressed in taste receptor cells that responds to bitter flavors by converting taste information into signals that are then transmitted to taste nerve cells and sent to the bitter detection center of the brain. Let’s review what Percepnet commented about this discovery in our December issue (only in Spanish in the original reference):

«[...] To identify other possible candidates to taste signal transduction elements, researchers from the Howard Hughes Medical Institute, in cooperation with the New York University Medical School, the Monell Chemical Senses Center and Cellular Genomics Inc. and the Hebei University in China, have used cDNA screening technologies to determine which genes were differentially expressed in mouse taste cells. One of the genes isolated was trpm5, a member of a channel protein family involved in the calcium intake, selectively coexpressed in a certain population of taste cells with certain molecules specialized in taste signalling such as -gustducine. Pérez et al. conclude that Trpm5 acts as a calcium channel, activated by the inner store depletion of this ion, although the activation mechanism is yet unknown. The authors propose that this element may be involved in the signalling cascade triggered by bitter tasting compounds and, possibly by other gustative inputs.»

This was an important discovery in the world of taste technology because the selective expression ot Trpm5 in taste buds enables to target scientists efforts to find compounds that block an specific protein on the tongue, Trpm5, signal transduction, by means of compounds that could be mixed into liquid or solid medications to help diminish bitter taste.

The taste signal transduction
The taste transduction mechanism allows the taste cells to detect tasting compounds and store this information in the taste cell. The mechanism involves the interaction of tastants with receptor cells in taste buds located in the papillae of the tongue. Each taste modality affects receptor cells through distinct pathways. The signalling mechanisms of the four taste modalities accepted (sweet, salty, bitter y and sour) and the two currently discussed (fat and umami), are only partially known. Salty and sour result from a sodium, potassium or hydrogen ion influx through channels found in receptor cells of taste buds. On the other hand, sweet, bitter and umami seem to require specific receptors.

Bitter substances generally activate one or more taste receptors, which catalyse the activation of the taste specific G protein gustducin (G proteins are heterotrimeric proteins that amplify signals generated at the cell surface by ligand-activated receptors). When gustducin is activated, it dissociates into alpha and beta-gamma subunits. Its alpha subunit decreases cAMP levels, a fact that may cause activation of ion channels resulting in a change in the taste cell potential. On the other hand, the beta and gamma subunits apparently activate a phospholipase which can generate a second messenger that can mobilize the calcium that will eventually modulate the taste cell membrane potential. This cascade of events induces makes the taste cell send the brain information of a bitter stimulus. However, there are other mechanisms for bitter substances that do not involve the G protein gustducin. Those substances traverse the taste cell membrane and directly modulate the signal transduction enzymes or ion channels. Therefore, a compound that blocks the activation of GPCR (G protein coupled receptors) or downstream signalling proteins will prevent the perception of bitterness.

Levels of bitter taste blocking
Flavor masking and processing approaches are the two methods for ameliorating the bitter taste of pharmaceuticals and foods. Flavor masking usually involves the addition of high amounts of sodium and sugar. Processing approaches include micro-encapsulation and ion exchange removal of contaminants. Although these methods can be somewhat successful in particular applications, they all have major drawbacks. The addition of sodium and sugar may lead to hypertension and obesity, two of the most spread risk factors leading to serious diseases and microencapsulation may not be suitable for those who only can take liquid dosages. The new molecular biology approaches block bitter taste transduction at various levels in the transduction pathway (see figure): at receptor-ligand interaction, at receptor-G protein interaction, at G protein activation level, at
G protein-effector interaction, at second messenger generation and finally at channel activation level. All the compounds that block bitterness are naturally occurring nucleotides already found in various foods, which means that compounds will not require further approval when added to food and drugs in small quantities.

GPCR: G Protein Coupled Receptor
Points at which transduction can be blocked: 1. Receptor-Ligand interaction; 2. Receptor-G protein interaction; 3. G protein activation; 4. G protein-Effector interaction; 5. Second messenger generation; 6. Channel activation.


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