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Bitter taste thresholds for 6-n-propylthiouracil are bimodally distributed, dividing subjects into tasters and nontasters. Their taste worlds differ with regard to the sweetness of sucrose and saccharin and to the bitterness of saccharin. These differences suggest that nontasters tend to perceive less bitterness in saccharin at concentrations used in beverages.
A vast number of structurally diverse bitter compounds need to be detected by a subfamily of only approximately 25 human bitter receptors. Failure in detecting them might be lethal, since some naturally occurring bitter compounds, such as strychnine, are very toxic. This review presents an overview about the enormous progress in the field of mammalian bitter taste research with special emphasis on humans, if data were available. It summarizes the current knowledge about the anatomical basis for bitter taste perception, intracellular signal transduction, evolution, expression and polymorphisms of hTAS2R genes, and the molecular basis for the recognition of bitter compounds.
Among various taste stimuli, bitter substances are most abundant and their chemical structures are greatly diverse from each other. It has been known that there are multiple receptor sites and transduction mechanisms. Already in neonates, bitter stimuli elicit rejection responses, indicating strong negative hedonic tone. Bitter taste is decidedly unpleasant when the sensation is strong. The development of a method to mask bitterness has widely been required in pharmaceutical sciences and food sciences. To mask bitterness, a specific bitterness inhibitor would be most useful. Such an inhibitor would also be useful in elucidating the receptor mechanisms of bitter substances. No inhibitor has, however, been available. Recently we found that a lipoprotein, PA-LG made of phosphatidic acid (PA) and beta-lactoglobulin (beta-LG), selectively suppresses the taste responses to bitter substances. In this paper we describe the protocol used for inhibition of the frog taste (glossopharyngeal) nerve responses to bitter stimuli by the lipoprotein. The frog taste system is used because it is sensitive to various bitter substances and surgery of the animal for the electrophysiological recording is rather easy. We also describe the protocol used for inhibition of human taste sensation to bitter stimuli.
Bitter taste perception provides animals with critical protection against ingestion of poisonous compounds. In the accompanying paper, we report the characterization of a large family of putative mammalian taste receptors (T2Rs). Here we use a heterologous expression system to show that specific T2Rs function as bitter taste receptors. A mouse T2R (mT2R-5) responds to the bitter tastant cycloheximide, and a human and a mouse receptor (hT2R-4 and mT2R-8) responded to denatonium and 6-n-propyl-2-thiouracil. Mice strains deficient in their ability to detect cycloheximide have amino acid substitutions in the mT2R-5 gene; these changes render the receptor significantly less responsive to cycloheximide. We also expressed mT2R-5 in insect cells and demonstrate specific tastant-dependent activation of gustducin, a G protein implicated in bitter signaling. Since a single taste receptor cell expresses a large repertoire of T2Rs, these findings provide a plausible explanation for the uniform bitter taste that is evoked by many structurally unrelated toxic compounds.
Bitter taste perception prevents mammals from ingesting poisonous substances because many toxins taste bitter and cause aversion. We hypothesize that human bitter taste receptor (TAS2R) genes might be relaxed from selective constraints because of the change in diet, use of fire and reliance on other means of toxin avoidance that emerged in human evolution. Here, we examine the intra-specific variations of all 25 genes of the human TAS2R repertoire. Our data show hallmarks of neutral evolution, including similar rates of synonymous (d(S)) and non-synonymous (d(N)) nucleotide changes among rare polymorphisms, common polymorphisms and substitutions; no variation in d(N)/d(S) among functional domains; segregation of pseudogene alleles within species and fixation of loss-of-function mutations. These results, together with previous findings of large numbers of loss-of-function mutations in olfactory, pheromonal and visual sensory genes in humans, suggest surprisingly reduced sensory capabilities of humans in comparison with many other mammals.
PURPOSE: The objective of this pilot study was to determine the prevalence of coronal dental caries among children with different genetic sensitivity levels of taste, as determined by 6-n-propylthiouracil (PROP). METHODS: Coronal caries and restorations in permanent and primary dentition were evaluated in 150 healthy school-aged children aged 6 to 12 years. A filter paper containing 6-n-propylthiouracil was used to determine each subject's genetic ability to taste bitter and sweet substances. Supertasters perceived stronger tastes from a variety of bitter and sweet substances than both medium tasters and nontasters. The data were analyzed by ANOVA with Duncan's multiple range test, Mantel-Haenszel chi-square, multiple linear regression analyses, and Pearson's coefficient of correlation. RESULTS: The nontasters had more mean decayed, missing, and filled surfaces (dfs/DMFS) than tasters. The values of mean decayed and filled surfaces of primary dentition and mean decayed, missing, and filled surfaces of permanent dentition (dfs/DMFS) and mean decayed surfaces of primary dentition and permanent dentition (ds/DS) were significantly higher in nontasters than in medium tasters, and in medium tasters compared with supertasters. After adjusting for missing teeth, the data were expressed as a percentage of the available surfaces, and the significant differences in dfs/DMFS and ds/DS persisted (r = -0.49, P < .001 and r = -0.51, P < .0001 respectively). CONCLUSIONS: After all associated factors were controlled, taste was the only independent variable significantly related to overall caries experience. The results of this study suggested an increased prevalence of overall caries experience in nontaster children.
The tasting of bitter compounds may have evolved as a protective mechanism against ingestion of potentially harmful substances. We have identified second messengers involved in bitter taste and show here for the first time that they are rapid and transient. Using a quench-flow system, we have studied bitter taste signal transduction in a pair of mouse strains that differ in their ability to taste the bitter stimulus sucrose octaacetate (SOA); however, both strains taste the bitter agent denatonium. In both strains of mice, denatonium (10 mM) induced a transient and rapid increase in levels of the second messenger inositol 1,4,5-trisphosphate (IP3) with a maximal production near 75-100 ms after stimulation. In contrast, SOA (100 microM) brought about a similar increase in IP3 only in SOA-taster mice. The response to SOA was potentiated in the presence of GTP (1 microM). The GTP-enhanced SOA-response supports a G protein-mediated response for this bitter compound. The rapid kinetics, transient nature, and specificity of the bitter taste stimulus-induced IP3 formation are consistent with the role of IP3 as a second messenger in the chemoelectrical transduction of bitter taste.
To assess the role of phosphatidylinositol turnover in taste transduction we have visualized, in rat tongue, ATP-dependent endoplasmic reticular accumulation of 45Ca2+, inositol 1,4,5-trisphosphate receptor binding sites, and phosphatidylinositol turnover monitored by autoradiography of [3H]cytidine diphosphate diacylglycerol formed from [3H]cytidine. Accumulated 45Ca2+, inositol 1,4,5-trisphosphate receptors, and phosphatidylinositol turnover are selectively localized to apical areas of the taste buds of circumvallate papillae, which are associated with bitter taste. Further evidence for a role of phosphatidylinositol turnover in bitter taste is our observation of a rapid, selective increase in mass levels of inositol 1,4,5-trisphosphate elicited by low concentrations of denatonium, a potently bitter tastant.
Sucrose octaacetate, which tastes bitter to humans, can reduce the energy intake of rats when added to their diet. The reduction in energy intake is transient, lasting no more than 5 weeks. Rats that no longer reduce intake in response to sucrose octaacetate still avoid food containing it in choice tests, although to a lesser degree than rats having no previous experience with sucrose octaacetate. The ability of sucrose octaacetate to reduce preference without reducing long-term intake accounts for the previous finding that a wet diet containing sucrose octaacetate can stimulate hyperphagia yet be less preferred than the control diet. Sucrose octaacetate was more effective in reducing intake of a wet than of a dry diet. This last observation indicates that adding water to a food makes it easier for an animal to taste its food.
Food choices and eating habits are largely influenced by how foods taste. Without being the dominant taste sensation, bitter taste contributes to the complexity and enjoyment of beverages and foods. Compounds that are perceived as bitter do not share a similar chemical structure. In addition to peptides and salts, bitter compounds in foods may include plant-derived phenols and polyphenols, flavonoids, catechins, and caffeine. Recent studies have shown that humans possess a multitude of bitter taste receptors and that the transduction of bitter taste may differ between one compound and another. Studies of mixture interactions suggest further that bitter compounds suppress or enhance sweet and sour tastes and interact with volatile flavor molecules. Caffeine, a natural ingredient of tea, coffee, and chocolate, has a unique flavor profile. Used as a flavoring agent, it enhances the sensory appeal of beverages. Research developments on the genetics and perception of bitter taste add to our understanding of the role of bitterness in relation to food preference.
Phenylthiocarbamide tastes intensely bitter to some individuals, but others find it completely tasteless. Recently, it was suggested that phenylthiocarbamide elicits bitter taste by interacting with a human G protein-coupled receptor (hTAS2R38) encoded by the PTC gene. The phenylthiocarbamide nontaster trait was linked to three single nucleotide polymorphisms occurring in the PTC gene. Using the crystal structure of bovine rhodopsin as template, we generated the 3D structure of hTAS2R38 bitter taste receptor. We were able to map on the receptor structure the amino acids affected by the genetic polymorphisms and to propose molecular functions for two of them that explained the emergence of the nontaster trait. We used molecular docking simulations to find that phenylthiocarbamide exhibited a higher affinity for the target receptor than the structurally similar molecule 6-n-propylthiouracil, in line with recent experimental studies. A 3D model was constructed for the hTAS2R16 bitter taste receptor as well, by applying the same protocol. We found that the recently published experimental ligand binding affinity data for this receptor correlated well with the binding scores obtained from our molecular docking calculations.
T2Rs comprise a G-protein-coupled receptor superfamily that contains functionally defined bitter taste receptors. Here we report the tissue expressions and coding single-nucleotide polymorphisms (cSNPs) in human T2R genes (hT2R3, hT2R4, and hT2R5) on chromosome 7q31. We first demonstrated that hT2R3, hT2R4, and hT2R5 are actually expressed in the circumvallate papillae of the human tongue by reverse transcription-polymerase chain reaction (RT-PCR). We identified six cSNPs within the T2R receptor genes. The hT2R4 and hT2R5 contained four and one cSNPs that cause missense mutations, respectively, while hT2R3 included one silent nucleotide mutation. However, we could not find any nonsense mutations that resulted in a frameshift or a premature stop codon within the open reading frames. Genotype frequencies of each cSNP were in Hardy-Weinberg equilibrium. The identification of nucleotide diversity and amino acid polymorphisms in human T2R receptors could help clarify individual differences in the acceptability and sensitivity to bitter compounds.
Animals can discriminate among many different types of foods. This discrimination process involves multiple sensory systems, but the sense of taste is known to play a central role. We asked how the taste system contributes to the discrimination of different "bitter" taste stimuli in Manduca sexta caterpillars. This insect has approximately eight bilateral pairs of taste cells that respond selectively to bitter taste stimuli. Each bilateral pair of bitter-sensitive taste cells has a different molecular receptive range (MRR); some of these taste cells also contain two signaling pathways with distinctive MRRs and temporal patterns of spiking. To test for discrimination, we habituated the caterpillar's taste-mediated aversive response to one bitter taste stimulus (salicin) and then asked whether this habituation phenomenon generalized to four other bitter taste stimuli (caffeine, aristolochic acid, Grindelia extract, and Canna extract). We inferred that the two compounds were discriminable if the habituation phenomenon failed to generalize (e.g., from salicin to aristolochic acid). We found that M. sexta could discriminate between salicin and those bitter taste stimuli that activate (1) different populations of bitter-sensitive taste cells (Grindelia extract and Canna extract) or (2) different signaling pathways within the same bitter-sensitive taste cell (aristolochic acid). M. sexta could not discriminate between salicin and a bitter taste stimulus that activates the same signaling pathway within the same bitter-sensitive taste cell (caffeine). We propose that the heterogeneous population of bitter-sensitive taste cells and signaling pathways within this insect facilitates the discrimination of bitter taste stimuli.
Bitter taste perception in humans is mediated by receptors encoded by 25 genes that together comprise the TAS2R (or T2R) gene family. The ability to identify the ligand(s) for each of these receptors is dependent on understanding allelic variation in TAS2R genes, which may have a significant effect on ligand recognition. To investigate the extent of coding variation among TAS2R alleles, we performed a comprehensive evaluation of sequence and haplotype variation in the human bitter taste receptor gene repertoire. We found that these genes exhibit substantial coding sequence diversity. In a worldwide population sample of 55 individuals, we found an average of 4.2 variant amino acid positions per gene. In aggregate, the 24 genes analyzed here, along with the phenylthiocarbamide (PTC) receptor gene analyzed previously, specify 151 different protein coding haplotypes. Analyses of the ratio of synonymous and nonsynonymous nucleotide substitutions using the Ka/Ks ratio revealed an excess of amino acid substitutions relative to most other genes examined to date (Ka/Ks = 0.94). In addition, comparisons with more than 1,500 other genes revealed that levels of diversity in the TAS2R genes were significantly greater than expected (pi = 0.11%; p < 0.01), as were levels of differentiation among continental populations (FST = 0.22; p < 0.05). These diversity patterns indicate that unusually high levels of allelic variation are found within TAS2R loci and that human populations differ appreciably with respect to TAS2R allele frequencies. Diversity in the TAS2R genes may be accounted for by natural selection, which may have favored alleles responsive to toxic, bitter compounds found in plants. These findings are consistent with the view that different alleles of the TAS2R genes encode receptors that recognize different ligands, and suggest that the haplotypes we have identified will be important in studies of receptor-ligand recognition.
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Although vegetable consumption associates with decreased risk for a variety of diseases, few Americans meet dietary recommendations for vegetable intake. TAS2R38 encodes a taste receptor that confers bitter taste sensing from chemicals found in some vegetables. Common polymorphisms in TAS2R38 lead to coding substitutions that alter receptor function and result in the loss of bitter taste perception. Our study examined whether bitter taste perception TAS2R38 diplotypes associated with vegetable consumption in participants enrolled in either an enhanced or a minimal nutrition counseling intervention. DNA was isolated from the peripheral blood cells of study participants (N = 497) and analyzed for polymorphisms. Vegetable consumption was determined using the Block Fruit and Vegetable screener. We tested for differences in the frequency of vegetable consumption between intervention and genotype groups over time using mixed effects models. Baseline vegetable consumption frequency did not associate with bitter taste diplotypes (P = 0.937), however after six months of the intervention, we observed an interaction between bitter taste diplotypes and time (P = 0.046). Participants in the enhanced intervention increased their vegetable consumption frequency (P = 0.020) and within this intervention group, the bitter non-tasters and intermediate-bitter tasters had the largest increase in vegetable consumption. In contrast, in the minimal intervention group, the bitter tasting participants reported a decrease in vegetable consumption. Bitter-non tasters and intermediate-bitter tasters increased vegetable consumption in either intervention more than those who perceive bitterness. Future precision medicine applications could consider genetic variation in bitter taste perception genes when designing dietary interventions.
Bitter taste perception is crucial for the survival of organisms because it enables them to avoid the ingestion of potentially harmful substances. Bitter taste receptors are encoded by a gene family that in humans has been shown to contain 25 putatively functional genes and 8 pseudogenes and in mouse 33 putatively functional genes and 3 pseudogenes. Lineage-specific expansions of bitter taste receptors have taken place in both mouse and human, but very little is known about the evolution of these receptors in primates. We report the analysis of the almost complete repertoires of bitter taste receptor genes in human, great apes, and two Old World monkeys. As a group, these genes seem to be under little selective constraint compared with olfactory receptors and other genes in the studied species. However, in contrast to the olfactory receptor gene repertoire, where humans have a higher proportion of pseudogenes than apes, there is no evidence that the rate of loss of bitter taste receptor genes varies among humans and apes.
The masking mechanisms of the bitter taste of propantheline bromide (PB) and oxyphenonium (OB) bromide by native and modified cyclodextrins, saccharides, surfactants, organic acids, nonionic and anionic polymers, and other compounds were investigated with ion selective electrodes. The intensity of the bitter taste for a mixed solution of cyclodextrin with PB or OB was quantitatively explained from the observed electromotive force with the following assumptions: the complex and the masking agent do not have any tastes and the bitter taste is independent of other tastes. Sodium dodecyl sulfate reduced the bitter taste remarkably, and this reduction was also explicable on the basis of the same mechanism. Sodium taurodeoxycholate enhanced the bitter taste, because of its strong bitterness, although it formed 1 : 1 complexes with PB and OB. The masking mechanism of saccharides was ascribed to overcoming the weak bitterness of the drug by the strong sweetness. Lambda-carrageenan suppressed the bitter taste remarkably. This suppression was ascribed to the binding of PB and OB to lambda-carrageenan, the effect of the solution viscosity on the bitter taste, and the covering of the bitter taste receptor by lambda-carrageenan. It was suggested that the moderate masking by other polymers was attributable to the effect of the solution viscosity or the receptor covering. Native and modified beta-cyclodextrins, sodium dodecyl sulfate, lambda-carrageenan, Tween 20, and sodium carboxymethyl cellulose are good masking agents for the bitter tastes of PB and OB. The drug ion selective electrode is a useful tool for understanding of the masking mechanism of the bitter taste, screening of masking agents, and estimation of appropriate concentrations of the masking agents.