Phenylthiocarbamide is a synthetic thiourea (N-C=S) compound. Its bimodal taste sensitivity has been used in genetics and anthropology research since the 1930s. An agonist of the TAS2R38 bitter taste receptor.
Phenylthiocarbamide (PTC) is a synthetic thiourea compound that has been used as research material in genetics and anthropology since the 1930s. It is known for large individual differences in taste sensitivity: some perceive it strongly bitter, while others perceive little to no bitterness. In studies of unrelated subjects, a single bitter taste receptor gene, TAS2R38, located in a small region on chromosome 7, gives rise to 5 haplotypes (combinations of alleles) worldwide, and these are reported to account for 55–85% of the bimodal distribution in PTC sensitivity and variation in sensitivity
The function of this gene has also been confirmed at the cell level. In cultured cells expressing the PAV-variant TAS2R38 receptor, intracellular calcium increased in a concentration-dependent manner in response to PTC at micromolar concentrations, whereas the AVI-variant receptor did not respond even at 1 millimolar, a high concentration of PTC. In psychophysical experiments with human subjects, individuals with two PAV alleles and those with two AVI alleles showed clearly separated rated intensities across all concentrations of PTC, and this difference was statistically highly significant (p<0.001)
However, just because they stimulate the same receptor does not mean that PROP (propylthiouracil), which is chemically related to PTC, can be treated the same way. The threshold difference due to differences in genotype between PAV and AVI exceeded 400-fold for PTC but remained at only 40-fold for PROP. Among individuals with two AVI alleles, some responded strongly to PROP, and among those with two PAV alleles, some showed little to no response; at concentrations exceeding the threshold, PROP sensitivity is thought to be influenced by genetic and environmental factors other than TAS2R38
Bufe B; Breslin PA; Kuhn C; Reed DR; Tharp CD; Slack JP; Kim UK; Drayna D; Meyerhof W / 2005 / journal article / full text checked
Checked for this overview: Confirmation of cell experiment showing that PAV variant responds while AVI variant does not respond even at 1 mM / Confirmation of psychophysical experiment showing a significant difference (p<0.001) between diplotypes / Confirmation of contrast in threshold difference: over 400-fold for PTC versus 40-fold for PROP
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Sensory (1)
6-n-propylthiouracil is not perceptually interchangeable with phenylthiocarbamidesupported
Scope: 32 subjects with known TAS2R38 diplotypes were tested with concentration series of both compounds. Threshold was defined as the 75% point on the psychometric function
Note: A mechanistic caveat about the practice of using PROP as a substitute for PTC. The direct basis is that 2 AVI/AVI subjects responded strongly to PROP while 2 PAV/PAV subjects showed almost no response.
The threshold, defined as the 75% correct point (inflection point) on the psychometric function, differed by more than 400-fold between PAV/PAV and AVI/AVI for PTC, but by only 40-fold for PROP. The concentration-intensity function for PROP did not separate by haplotype as clearly as the PTC ratings did. The observation that 2 AVI/AVI subjects responded strongly to PROP while 2 PAV/PAV subjects showed almost no response strongly suggests that suprathreshold PROP sensitivity is under additional genetic and environmental control.
Limitations: The paper avoids quantifying the total variance explained. The authors suggest that variation among heterozygotes may reflect variation in the mRNA ratio of PAV and AVI transcripts, but this remains a proposed mechanism.
TAS2R38 explains the bimodal individual variation in phenylthiocarbamideestablished
Scope: Linkage-disequilibrium mapping in unrelated subjects (Kim 2003), genotype-stratified psychophysics (Bufe 2005), threshold phenotyping across 6 haplotypes (Behrens 2013)
A small region on chromosome 7 at 7q shows strong linkage disequilibrium between SNP markers and PTC taste sensitivity in unrelated subjects; this region contains a single TAS2R gene with 3 coding SNPs, giving rise to 5 haplotypes worldwide. These haplotypes fully explain the bimodal distribution of PTC taste sensitivity and account for 55–85% of the variance in PTC sensitivity.
Limitations: Abstract level: the sample size, the population behind the 55–85% range, and the phenotype values for each haplotype are not given in the abstract. The full text in Science is not accessible.
Suprathreshold PTC intensity functions showed a clear separation between every AVI/AVI function and every PAV/PAV function, and all diplotype groups differed significantly from one another at every PTC concentration (p < 0.001).
Limitations: The sample per diplotype group is small. Heterozygotes are intermediate in PTC intensity but resemble PAV/PAV in recognition threshold, so which phenotype is measured matters.
In 56 subjects covering the 6 TAS2R38 haplotypes, the association with detection thresholds for 4 thioamide compounds (PTC, PROP, goitrin, and methimazole) was strongly significant, at P<0.005 and β>1.85 for all 3 SNPs, and P<0.001 for the PAV/AVI haplotype. For sinigrin (only a subpopulation of N=25), all 3 SNPs were also statistically significant, but the P-values, at 0.03–0.04, were higher than for the thioamide compounds, and the authors point to insufficient power from the small sample.
Limitations: Abstract level. Haplotypes other than PAV and AVI showed no association with phenotype, which the authors attribute to their low frequency. It is used here to read the correspondence between genotype and threshold.
Context: Mean thresholds varied more than 40-fold among compounds (from about 50 µM for PTC to about 2000 µM for sinigrin), and within-compound individual variation ranged from 40-fold for salicin, goitrin, and sinigrin to 8000-fold for PTC. Verbatim: "Mean thresholds varied more than 40-fold among compounds, from a minimum of ~50 µM (PTC) to a maximum of ~2000 µM (sinigrin), whereas within-compound threshold ranges varied from 40-fold (salicin, goitrin, and sinigrin) to 8000-fold (PTC) (Figure 2)."
Limitations: The number of subjects differs by compound (sinigrin uses only a subpopulation).
TAS2R38phenylthiocarbamide shows a haplotype-dependent in vitro response to: supported
Scope: Heterologous expression of the PAV and AVI variants of TAS2R38 with calcium imaging. PROP tested alongside PTC
Micromolar concentrations of PTC raised cytoplasmic calcium in cells expressing the PAV-type receptor in a concentration-dependent manner, and the receptor responded equally strongly to PROP, whereas hTAS2R38-AVI did not respond even to the high concentration of 1 mM of PTC or PROP (this sentence has been checked verbatim against the source).
Limitations: The EC50 values are in Figure 1C but are not given as numbers in the main text, so potency values are not recorded here.
Context: Places the TAS2R38 result in its contemporaneous context and generalizes the design: the authors state that, until their study, the phenylthiocarbamide receptor hT2R38 had been the only gene directly linked to variation in human bitter taste, and go on to report that polymorphisms in 2 further hT2R genes produce different receptor activity and different taste sensitivity to 3 bitter molecules.
Limitations: Does not retest the PAV and AVI variants of TAS2R38; it supports the allele–receptor-activity design rather than Bufe 2005's specific numbers. An abstract-level extraction.