Polymorphism

Description

In 1931 Fox (1) observed that to some individuals the simple chemical compound phenylthiocarbamide (PTC), has an intensely bitter taste, while to others it is tasteless. Being a chemist he also showed that a number of other closely related substances were tested by the PTC tasters but not by the non-tasters. The ability to taste these substances was shown by Blaklee (2) and by Snyder (3) to behave as a Mendelian dominant character.

Harris and Kalmus (4) showed that the distinction was by no means absolute one, and that reliable results could be obtained only by the use of solutions of known concentration. They devised a method for ascertaining the lowest concentration that could be tasted by each person. They prepared a saturated solution of PTC in distilled water, and from this a series of twofold dilutions. Starting with the weakest solution, the various dilutions are successively presented to the subject until he claims to be able to taste one. Two glasses of this dilution and two of distilled water are then presented, and he is asked to say which are which. If be answers correctly the dilution is taken to mark his threshold, but if he gives the wrong answer the experiment is repeated with the next stronger solution, and so on.

Phenylthiocarbamide structure.

Nearly every population shows a bimodal distribution of thresholds with a clear-cut intermediate dilution level at which few or no thresholds fall. Those who can taste solutions dilute than this critical value are classed as tasters and those whose thresholds fall at below concentration as non- tasters.

The recognition that the substances which define the taster polymorphism are thyroid inhibitors, and that the polymorphism is associated with differences in susceptibility to thyroid diseases has been noted in the literature.

Discussion

To some people the chemical substance phenylthiocarbamide tastes intensely bitter while to others it is almost tasteless. The ability to taste this and a number of other chemically related substances is inherited. There are two genes, T for tasting and t for non-tasting. T is dominant in expression over t. This system was one of the first genetically simple systems to be discovered in man; it has therefore been widely applied in population studies, and there are considerable differences between populations in their taster frequencies.

It will be noticed that the results for the tasting gene parallel in general what has already been observed for the Rh negative and A2 genes, that is, that the European populations tend to differ rather strikingly from Asiatic populations. In both cases there is insufficient information about Africans.

The ability to taste PTC is present in about 70% of the overall human population, varying from 58% for Australoid peoples to 98% for Native American populations. One study has found that non-smokers and those not habituated to coffee or tea have a statistical higher percentage of tasters than the general population. There is conflicting evidence whether a higher percentage of women taste PTC versus men.(5)

It was a matter of considerable interest, of course, to find what the taste reactions of the anthropoid apes would be. This question was investigated by Fisher, Ford, and Huxley in 1939. They found that the chimpanzees in the London zoo showed definite differences in taste threshold for phenyl-thio-carbamide, just as do human beings; since these differences seemed to be consistent and peculiar to the individual, we are doubtless justified in supposing that they are inherited since it is hard to see how they could be the result of conditioning.(6)

Phenylthiocarbamide and all the other synthetic substances which elicit the taster-non-taster phenomenon have thyroid inhibitor properties, some of them have been used therapeutically for this purpose. Certain substances of this class also occur in vegetable foods such as cabbage; epidemics of thyroid disease have many times been caused by excessive consumption of these foods, such as in times of famine. It is not surprising that associations with tasting and non-tasting have been found in thyroid diseases.

Iodine forms part of the molecules of the thyroid hormones, and iodine deficiency is well known as a cause of thyroid disease. Attempts have therefore been made to explain frequency differences in terms of natural selection related to the amounts of iodine and of thiocarbamides in the normal diet. (7)

Distribution

Percentage of "Tasters" in Different Localities

(8,9,10)

Thyroid disease

Phenylthiocarbamide is a thyroid inhibitor, and knowledge of this led Professors Harry Harris and H. Kalmus, and Dr W. R. Trotter, and later Dr F. D. Kitchin and his colleagues, to look for an association between tasting and thyroid diseases.

They and others have shown that there is indeed such as association, for persons with ordinary nodular non-toxic goiters include an excess of non-tasters while those with toxic goiters, and over activity of the thyroid gland, include an excess of tasters. There is some evidence that even in persons who are clinically normal there is a higher frequency of tasters among those with higher thyroid activity, and that tasters tend to develop more rapidly at puberty than non-tasters.

In this system we have a particularly complete picture of the environmental factors involved. As we have seen, the thyroid hormone molecule contains iodine, so that for normal thyroid activity, a certain level of iodine is needed in the diet. Such small quantities of iodine (normally occurring as iodide), are tasteless to all individuals. It is moreover known that unduly high levels of iodine can produce thyrotoxicosis. On the other hand there are often present in the diet, especially in cabbages, thiocarbamide derivatives which are thyroid inhibitors, and which PTC tasters taste as bitter. We may suppose therefore that tasters, but not non-tasters, will limit their intake of such substances, with tasters more liable to thyroid over activity and less to under activity than non-tasters. Since both under activity and over activity can affect fertility and can indeed be fatal, we can envisage a delicately balanced polymorphism of the two allelic: genes, based on the levels of iodine and of thyroid inhibitors in the diet, such that if iodine is deficient or inhibitors in excess tasters will be favored selectively, while if there is an excess of iodine, or a lack of inhibtors, non-tasters will be favored.

Sunderland has drawn attention to a particular case where differences in taster frequency are possibly of practical significance. The geology of north Lancashire and that of Derbyshire are closely similar, with a preponderance of lower Carboniferous limestones and, presumably in both areas, with a deficiency of iodine in the drinking water. Yet simple iodine deficiency goiter is much commoner in Derbyshire ('Derbyshire neck') than in North Lancashire, and this is accompanied by an appreciably higher frequency of tasters in the low-goiter area. On the above selective hypothesis we should expect that the excess of goiter-susceptible non-tasters in Derbyshire would (in the absence of goiter prophylaxis) be gradually reduced, and with it the incidence of goiter would also be lowered.(11)

Propylthiouracil (PTU)

Because there is some toxicity associated with the use of PTC, many researchers have moved over to using the analog Propylthiouracil (PTU).

Propylthiouracil (PTU).

Propylthiouracil (PTU) is a thioamide drug used to treat hyperthyroidism. It is a medicine that is used to decrease the amount of thyroid hormone produced by the thyroid gland. PTU inhibits many steps in the synthesis of thyroid hormones, including the addition of iodide to thyroglobulin, a necessary step in the synthesis of thyroxine, and by inhibiting the enzyme thyroperoxidase which converts T4 to T3.

Notably, PTU does not inhibit the action of the sodium-dependent iodide transporter located on follicular cells' basolateral membranes. Inhibition of this step requires competitive inhibitors such as perchlorate and thiocyanate.

It has long been proposed that there is a relationship between athyreotic hypothyroidism (athyreotic cretinism) and PTC nontasting (12). Both PTC and PROP are structurally similar to the naturally occurring antithyroid substance l-goitrin; all members of this class of chemicals have antithyroidal activity and are not tasted by PTC nontasters. Nearly all individuals with athyreotic hypothyroidism are nontasters.

Genomics

Five haplotypes arising from 3 coding SNPs in the TAS2R38 gene (607751) are associated with distinct phenotypes of phenylthiocarbamide (PTC) taste sensitivity.

The sense of bitter taste is mediated by a group of bitter taste receptor proteins that reside on the surface of taste cells within the taste buds of the tongue. These proteins are 7-transmembrane domain, G protein-coupled receptors that are encoded by the TAS2R gene family, which contains at least 25 functional genes (13).

Genetics of PTC tasting in humans.(a) Scheme of the TAS2R38 receptor and localization of its polymorphic sites. (b) Concentration response curves of the effects of PTC on cells expressing the PAV or AVI does not respond to PTC even in 100-fold higher concentrations. (c) Averaged responses to various concentrations of PTC in subjects homozygous for the PAV and AVI TAS2R38 haplotypes. In line with the receptor function determined in vitro, the subjects homozygous for PAV are very sensitive to PTC, while the variants of TAS2R38. Note that the AVI variant subjects homozygous for AVI are nearly taste-blind.(14)

Blood group associations

Evidence supports a genetic link between the ability to taste PTC and the Kell Blood Group. (15) (16) Bitter taste receptor proteins in the taste buds of the tongue that recognise PTC are encoded on chromosome locus 7 q35-6, and the Kell blood group protein is encoded on nearby chromosome 7 q33.

Links

• OMIM: Thiourea Tasting

References