Variability in a taste-receptor gene determines whether we taste toxins in food
2006; Elsevier BV; Volume: 16; Issue: 18 Linguagem: Inglês
10.1016/j.cub.2006.08.049
ISSN1879-0445
Autores Tópico(s)Advanced Chemical Sensor Technologies
ResumoTAS2R bitter receptors are thought to have evolved to detect toxins in plants and foods and to modulate ingestion of them [1Mueller K.L. Hoon M.A. Erlenbach I. Chandrashekar J. Zuker C.S. Ryba N.J.P. The receptors and coding logic for bitter taste.Nature. 2005; 434: 225-229Crossref PubMed Scopus (365) Google Scholar]. Indeed, virtually every plant, edible or otherwise, contains toxins. Although this toxin-detector hypothesis of bitter taste is prevalent, there is no indication that TAS2R receptors detect specific toxins enmeshed within natural foods, a necessary link for the natural selection argument. Several expressed TAS2R receptors, however, are known to respond to pure solutions of toxins. For example, some variants of the antithyroid-toxin receptor hTAS2R38 respond to phenylthiocarbamide (PTC) and propylthiouracil (PROP) [2Bufe B. Breslin P.A.S. Kuhn C. Reed D.R. Tharp C.D. Slack J.P. Kim U.-K. Drayna D. Meyerhof W. The molecular basis of individual differences in phenylthiocarbamide and propylthiouracil bitterness perception.Curr. Biol. 2005; 15: 322-327Abstract Full Text Full Text PDF PubMed Scopus (494) Google Scholar, 3Kim U.-K. Jorgenson E. Coon H. Leppert M. Risch N. Drayna D. Positional cloning of the human quantitative trait locus underlying taste sensitivity to phenylthiocarbamide.Science. 2003; 299: 1221-1225Crossref PubMed Scopus (623) Google Scholar], compounds which contain a thiourea (N-C=S) moiety. We report here that genotypes of hTAS2R38 specifically determine humans' bitterness perception of plants that synthesize glucosinolates, a class of anti-thyroid compounds that also contain the thiourea moiety. The natural selection argument for detecting thyroid toxins in plants is supported by data in which sensitivity to PTC was shown to be associated with decreased risk of both goiter (thyroid enlargement) and central neural defects in an Andean community with endemic goiter; no such association was found in a neighboring community that was treated en masse with iodine injections [4Greene L.S. Physical growth and development, neurological maturation, and behavioral functioning in two Ecuadorian Andean communities in which goiter is endemic: II. PTC sensitivity and neurological maturation.Am. J. Phys. Anthrop. 1974; 41: 139-152Crossref PubMed Scopus (26) Google Scholar]. Endemic goiter arises under conditions of low iodine ingestion as an adaptive response to maintain levels of thyroid hormones, which incorporate inorganic iodine in a process facilitated by thyroid peroxidase [5Ermans A.M. Disorders of iodine deficiency: Endemic goiter.in: Werner S.C. Ingbar S.H. The Thyroid: A Fundamental and Clinical Text. Harper and Row, Publishers, Inc., New York1978: 537-553Google Scholar]. Ingestion of glucosinolates in plants exacerbates the hormone problem by inhibiting thyroid peroxidase activity, as well as blocking active transport of iodide into the thyroid [6Green W.L. Mechanisms of action of antithyroid compounds.in: Werner S.C. Ingbar S.H. The Thyroid: A Fundamental and Clinical Text. Fourth Edition. Harper and Row, Publishers, Inc., New York1978: 77-87Google Scholar]. Thus, one would expect that the expression of a ‘sensitive’ allele of hTAS2R38 would convey an important reproductive advantage to individuals in such environments. The most common sensitive allele of hTAS2R38 is labeled PAV and the insensitive allele is AVI after amino acid identities at positions 49, 262, and 296 [3Kim U.-K. Jorgenson E. Coon H. Leppert M. Risch N. Drayna D. Positional cloning of the human quantitative trait locus underlying taste sensitivity to phenylthiocarbamide.Science. 2003; 299: 1221-1225Crossref PubMed Scopus (623) Google Scholar]. While PTC is the ‘defining’ ligand for the PAV-hTAS2R38 receptor, it is a synthetic antithyroid medicine and does not occur in nature. However, many Cruciferous vegetables of the geni Brassica, Raphanus, and Nasturtium, such as kale, radish, and watercress respectively, are well known to contain PTC-like glucosinolates [7Fahey J.W. Zalcmann A.T. Talalay P. The chemical diversity and distribution of glucosinolates and isothiocyanates among plants.Phytochemistry. 2001; 56: 5-51Crossref PubMed Scopus (2036) Google Scholar]. Here we divided a large test array of foods into glucosinolate-containing vegetables and those vegetables that lack known glucosinolates based on the extant literature and asked subjects to rate them all for bitterness (see the Supplemental data available on line with this issue, in particular Tables S1–3, Figure S2 and the experimental procedures) [7Fahey J.W. Zalcmann A.T. Talalay P. The chemical diversity and distribution of glucosinolates and isothiocyanates among plants.Phytochemistry. 2001; 56: 5-51Crossref PubMed Scopus (2036) Google Scholar]. Overall, sensitive (PAV/PAV) subjects rated the glucosinolate-generating vegetables as 60% more bitter than did the insensitive (AVI/AVI) subjects, while these two genotype groups found the nonglucosinolate-generating vegetables equally bitter overall (Figure 1 A,B). Heterozygotic subjects (PAV/AVI) gave intermediate results, as expected [2Bufe B. Breslin P.A.S. Kuhn C. Reed D.R. Tharp C.D. Slack J.P. Kim U.-K. Drayna D. Meyerhof W. The molecular basis of individual differences in phenylthiocarbamide and propylthiouracil bitterness perception.Curr. Biol. 2005; 15: 322-327Abstract Full Text Full Text PDF PubMed Scopus (494) Google Scholar] (Figure 1A). All three genotype groups differed significantly from each other in their perception of the glucosinolate vegetables, but not for the non-glucosinolates. Without exception, every individual glucosinolate-producing vegetable was rated as more bitter by the PAV/PAV than the AVI/AVI subjects (Figure 1C). The difference in ratings reached significance for six of these vegetables: watercress, mustard greens, turnip, broccoli, rutabaga and horseradish (p < 0.05) (Figure 1C). Consistent with their intermediate sensitivity, heterozygous PAV/AVI subjects rated glucosinolate vegetables as more bitter than did AVI/AVI subjects for a clear majority of species but not all of them, one of which reached significance: watercress (p < 0.05) (Supplemental data, Figure S1A). In contrast, neither of the PAV-genotype groups rated non-glucosinolate vegetables as more bitter than did the AVI/AVI group with the intriguing exception of dandelion greens (Figure 1D and Supplemental data, Figure S1B and inset). At present dandelion is not known to contain glucosinolates. Among cruciferous vegetables the ratios of bitterness ratings between homozygous PAV and AVI subjects were greatest for rutabaga and turnip, and smallest for cabbage, which suggests that rutabaga and turnip contain the most specific ligands for the PAV-hTAS2R38 receptor (Figure 1C, black-to-white bar ratios). These observations correspond well with the inhibition of radioactive iodine (I131) uptake into thyroids of living humans after single vegetable meals. Meals consisting only of rutabaga or turnip very strongly inhibited iodine uptake by the thyroid, while cabbage meals inhibited iodine uptake only weakly [8Greer M.A. Astwood E.B. The antithyroid effect of certain foods in man as determined with radioactive iodine.Endocrinology. 1948; 43: 105-119Crossref PubMed Scopus (17) Google Scholar]. The agreement between which vegetables activate bitterness via the PAV-hTAS2R38 receptor and the capacity of these vegetables to inhibit iodine uptake supports the idea that the human TAS2R38 receptor responds to thyroid toxins proportionately to their anti-thyroid activity. The approximately two hundred TAS2R alleles that humans possess should detect the thousands of toxins encountered in our evolutionary diet, but little is known of the relationships between diet, toxin, and receptors [1Mueller K.L. Hoon M.A. Erlenbach I. Chandrashekar J. Zuker C.S. Ryba N.J.P. The receptors and coding logic for bitter taste.Nature. 2005; 434: 225-229Crossref PubMed Scopus (365) Google Scholar, 9Kim U.-K. Breslin P.A.S. Reed D. Drayna D. Genetics of human taste perception.J. Dent. Res. 2004; 83: 448-453Crossref PubMed Scopus (111) Google Scholar, 10Kim U.-K. Wooding S. Ricci D. Jorde L.B. Drayna D. Worldwide haplotype diversity and coding sequence variation at human bitter taste receptor loci.Hum. Mut. 2005; 26: 199-204Crossref PubMed Scopus (165) Google Scholar]. Presently, vegetable bitterness ratings were related to hTAS2R38 genotypes and the synthesis of glucosinolate toxins by Brassicaceae vegetables specifically. Glucosinolates in our vegetables block the formation of organic iodine and the transport of iodine into the thyroid, resulting in both retarded sexual maturation as well as mental retardation in low iodine regions [11Bourdoux P. Delange F. Gerard M. Mafuta M. Hanson A. Ermans A.M. Evidence that cassava ingestion increases thiocyanate formation: A possible etiologic factor in endemic goiter.J. Clin. Endocrinol. Met. 1978; 46: 613-621Crossref PubMed Scopus (68) Google Scholar, 12Clements F.W. Wishart J.W. A thyroid-blocking agent in the etiology of endemic goiter.Clin. Exp. Met. 1956; 5: 623-639Google Scholar]. Despite the existence of modern diets, over one billion people are presently at risk of thyroid insufficiency, which creates a strong selective pressure to detect these compounds in our diet and minimize their intake especially in low iodine regions [12Clements F.W. Wishart J.W. A thyroid-blocking agent in the etiology of endemic goiter.Clin. Exp. Met. 1956; 5: 623-639Google Scholar, 13Previc F.H. Thyroid hormone production in chimpanzees and humans: Implications for the origins of human intelligence.Am. J. Phys. Anthrop. 2002; 118: 402-403Crossref PubMed Scopus (18) Google Scholar]. This study demonstrates the importance of individual human taste gene alleles for the perception of food and illustrates how possession of even a single allele of a bitter taste receptor gene may greatly impact how a sub-population perceives an entire family of vegetables. The editors of Current Biology welcome correspondence on any article in the journal, but reserve the right to reduce the length of any letter to be published. All Correspondence containing data or scientific argument will be refereed. Queries about articles for consideration in this format should be sent by e-mail to [email protected] We thank Suzanne M. Alarcon and Nelsa Estrella for their technical help during the study. We also thank Danielle Reed for help with pilot testing and selected genotyping. This work was supported by grants from NIH DC02995 and P50 DC06760 to P.A.S.B. Download .pdf (.49 MB) Help with pdf files Document S1. Supplemental Experimental Procedures
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