Denatonium benzoate (THS-839)

Human intestinal bitter taste receptors regulate innate immune responses and metabolic regulators in obesity

Bitter taste receptors (taste 2 receptors, TAS2Rs) serve as warning sensors in the lingual system against the ingestion of potentially poisonous food. Here, we investigated the functional role of TAS2Rs in the human gut and focused on their potential to trigger an additional host defense pathway in the intestine. Human jejunal crypts, especially those from individuals with obesity, responded to bitter agonists by inducing the release of antimicrobial peptides (α-defensin 5 and regenerating islet-derived protein 3 α [REG3A]) but also regulated the expression of other innate immune factors (mucins, chemokines) that affected E. coli growth. We found that the effect of aloin on E. coli growth and on the release of the mucus glycoprotein CLCA1, identified via proteomics, was affected by TAS2R43 deletion polymorphisms and thus confirmed a role for TAS2R43. RNA-Seq revealed that denatonium benzoate induced an NRF2-mediated nutrient stress response and an unfolded protein response that increased the expression of the mitokine GDF15 but also ADM2 and LDLR, genes that are involved in anorectic signaling and lipid homeostasis. In conclusion, TAS2Rs in the intestine constitute a promising target for treating diseases that involve disturbances in the innate immune system and body weight control. TAS2R polymorphisms may be valuable genetic markers to predict therapeutic responses.

Denatonium benzoate bitter taste perception in chronic rhinosinusitis subgroups

Background: Chronic rhinosinusitis (CRS) with nasal polyps (CRSwNP) and CRS without nasal polyps (CRSsNP), and aspirin-exacerbated respiratory disease (AERD) have varying levels of inflammation and disease severity. Solitary chemosensory cells (SCCs) are enriched in nasal polyps, are the primary source of interleukin 25 (IL-25) in upper airways, leading to type 2 inflammation, and are activated by bitter-tasting denatonium benzoate (DB). Thus, we sought to evaluate DB taste perception at a range of concentrations in order to identify 1 that most differentiates CRS subgroups from controls.
Methods: CRSsNP (n = 25), CRSwNP (n = 26), and AERD (n = 27) patients as well as controls (n = 25) tasted 6 DB concentrations in a fixed, random order, rating on a category scale of 0 (no intensity) to 12 (extremely intense). Sinonasal epithelial cultures were treated with and without denatonium and analyzed for IL-25 via flow cytometry.
Results: CRSsNP patients rated DB as significantly less intense than did controls at all concentrations: 5.62 × 10^-9 M, 1.00 × 10^-8 M, 1.78 × 10^-8 M, 3.16 × 10^-8 M, 5.62 × 10^-8 M, and 1.00 × 10^-7 M (all p < 0.0083). CRSwNP patients did not show significant differences from controls. AERD patients rated DB as significantly more intense than did controls at concentrations of 1.00 × 10^-8 M and 3.16 × 10^-8 M (p < 0.0083). In vitro data demonstrated significant increase in IL-25-positive cells after denatonium stimulation (n = 5), compared to control (n = 5) (p = 0.012).
Conclusion: Our findings link in vitro DB stimulation of sinonasal tissue with increased IL-25 and show differential DB taste perception in CRS subgroups relative to the control group, with CRSsNP being hyposensitive and AERD being hypersensitive. We propose a concentration of 3.16 × 10^-8 M for future study of clinical utility.

Denatonium benzoate: review of efficacy and safety

The efficacy and toxicity studies on denatonium benzoate are limited and may be subject to varying interpretations when viewed in the context of a potential poisoning situation. Efficacy studies to date in children have shown that in a controlled environment, addition of denatonium benzoate to an otherwise palatable liquid will decrease the volume ingested. Important considerations include the fact that the number of studies are small (two utilizing orange juice as the liquid; one using a dilute liquid detergent), and these studies involved single-test situations wherein the liquid was available to the child for a limited period of time. Inadequate data are available to analyze one orange juice study and in the other study, 7 of 30 children took more than one swallow. Depending on the "pleasantness" of the liquid (color, smell, similarity to 'drinkable' liquids in appearance) prior to addition of denatonium, it is possible that children may take more than one swallow. Toxicity data indicate a low toxicity profile. However, there are significant gaps in our knowledge, especially relating to chronic toxicity in humans, teratogenicity, and human hypersensitivity potential. The role of denatonium benzoate in preventing serious poisonings has yet to be defined. Aversive agents such as denatonium should augment but not replace proven methods of poison prevention including parental education and child-resistant closures. When selecting products for inclusion of denatonium benzoate, consideration should be given to the inherent toxicity of the product as well as the potential for long-term human exposure.(ABSTRACT TRUNCATED AT 250 WORDS)

The effect of adulteration with a bitter tastant, denatonium benzoate, on the reinforcing value of sucrose

According to the Multiplicative Hyperbolic Model of reinforcer value (MHM), the value of a reinforcer is an increasing hyperbolic function of its size (q). A recent experiment examined the effect of adulterating a sucrose solution with citric acid on the value of a sucrose reinforcer. In contrast to expectations derived from MHM, the effect of citric acid was consistent with the summation of positive (sucrose) and negative (citric acid) values. The present experiment extended these observations to a bitter tastant, denatonium benzoate (DB). Rats were trained under an adjusting-magnitude schedule in which a response on lever B delivered a fixed volume of a sucrose/DB mixture, while a response on lever A delivered a sucrose solution, the volume of which, q_A, was adjusted according to the rats' choices. When B was preferred in a given block of trials, q_A was increased in the following block; when A was preferred, q_A was reduced in the following block. q_B was varied across five phases of the experiment and the corresponding indifference magnitudes of A were measured. The results indicated that, as was the case with citric acid, the value of the mixture reflected the summation of positive (sucrose) and negative (DB) values.

Denatonium benzoate as a deterrent to ingestion of toxic substances: toxicity and efficacy

When ingested at 10 ppm by human beings, denatonium benzoate has an extremely bitter, unpleasant taste. The addition of denatonium benzoate to liquid dish detergents and orange juice reduces the amount ingested by children. The toxicity of denatonium benzoate is low with acute po LD50's in rats of 485-740 mg/kg. The use of bittering agents, such as denatonium benzoate, could reduce the ingestion of toxic substances by dogs, cats, other animals and children and warrants further investigation.