Extraoral bitter taste receptors as mediators of off‐target drug effects

Abstract

We present a novel hypothesis that could explain many off-target effects of diverse pharmaceuticals. Specifically, we propose that any drug with a bitter taste could have unintended actions in the body through stimulation of extraoral type 2 taste receptors (T2Rs). T2Rs were first identified in the oral cavity, where they function as bitter taste receptors. However, recent findings indicate that they are also expressed outside the gustatory system, including in the gastrointestinal and respiratory systems. T2R ligands include a diverse array of natural and synthetic compounds, many of which are toxins. Notably, many pharmaceuticals taste bitter, with compounds such as chloroquine, haloperidol, erythromycin, procainamide, and ofloxacin known to activate T2Rs. Bitter-tasting compounds can have specific physiological effects in T2R-expressing cells. For example, T2Rs are found in some gastrointestinal endocrine cells, including those that secrete the peptide hormones (e.g., ghrelin and glucagon-like peptide-1) in response to stimulation by bitter-tasting compounds. In the respiratory system, stimulation of T2Rs expressed in respiratory epithelia and smooth muscle has been implicated in protective airway reflexes, ciliary beating, and bronchodilation. If our hypothesis is confirmed, it would offer a new paradigm for understanding the off-target actions of diverse drugs and could reveal potential new therapeutic targets.

Antidepressant-like Activity of Andrographis paniculata in Type-2 Diabetic Rats

“…Therefore, it seems reasonable to assume that high efficacies of AP and andrographolide observed in our studies could as well be due to its regulatory effects on gut microbial ecology and enteric nervous system. That such could indeed be the case is suggested also by the fact that andrographolide and other constituents of possess antibacterial and antiviral activities and that andrographolide and its structural analogues present in AP are extremely bitter substance with high affinity to specific bitter receptors present also in the entire gastrointestinal tract and other organs [60,61]. It has been reported also that andrographolide forms strong covalent bonds with endogenous thiols and macromolecules involved in regulation of oxidative and other processes leading to metabolic disturbances [62].…”

Expression and Functional Activity of the Bitter Taste Receptors TAS2R1 and TAS2R38 in Human Keratinocytes

“…Previously, Clark et al [15] have speculated that TAS2Rs might be expressed in other extraoral tissues apart from the respiratory and gastrointestinal endocrine cells. In the present study, TAS2R1 and TAS2R38 protein expression was determined for the first time in human keratinocytes, both in situ in the skin and in cultured cells.…”

Amino Acid Derivatives as Bitter Taste Receptor (T2R) Blockers

“…Most of the drugs used in various disease conditions are bitter and have off-target effects. Recent studies have shown that T2Rs play a key role in these off-target effects as these drugs can activate T2Rs (40). Highly potent bitter blockers can be used to reduce the side effects of bitter drugs.…”