Department of Anatomy and Neurobiology, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
FASEB J. 2012 Dec;26(12):4827-31. doi: 10.1096/fj.12-215087. Epub 2012 Sep 10.
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.
我们提出了一个新的假说，可以解释许多不同药物的非靶向效应。具体来说，我们提出任何具有苦味的药物都可能通过刺激口腔外的 2 型味觉受体（T2R）在体内产生意想不到的作用。T2R 最初在口腔中被发现，在那里它们作为苦味受体发挥作用。然而，最近的研究结果表明，它们也在味觉系统之外表达，包括在胃肠道和呼吸系统中。T2R 的配体包括各种各样的天然和合成化合物，其中许多是毒素。值得注意的是，许多药物具有苦味，已知氯喹、氟哌啶醇、红霉素、普鲁卡因胺和氧氟沙星等化合物可激活 T2R。苦味化合物在表达 T2R 的细胞中具有特定的生理效应。例如，T2R 存在于一些胃肠道内分泌细胞中，包括那些对苦味化合物刺激分泌肽激素（如胃饥饿素和胰高血糖素样肽-1）的细胞。在呼吸系统中，刺激表达在呼吸上皮和平滑肌中的 T2R 被认为与保护性气道反射、纤毛运动和支气管扩张有关。如果我们的假说是正确的，它将为理解各种药物的非靶向作用提供一个新的范例，并可能揭示潜在的新治疗靶点。
