Inverse Agonistic Activity of Antihistamines and Suppression of Histamine H1 Receptor Gene Expression

Abstract

Pollinosis is a seasonal allergic rhinitis caused by hypersensitivity to tree or grass pollens, which affects more than 36 million people in the U.S. and about 16% of the Japanese population (1, 2). Histamine is a major chemical mediator involved in allergic reactions. Its actions are mainly mediated by the histamine H 1 receptor (H1R) and H1R activation results in the symptoms of allergic rhinitis.It has been reported that expression of H1R mRNA is increased in patients with allergic rhinitis (3,4). We have demonstrated that intranasal application of toluene-2,4-diisocyanate (TDI) induces histamine release from mast cells via neurogenic inflammation and causes nasal hypersensitivity in rats (5), with H1R expression being up-regulated at both the mRNA and protein levels in the nasal mucosa of TDI-sensitized rats (6). We have also demonstrated that the level of H1R expression is strongly correlated with the severity of allergy symptoms in TDIsensitized rats and in patients with pollinosis (7), while agents that suppress H1R gene up-regulation alleviate allergy symptoms (8, 9). These findings, combined with the report that the strength of H1R signaling depends on the level of expression of this receptor (10), suggest that H1R is an allergy-sensitive gene and that its expression influences the severity of allergy symptoms. Therefore, drugs targeting the signaling pathway involved in histamine-induced up-regulation of H1R gene expression could be useful for treating allergic diseases.Antihistamines are widely employed as the first-line treatment for nasal symptoms of pollinosis because these drugs are thought to antagonize histamine and prevent it from binding to the H1R. According to the two-state model, however, the active and inactive states of a receptor exist in equilibrium, so antihistamines could act as inverse agonists that combine with and stabilize the inactive form of H1R to shift the equilibrium toward the inactive state and down-regulate constitutive receptor activity, even in the absence of histamine (11). Therefore, antihistamines might not only antagonize histamine by blocking its binding with the H1R, but could also suppress constitutive H1R activity. Although the clinical importance of constitutive activity has not been clarified, it can be hypothesized that inverse agonists would more potently alleviate allergic symptoms than neutral antagonists by inhibiting constitutive activity. However, the influence of the inverse agonistic activity of antihistamines on H1R gene expression has not been evaluated.We previously demonstrated that histamine stimulates up-regulation of H1R gene expression in HeLa cells that endogenously express this receptor (6). In the present study, we examined the effect of inverse agonists on upregulation of H1R gene expression by HeLa cells. Our Tokushima 770-8505, Japan Received September 29, 2011; Accepted November 15, 2011 Abstract. Histamine H 1 receptor (H1R) expression influences the severity of allergy symptoms. We examined the effect of inverse agonists on H1R g...

Maackiain is a novel antiallergic compound that suppresses transcriptional upregulation of the histamine H1 receptor and interleukin‐4 genes

“…However, nowadays, it is considered that antihistamines act as inverse agonists and antagonize histamine by blocking its binding with the H1R and suppress constitutive H1R activity (Simons ; Mizuguchi et al. ). Recently, we reported that the H1R gene expression strongly correlated with the severity of allergic symptoms in toluene‐2,4‐diisocyanate (TDI)‐sensitized allergy model rats and patients with pollinosis (Mizuguchi et al.…”

Suppression of IFN-g Production in Murine Splenocytes by Histamine Receptor Antagonists

“…Among the compounds tested here, pyrilamine and diphenhydramine exhibited relatively strong effects. Because previous studies have indicated that several H1 antagonists including pyrilamine could function as inverse agonists [26][27][28][29], we verified this possibility using the Hh1r -/mice. Previous studies demonstrated that H1 receptors should be involved in promotion of Th1 responses including IFN-γ production [8,15].…”

Elucidation of Inverse Agonist Activity of Bilastine

“…Therefore, HeLa cells are useful to evaluate inverse agonist activity of H 1 -antihistamines. Using HeLa cell system, we have reported that carebastine, mepyramine, fexofenadine, cetirizine, chlorpheniramine, diphenhydramine, and epinastine were inverse agonists and oxatomide, loratadine, and olopatadine were neutral antagonists [9][10][11]. According to our previous data, we selected fexofenadine and levocetirizine as controls of inverse agonists, and olopatadine and oxatomide as controls of neutral antagonists.…”

“…We showed that levocetirizine, which is a piperazine derivative, is an inverse agonist, while, oxatomide, which belongs to the same group as levocetirizine, is a neutral antagonist. In addition, we reported that mepyramine, diphenhydramine, and chlorpheniramine (belongs to ethylamines, ethanolamines, and alkylamines, respectively) are also inverse agonists [9][10][11]. Thus, it is difficult to explain which structures contribute to inverse agonist activity of H 1 -antihistamines.…”

“…Therefore, H 1 -antihistamines with inverse agonist activity are more potent than neutral antagonists, as they suppress this intrinsic signal in addition to the H 1 -antihistamine effect. Recently, we have demonstrated that HeLa cells expressing H1R endogenously are useful to assess inverse activity of H 1 -antihistamines [9][10][11].…”