Isoliquiritigenin selectively inhibits H₂ histamine receptor signaling

Isoliquiritigenin, one of the major constituents of Glycyrrhiza uralensis (licorice), is a natural pigment with a simple chalcone structure 4,2′,4′-trihydroxychalcone. In this study, isoliquiritigenin showed selective H₂ histamine receptor (H₂R) antagonistic effect and remarkably reduced several H₂R-mediated physiological responses. Preincubation of U937 and HL60 hematopoietic cells with isoliquiritigenin significantly inhibited H₂R agonist-induced cAMP response in a concentration-dependent manner without affecting the viability of cells. Isoliquiritigenin also blocked the binding affinity of [³H]tiotidine to membrane receptors in HL-60 cells. Isoliquiritigenin did not affect the elevation of cAMP levels induced by cholera toxin, forskolin, or isoproterenol, indicating that the action site of isoliquiritigenin is not G_s protein, effector enzyme, adenylyl cyclase, or β₂-adrenoceptor. Isoliquiritigenin affected neither H₁R- nor H₃R-mediated signaling. In molecular docking studies, isoliquiritigenin exhibited more favorable interactions with H₂R than histamine. Isoliquiritigenin prominently inhibited H₂R selective agonist dimaprit-induced cAMP generation in MKN-45 gastric cancer cell. Moreover, isoliquiritigenin reduced gastric acid secretion and protected gastric mucosal lesion formation in pylorus-ligated rat model. Taken together, the results demonstrate that isoliquiritigenin is an effective H₂R antagonist and provides the basis for designing novel H₂R antagonist.