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 H 2 histamine receptor ( H 2 R) 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 [H-3] 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 beta 2-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.