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Isoliquiritigenin Selectively Inhibits H₂ Histamine Receptor Signaling

Division of Molecular and Life Science, System Bio-Dynamics-National Core Research Center, Pohang University of Science and Technology, Pohang, Korea (D.-C.K., S.-H.K., K.-T.K.); Division of Research and Development, Neuronex, Inc., Pohang, Korea (D.-C.K.); Department of Physiology, Seoul National University College of Dentistry, Seoul, Korea (S.-Y.C.); Korea Research Institute of Bioscience and Biotechnology, Yuseong, Daejeon, Korea, (B.-S.Y., I.-D.Y.); and School of Biological Sciences, Nanyang Technological University, Singapore (N.R.P.R., H.S.Y.)

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 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.

Address correspondence to: Dr. Kyong-Tai Kim, Department of Life Science, POSTECH, San 31, Hyoja Dong, Pohang, 790-784, Republic of Korea. E-mail: ktk{at}postech.ac.kr