title: Structure-activity relationships of flavonoids as potential inhibitors of glycogen phosphorylase.
abstract: Flavonoids are ubiquitous components in vegetables, fruits, tea, and wine. Therefore, they are often consumed in large quantities in our daily diet. Several flavonoids have been shown to have potential as antidiabetic agents. In the present study, we focused on inhibition of glycogen phosphorylase (GP) by flavonoids. 6-Hydroxyluteolin, hypolaetin, and quercetagetin were identified as good inhibitors of dephosphorylated GP (GPb), with IC 50 values of 11.6, 15.7, and 9.7 microM, respectively. Furthermore, a structure-activity relationship study revealed that the presence of the 3' and 4' OH groups in the B-ring and double bonds between C2 and C3 in flavones and flavonols are important factors for enzyme recognition and binding. Quercetagetin inhibited GPb in a noncompetitive manner, with a K i value of 3.5 microM. Multiple inhibition studies by Dixon plots suggested that quercetagetin binds to the allosteric site. In primary cultured rat hepatocytes, quercetagetin and quercetin suppressed glucagon-stimulated glycogenolysis, with IC 50 values of 66.2 and 68.7 microM, respectively. These results suggested that as a group of novel GP inhibitors, flavonoids have potential to contribute to the protection or improvement of control of diabetes type II.
authors.affiliation: Department of Hospital Pharmacy, University of Toyama, Toyama 930-0194, Japan. kato@med.u-toyama.ac.jp
authors.forename: Atsushi
authors.initials: A
authors.lastname: Kato
authors.forename: Norio
authors.initials: N
authors.lastname: Nasu
authors.forename: Kenji
authors.initials: K
authors.lastname: Takebayashi
authors.forename: Isao
authors.initials: I
authors.lastname: Adachi
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Minami
authors.forename: Fujiko
authors.initials: F
authors.lastname: Sanae
authors.forename: Naoki
authors.initials: N
authors.lastname: Asano
authors.forename: Alison A
authors.initials: AA
authors.lastname: Watson
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Nash
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D005419:Flavonoids / Q000737:chemistry* / Q000494:pharmacology*; D005934:Glucagon / Q000494:pharmacology; D024981:Glycogen Phosphorylase / Q000037:antagonists & inhibitors*; D050261:Glycogenolysis / Q000187:drug effects; D022781:Hepatocytes / Q000201:enzymology; D008297:Male; D011794:Quercetin / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D013329:Structure-Activity Relationship
chemical_list: D004791:Enzyme Inhibitors; D005419:Flavonoids; D005934:Glucagon; D011794:Quercetin; D024981:Glycogen Phosphorylase