Mechanism of peroxisome proliferator-activated receptor gamma (PPARγ) transactivation by hesperetin glucuronides is distinct from that by a thiazolidine-2,4-dione agent.
Hesperidin, a flavanone glycoside present abundantly in citrus fruits, is predominantly metabolized to hesperetin-7-O-β-D-glucuronide (H7-OG) and hesperetin-3'-O-β-D-glucuronide (H3'-OG), which exhibit partial agonistic activity towards peroxisome proliferator-activated receptor gamma (PPARγ). Here, in order to understand the mechanism(s) of action of PPARγ transactivation elicited by hesperetin glucuronides, we compared the transactivation activities of PPARγ (ligand-binding domain (LBD)) mutants by hesperetin glucuronides and troglitazone, a thiazolidine-2,4-dione class PPARγ full agonist. The assay results indicated that the mechanisms of activation of PPARγ by hesperetin glucuronides and by troglitazone are distinct, probably due to a difference in the binding sites of these compounds on the PPARγ LBD. Flavanone-class PPARγ partial agonists, luteolin and hesperetin glucuronides, showed similar activation profiles of the PPARγ LBD mutants, even though they have different side chain functionalities.
Department of Pharmaceutical Sciences, Graduate School of Medicine, Dentistry and Pharmaceutical  Sciences, Okayama University.
Kanae
K
Gamo
Takuma
T
Shiraki
Nobuyasu
N
Matsuura
Hiroyuki
H
Miyachi
D000818:Animals; D001665:Binding Sites / Q000187:drug effects; D019556:COS Cells; D002478:Cells, Cultured; D002522:Chlorocebus aethiops; D006569:Hesperidin / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D047495:PPAR gamma / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D013329:Structure-Activity Relationship; D045162:Thiazolidinediones / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
D047495:PPAR gamma; D045162:Thiazolidinediones; C500090:thiazolidine-2,4-dione; D006569:Hesperidin; C013015:hesperetin