Participation of epoxygenase activation in saikogenin D-induced inhibition of prostaglandin E(2) synthesis.
We examined the effect of saikogenin D on arachidonic acid metabolism in C6 rat glioma cells to clarify its anti-inflammatory mechanism. Incubation of C6 cells with saikogenin D for 20 min resulted in the inhibition of prostaglandin E(2) production and the accumulation of an arachidonic acid metabolite that was found to be 11,12-dihydroxyeicosatrienoic acid, a metabolite of 11,12-epoxyeicosatrienoic acid. C6 cells expressed rat epoxygenase mRNAs, CYP1A1, CYP2B1 and CYP2J3, which converted arachidonic acid to epoxyeicosatrienoic acids. 11,12-Epoxyeicosatrienoic acid inhibited A23187-induced prostaglandin E(2) production and SKF-525A, an inhibitor of epoxygenase, attenuated the saikogenin D-induced inhibition of prostaglandin E(2) production in C6 cells. Furthermore, 11,12-epoxyeicosatrienoic acid and 11,12-dihydroxyeicosatrienoic acid, but not saikogenin D, inhibited the activity of cyclooxygenase in a cell-free condition. These data suggest that saikogenin D activates epoxygenases that rapidly convert arachidonic acid to epoxyeicosanoids and dihydroxyeicosatrienoic acids, and then the metabolites secondarily inhibit prostaglandin E(2) production.
Toriniwa
Yasufumi
Y
Department of Cellular Signaling, Graduate School of Pharmaceutical Sciences, Tohoku University, Japan.
Lv
Xiaochuan
X
Kodama
Yasuo
Y
Ohizumi
Yasushi
Y
Yoshida
Makoto
M
Nakahata
Norimichi
N
D015126:8,11,14-Eicosatrienoic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D016718:Arachidonic Acid / Q000378:metabolism; D045744:Cell Line, Tumor; D019363:Cytochrome P-450 CYP1A1 / Q000235:genetics / Q000502:physiology*; D019362:Cytochrome P-450 CYP2B1 / Q000235:genetics / Q000502:physiology*; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000502:physiology*; D015232:Dinoprostone / Q000096:biosynthesis*; D004789:Enzyme Activation / Q000187:drug effects; D009828:Oleanolic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology; D010105:Oxygenases / Q000235:genetics / Q000502:physiology*; D011335:Proadifen / Q000494:pharmacology; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats
D000893:Anti-Inflammatory Agents; D012333:RNA, Messenger; D016718:Arachidonic Acid; C009198:saikogenin A; C046783:11,12-epoxy-5,8,14-eicosatrienoic acid; D009828:Oleanolic Acid; D003577:Cytochrome P-450 Enzyme System; D011335:Proadifen; D010105:Oxygenases; C106098:Cyp2j3 protein, rat; D019363:Cytochrome P-450 CYP1A1; D019362:Cytochrome P-450 CYP2B1; D011451:Prostaglandin-Endoperoxide Synthases; D015126:8,11,14-Eicosatrienoic Acid; D015232:Dinoprostone