Stimulation of prostaglandin G/H synthase-2 expression by arachidonic acid monoxygenase product, 14,15-epoxyeicosatrienoic acid.
The relationship between arachidonic acid (AA) mobilization and transcription of immediate-early genes, particularly of prostaglandin G/H synthase-2 (PGHS-2), in intestinal crypt epithelial cells was analyzed. PGHS-2 mRNA and protein synthesis were stimulated by its own substrate, AA; actinomycin D, a transcription inhibitor, prevented the AA-induced increase in PGHS-2 mRNA. Eicosatetraynoic acid, an inhibitor of AA utilization, significantly reduced PGHS-2 mRNA synthesis elicited by AA. Inhibitors of cytochrome P450 monoxygenases, ketoconazole and miconazole, also prevented PGHS-2 mRNA synthesis in a dose-dependent manner. Phenyl chalcone oxide, an epoxide hydrolase inhibitor, potentiated AA-induced PGHS-2 mRNA synthesis. Of the four regioisomers of arachidonic acid epoxides, only 14,15-epoxyeicosatrienoic acid elicited the expression of PGHS-2 in intestinal crypt epithelial cells. This is the first direct evidence of stimulation of an immediate-early gene product, specifically PGHS-2, by an AA epoxygenase metabolite, 14,15-epoxyeicosatrienoic acid, as well as of a heterologous regulation of PGHS-2 synthesis by these monoxygenase products.
Peri
K G
KG
Research Center, Ste. Justine Hospital, Montreal, Canada.
Varma
D R
DR
Chemtob
S
S
D015117:5,8,11,14-Eicosatetraynoic Acid / Q000494:pharmacology; D015126:8,11,14-Eicosatrienoic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases; D002460:Cell Line; D051546:Cyclooxygenase 2; D000072467:Cytochrome P450 Family 2; D003609:Dactinomycin / Q000494:pharmacology; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects*; D007413:Intestinal Mucosa; D007527:Isoenzymes / Q000096:biosynthesis*; D007536:Isomerism; D007700:Kinetics; D006899:Mixed Function Oxygenases; D010105:Oxygenases / Q000378:metabolism; D011451:Prostaglandin-Endoperoxide Synthases / Q000096:biosynthesis*; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D014158:Transcription, Genetic / Q000187:drug effects*
D007527:Isoenzymes; D012333:RNA, Messenger; D015117:5,8,11,14-Eicosatetraynoic Acid; D003609:Dactinomycin; C046782:14,15-epoxy-5,8,11-eicosatrienoic acid; D006899:Mixed Function Oxygenases; D010105:Oxygenases; D001189:Aryl Hydrocarbon Hydroxylases; C033914:Cyp2b19 protein, mouse; D000072467:Cytochrome P450 Family 2; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; D015126:8,11,14-Eicosatrienoic Acid