title: Cyclo-oxygenase-2 contributes to constitutive prostanoid production in rat kidney and brain.
abstract: Cyclo-oxygenases (COXs) catalyse the synthesis of PGH2 (prostaglandin H2), which serves as the common substrate for the production of PGE2, PGD2, PGF(2alpha), prostacyclin (or PGI2) and TXs (thromboxanes). While COX-1 is the major isoform responsible for prostanoid synthesis in healthy tissues, little information is available on the contribution of constitutive COX-2 to the various prostanoid synthetic pathways under non-inflammatory conditions. To evaluate further the role of COX-2 in prostanoid biosynthesis, rats were acutely treated with the selective COX-1 inhibitor SC-560 [5-(4-chlorophenyl)-1-(4-methoxyphenyl)-3-trifluoromethylpyrazole] or the selective COX-2 inhibitors MF tricyclic [3-(3,4-difluorophenyl)-4-(4-(methylsulphonyl)phenyl)-2-(5H)-furanone] and DFU [5,5-dimethyl-3-(3-fluorophenyl)-4-(4-methylsulphonyl)phenyl-2-(5H)-furanone]. Selected tissues were then processed for a complete analysis of their prostanoid content by liquid chromatography MS. Whereas the treatment with SC-560 caused a 60-70% inhibition in the total prostanoid content of most tissues examined, a significant decrease (35-50%) in total prostanoid content following selective COX-2 inhibition was solely detected for kidney and brain tissues. Analysis of the individual prostanoids reveals significant inhibition of 6-oxo-PGF(1alpha), PGE2, PGD2, PGF(2alpha) and TXB2 in the kidney and inhibition of all these prostanoids with the exception of PGD2 in the forebrain. These results demonstrate that constitutively expressed COX-2 contributes to the production of prostanoids in kidney and brain for each of the PGE2, PGI2 and TXB2 pathways under non-inflammatory conditions. Approaches to modulate inflammation through specific inhibition of terminal synthases, such as mPGES-1 (microsomal PGE2 synthase-1), thus have the potential to differ from COX-2 inhibitors and non-selective non-steroidal anti-inflammatory drugs with regard to effects on constitutive prostanoid synthesis and on renal function.
authors: Department of Biochemistry and Molecular Biology, Merck Frosst Centre for Therapeutic Research, 16711 Trans-Canada Highway, Kirkland, QC, Canada H9H 3L1.
authors: Pierre-Olivier
authors: PO
authors: Hétu
authors: Denis
authors: D
authors: Riendeau
mesh_terms: D000818:Animals; D016718:Arachidonic Acid / Q000378:metabolism; D001921:Brain / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D051545:Cyclooxygenase 1 / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000378:metabolism*; D016861:Cyclooxygenase Inhibitors / Q000378:metabolism; D005663:Furans / Q000494:pharmacology; D007213:Indomethacin / Q000494:pharmacology; D007668:Kidney / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D008297:Male; D011453:Prostaglandins / Q000096:biosynthesis* / Q000378:metabolism; D011720:Pyrazoles / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013379:Substrate Specificity
chemical_list: C106876:5,5-dimethyl-3-(3-fluorophenyl)-4-(4-methylsulfonyl)phenyl-2(5H)-furanone; D016861:Cyclooxygenase Inhibitors; D005663:Furans; D011453:Prostaglandins; D011720:Pyrazoles; C115461:SC 560; C102563:3-(3,4-difluorophenyl)-4-(4-(methylsulfonyl)phenyl)-2(5H)-furanone; D016718:Arachidonic Acid; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D007213:Indomethacin