Regulation of prostaglandin biosynthesis in vivo by glutathione.
Intraperitoneal administration of urate crystals to mice reduced subsequent macrophage conversion of arachidonic acid (AA) to prostaglandins (PGs) and 12-hydroxyeicosatetraenoic acid for up to 6 h. In contrast, levels of 12-hydroxyheptadecatrienoic acid (12-HHT) were markedly elevated. This metabolic profile was previously observed in vitro when recombinant cyclooxygenase (COX) enzymes were incubated with reduced glutathione (GSH). Analysis of peritoneal GSH levels revealed a fivefold elevation after urate crystal administration. The GSH synthesis inhibitor L-buthionine-[S,R]-sulfoximine partially reversed the urate crystal effect on both GSH elevation and PG synthesis. Moreover, addition of exogenous GSH to isolated peritoneal macrophages shifted AA metabolism from PGs to 12-HHT. Urate crystal administration reduced COX-1, but induced COX-2 expression in peritoneal cells. The reduction of COX-1 may contribute to the attenuation of PG synthesis after 1 and 2 h, but PG synthesis remained inhibited up to 6 h, when COX-2 levels were high. Overall, our results indicate that elevated GSH levels inhibit PG production in this model and provide in vivo evidence for the role of GSH in the regulation of PG biosynthesis.
Margalit
A
A
Department of Pharmacology, Searle Research and Development, St. Louis, Missouri 63198, USA.
Hauser
S D
SD
Zweifel
B S
BS
Anderson
M A
MA
Isakson
P C
PC
D019377:12-Hydroxy-5,8,10,14-eicosatetraenoic Acid / Q000096:biosynthesis; D000818:Animals; D016718:Arachidonic Acid / Q000378:metabolism; D019328:Buthionine Sulfoximine / Q000494:pharmacology; D003460:Crystallization; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005231:Fatty Acids, Unsaturated / Q000096:biosynthesis; D005260:Female; D005978:Glutathione / Q000378:metabolism / Q000494:pharmacology*; D005981:Glutathione Synthase / Q000037:antagonists & inhibitors; D007700:Kinetics; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D010084:Oxidation-Reduction; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D011453:Prostaglandins / Q000096:biosynthesis*; D011994:Recombinant Proteins / Q000378:metabolism; D014527:Uric Acid / Q000008:administration & dosage / Q000494:pharmacology
D004791:Enzyme Inhibitors; D005231:Fatty Acids, Unsaturated; D011453:Prostaglandins; D011994:Recombinant Proteins; D014527:Uric Acid; D016718:Arachidonic Acid; C008033:12-hydroxy-5,8,10-heptadecatrienoic acid; D019328:Buthionine Sulfoximine; D019377:12-Hydroxy-5,8,10,14-eicosatetraenoic Acid; D011451:Prostaglandin-Endoperoxide Synthases; D005981:Glutathione Synthase; D005978:Glutathione