REGULATION OF PROSTAGLANDIN BIOSYNTHESIS IN-VIVO BY GLUTATHIONE

Intraperitoneal administration of urate crystals to mice reduced subse quent 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 (18-HHT) were markedly ele vated. This metabolic profile was previously observed in vitro when re combinant cyclooxygenase (COX) enzymes were incubated with reduced glu tathione (GSH). Analysis of peritoneal GSH levels revealed a fivefold elevation after urate crystal administration, The GSH synthesis inhibi tor L-buthionine-[S,R]-sulfoximine partially reversed the urate crysta l effect on both GSH elevation and PG synthesis. Moreover, addition of exogenous GSH to isolated peritoneal macrophages shifted AP, metaboli sm 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 hig h. Overall, our results indicate that elevated GSH levels inhibit PG p roduction in this model and provide in vivo evidence for the role of G SH in the regulation of PG biosynthesis.