Arachidonic acid metabolism of cultured peritoneal rat macrophages and its manipulation by nonsteroidal antiinflammatory agents.
[3H]Arachidonic acid (AA) metabolism by cultured rat peritoneal macrophages (M phi) was examined. Ninety percent of incorporated [3H]AA localized in phospholipids (phosphatidylcholine, 30%; phosphatidylinositol, 23.9%; phosphatidylethanolamine, 23.7%) whereas 8.3% and 1.5% was found in the free fatty acid and neutral lipid fractions. 12-O-tetradecanoate phorbol-13-acetate (TPA) induced the reduction of label from phosphatidylcholine, phosphatidylinositol and phosphatidylethanolamine (42%, 46% and 47%, respectively) and an accumulation of label into free fatty acids (34%) or neutral lipid (61%) fractions. Simultaneously, 12% of the incorporated label was released into the medium as [3H]6-keto prostaglandin (PG)F1 alpha, [3H]thromboxane B2 (TxB2), [3H]PGE2, [3H]hydroxyheptadecanoic acid (HHT), [3H]15-hydroxyeicosatetraenoic acid (HETE), [3H]12-HETE and [3H]AA. Exposure to 0.3-3 microM indomethacin reduced TPA-induced label release into the medium which was distinguished by dose-dependent reductions in all [3H]prostanoids as well as [3H]15- and [3H]12-HETE and a reciprocal increase in [3H]AA. Nordihydroguaiaretic acid (NDGA) altered AA metabolism at concentrations which approached its toxic dose (greater than 20 microM). Cells exposed to 10 microM NDGA reduced TPA-induced label release into the medium which was characterized by reductions in [3H]-TxB2, [3H]PGE2 and [3H]HHT, no change in [3H]15-HETE, [3H]12-HETE or [3H]AA and the appearance of [3H]PGF2 alpha. Cellular label redistributions of lipid fractions in cells exposed to NDGA or indomethacin were significantly less than that of control cultures indicating inhibition of acylhydrolase activity. Indomethacin or NDGA, therefore modify AA metabolism of cultured rat M phi by influencing more than one target enzyme.
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D016718:Arachidonic Acid; D001095:Arachidonic Acids / Q000378:metabolism*; D002478:Cells, Cultured; D007213:Indomethacin / Q000494:pharmacology; D008264:Macrophages / Q000378:metabolism*; D008297:Male; D009637:Masoprocol / Q000494:pharmacology; D011453:Prostaglandins / Q000096:biosynthesis; D051381:Rats; D011919:Rats, Inbred Strains; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology
D000894:Anti-Inflammatory Agents, Non-Steroidal; D001095:Arachidonic Acids; D011453:Prostaglandins; D016718:Arachidonic Acid; D009637:Masoprocol; D013755:Tetradecanoylphorbol Acetate; D007213:Indomethacin