Regulation of eicosanoid biosynthesis in vitro and in vivo by the marine natural product manoalide: a potent inactivator of venom phospholipases.
The marine natural produce manoalide has been reported to inactivate venom phospholipase A2 from several sources and phospholipase A2 from polymorphonuclear leukocytes. In this investigation, the regulation of eicosanoid production was studied both in an in vitro and in an in vivo model. The release of arachidonic acid and prostaglandin E2 was inhibited by manoalide when cultured mouse peritoneal macrophages were stimulated with phorbol myristate acetate (apparent IC50 = 0.23 microM), calcium ionophore A23187 (apparent IC50 = 0.23 microM) and zymosan (apparent IC50 = 0.18 microM). Leukotriene C4 production was inhibited by manoalide when macrophages were stimulated by A23187 (IC50 = 0.35 microM) but was enhanced when the cells were stimulated with zymosan. In an in vivo model, manoalide antagonized zymosan-induced peritoneal writhing in the mouse (ED50 = 0.71 mg/kg) and inhibited the i.p. release of 6-keto-prostaglandin F1 alpha (ED50 = 0.2 mg/kg) and leukotriene C4 (ED50 = 0.24 mg/kg). Our results suggest that: 1) manoalide modifies arachidonic acid release and metabolism to prostaglandins and leukotrienes in mouse cultured peritoneal macrophages stimulated by phorbol myristate acetate, calcium ionophore A23187 and zymosan and 2) the analgesic properties of manoalide seem to be partially correlated with reduced eicosanoid production in zymosan-stimulated mouse peritoneal exudates.
Mayer
A M
AM
Department of Biological Sciences, University of California, Santa Barbara.
Glaser
K B
KB
Jacobs
R S
RS
D015121:6-Ketoprostaglandin F1 alpha / Q000096:biosynthesis; D000700:Analgesics / Q000494:pharmacology*; D000818:Animals; D016718:Arachidonic Acid; D001095:Arachidonic Acids / Q000378:metabolism; D000001:Calcimycin / Q000494:pharmacology; D015232:Dinoprostone / Q000096:biosynthesis*; D066298:In Vitro Techniques; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D010740:Phospholipases / Q000037:antagonists & inhibitors*; D010741:Phospholipases A / Q000037:antagonists & inhibitors*; D054467:Phospholipases A2; D013189:SRS-A / Q000096:biosynthesis*; D013729:Terpenes / Q000494:pharmacology*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D015054:Zymosan / Q000494:pharmacology
D000700:Analgesics; D001095:Arachidonic Acids; D013189:SRS-A; D013729:Terpenes; D016718:Arachidonic Acid; D000001:Calcimycin; D015121:6-Ketoprostaglandin F1 alpha; D015054:Zymosan; C045673:manoalide; D010740:Phospholipases; D010741:Phospholipases A; D054467:Phospholipases A2; D015232:Dinoprostone; D013755:Tetradecanoylphorbol Acetate