The marine product
variabilin was identified as a novel inhibitor of
phospholipase A2 (PLA2), which exhibited IC50 values of 6.9 microM and 7.9 microM for human synovial secretory PLA2 and U937 cells cytosolic PLA2 activities, respectively. This compound was less potent on
bee venom or
zymosan-injected rat air pouch
enzymes and failed to affect Naja naja
venom PLA2. The production of
leukotriene B4 by human neutrophils stimulated with
calcium ionophore A23187 was also inhibited by
variabilin, which was without effect on
5-lipoxygenase,
cyclo-oxygenase 1 and
cyclo-oxygenase 2 activities in cell-free assays. Other functions of human neutrophils, such as degranulation and
superoxide generation, were also significantly reduced in vitro.
Variabilin administered topically suppressed the mouse ear
edema induced by 12-O-tetradecanoylphorbol 13-acetate, whereas the ear
edema induced by
arachidonic acid was unaffected; this suggests an action previous to
arachidonic acid metabolism. This compound administered p.o. at 30 mg/kg and 45 mg/kg significantly inhibited mouse paw
edema induced by
carrageenan and, at 0.01 to 1.0 micromol/pouch in the mouse air pouch injected with
zymosan, exerted a marked inhibition on
PGE2 and
leukotriene B4 levels in exudates (ID50 values of approximately 0.028-0.029 micromol/pouch), without affecting cell migration. Our results indicate that
variabilin is an inhibitor of human secretory and cytosolic PLA2 activities that controls
eicosanoid production in vitro and in vivo, inhibits neutrophil degranulation and
superoxide generation in vitro and shows anti-inflammatory activity after topical or p.o. administration to mice.