Vol. 282, Issue 1, 123-131, 1997

Variabilin: A Dual Inhibitor of Human Secretory and Cytosolic Phospholipase A₂ With Anti-inflammatory Activity¹

V. Escrig, A. Ubeda, M. L. Ferrandiz, J. Darias, J. M. Sanchez, M. J. Alcaraz and M. Paya

Department of Pharmacology, University of Valencia and Institute of Natural Products and Agrobiology, Tenerife, Spain

The marine product variabilin was identified as a novel inhibitor of phospholipase A₂ (PLA₂), which exhibited IC₅₀ values of 6.9 µM and 7.9 µM 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 µmol/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 µmol/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.