Abstract

Fuscoside (FSD) is a potent and long-lasting anti-inflammatory drug that selectively inhibits leukotriene production in murine models of inflammation. In the present study, the effects of FSD on the lipoxygenase pathways in human polymorphonuclear leukocytes are explored in order to better understand the mechanism of action of this novel drug. In adherent and suspended polymorphonuclear leukocytes, FSD irreversibly inhibits leukotriene B4 (LTB4) synthesis (IC50 = 10 microM) and the release of 14C-labeled LTB4 from neutrophils prelabeled with [14C]arachidonic acid. Unlike the reversible 5-lipoxygenase inhibitor L-651,896, FSD has no observable effect on LTB4 biosynthesis in whole blood, but does express activity as blood is successively diluted. In 10,000 x g supernatants of human platelets and polymorphonuclear leukocytes, FSD does not inhibit platelet 12-lipoxygenase, but is extremely effective in inhibiting the metabolism of arachidonic acid and 5-hydroperoxyeicosatetraenoic acid to LTB4 via neutrophil 5-lipoxygenase. FSD has no effect on the conversion of leukotriene A4 to LTB4 in this system. Interestingly, concurrent with FSD inhibition of leukotriene synthesis is a concentration-dependent increase in 5-hydroxyeicosatetraenoic acid, suggesting that FSD may selectively inhibit the leukotriene A4 synthase activity associated with human 5-lipoxygenase. FSD is therefore representative of a new class of nonantioxidant 5-lipoxygenase inhibitors that may be effective local therapeutic agents in the management of diseases such as psoriasis, arthritis and inflammatory bowel and lung diseases.