EFFECT OF MANOALIDE ON HUMAN 5-LIPOXYGENASE ACTIVITY

The marine natural product manoalide (MLD) has been described to inact ivate phospholipase A(2) (PLA(2)) from several sources as well as to i nhibit synthesis of eicosanoids in human polymorphonuclear leukocytes (HPMNL). MLD also reduces chemically-induced inflammation in vivo. In this investigation we have examined the effect of MLD on A23187-induce d generation of leukotriene B-4 (LTB(4)) and thromboxane B-2 (TXB(2)) in HPMNL as well as 5-lipoxygenase (5-LO) activity from HPMNL sonicate d preparations. In the intact cell system, MLD inhibited with similar potency biosynthesis of LTB(4) and TXB(2) (IC50 1.7 and 1.4 mu M, resp ectively). In order to discern if inhibition of 5-LO is involved in th e effect of MLD, we examined the action of this compound on 5-LO activ ity from 10,000 x g and 100,000 x g supernatants of sonicated HPMNL ho mogenates. The enzymatic activity was not affected at concentrations o f MLD up to 50 mu M. These data indicate that MLD is not a direct inhi bitor of 5-LO activity from HPMNL and support the hypothesis that its anti-inflammatory action could be related with a reduction of eicosano id biosynthesis via inhibition of PLA(2).