INHIBITION BY ABRUQUINONE-A OF PHOSPHOINOSITIDE-SPECIFIC PHOSPHOLIPASE-C ACTIVATION IN RAT NEUTROPHILS

In rat neutrophils, formyl-Met-Leu-Phe (fMLP)-induced inositol phospha te formation was inhibited by abruquinone A (IC50 value about 32.7 +/- 6.4 mu M) as well as by a putative phospholipase C inhibitor, [6-[[17 -methoxyestra-1,3,5(10)-trien-17-yl]amino]hexal]-1 H-pyrrole-2,5-dion e (U73122) (IC50 value about 11.3 +/- 1.2 mu M). The reduction in inos itol phosphate levels appeared to reflect inhibition of phospholipase C activity because the hydrolysis of phosphatidylinositol 4,5-bisphosp hate (PIP2) catalyzed by a soluble fraction from neutrophils was also inhibited by abruquinone A (IC50 value about 31.4 +/- 5.6 mu M) over t he same range of concentrations. Although abruquinone A alone induced Ca2+ and Mn2+ influx into neutrophils in Ca2+-containing medium, abruq uinone A, like U73122, inhibited Ca2+ release (IC50 value about 23.5 /- 0.5 mu M) from internal stores in Ca2+-free medium. These results i ndicate that abruquinone A inhibits the activity of phosphoinositide-s pecific phospholipase C in neutrophils.