We investigated the effect of bioflavonoid quercetin on tyrosine phosphorylation and phospholipase D (PLD, EC 3.1.4.4) activation in rabbit peritoneal neutrophils stimulated by N-formylmethionyl-leucyl-phenylalanine (fMLP). The quercetin dose-dependently inhibited degranulation and superoxide production in fMLP-stimulated neutrophils. A strong inhibitory effect of quercetin on the tyrosine phosphorylation of several proteins (40, 42, 43, 45, 46 and 75 kDa) was observed when the neutrophils were pretreated with different concentrations of quercetin. Furthermore, quercetin inhibited mitogen activated protein kinase (MAP kinase) and PLD activation induced by fMLP in a dose-dependent manner. The reduction in PLD activity was 30% at 0.1 microM and 70% at 100 microM of quercetin. These results suggest that impairment of neutrophil functions by quercetin may be due, at least in part, to inhibition of tyrosine phosphorylation and PLD activation.