Figure 8.

A working model outlining a structural basis for the actions of flavonoids and their metabolites in inhibition of collagen-stimulated platelet function. Flavonoids (quercetin, apigenin and catechin) and metabolites [tamarixetin, quercetin-3′-sulphate (Q-3′-S) and quercetin-3-glucuronide (Q-3-G)] inhibit platelet aggregation and 5-HT secretion in a differential manner due to variable attenuation of multiple mechanisms. These variations in inhibitory ability are due to distinct structural features including a planar, C-3 hydroxylated and C-4 carbonyl substituted C ring, a B ring catechol moiety and methyl, sulphate and glucuronide groups which are metabolically added. Mechanisms include inhibition of PLCγ2 and Syk tyrosine phosphorylation as well as Fyn kinase activity mediated directly within the cytosol. Although flavonoid and metabolite binding affinities for collagen and fibrinogen did not correlate with their inhibitory potencies, binding to collagen and fibrinogen, disrupting the interactions of these proteins with GPVI and α_IIbβ₃, respectively, may be a potential mode of action. While potent inhibition of platelet function is more dependent on a planar C ring conjugated to a C-4 carbonyl group and a B ring catechol moiety (quercetin and apigenin), elimination of the C ring C-3 hydroxyl group (apigenin) reduces potency for inhibition of signalling. In vivo, methylated and sulphated metabolites of flavonols may be more active inhibitors of platelet function than glucuronidated metabolites. The differential inhibition of signalling by apigenin suggests internalization and preferential inhibition of Syk and PLCγ2 rather than Fyn by this flavone indicates a degree of selectivity.