Selectivity of neutrophil 5-lipoxygenase and cyclo-oxygenase inhibition by an anti-inflammatory flavonoid glycoside and related aglycone flavonoids.

A newly described plant-derived flavonoid, hypolaetin-8-glucoside, which has anti-inflammatory and gastroprotective actions in-vivo, and its corresponding aglycone, hypolaetin, have been compared with 14 other flavonoids for inhibition of eicosanoid generation via the 5-lipoxygenase and cyclo-oxygenase pathways in elicited rat peritoneal leukocytes stimulated with calcium ionophore. Comparable results for the inhibitory profiles of the compounds were obtained using either radioimmunoassay of released eicosanoids or radio-TLC of metabolites formed from labelled arachidonate, but there were differences in absolute potency of the inhibitors. Hypolaetin-8-glucoside was a weak but selective inhibitor of 5-lipoxygenase (IC50 56 microM vs 5-lipoxygenase; greater than 1000 microM vs cyclo-oxygenase), whereas the aglycone hypolaetin was a more potent and selective 5-lipoxygenase inhibitor (IC50 4.5 microM vs 70 microM). Results with three other glycoside/aglycone pairs confirmed that addition of sugar residues greatly reduces inhibitory potency whilst retaining selectivity against 5-lipoxygenase. Analysis of 12 aglycone flavonoids showed that inhibitory potency and selectivity against 5-lipoxygenase is conferred by the presence of 3'4'-vicinal diol (catechol) in ring B as part of a 3,4-dihydroxycinnamoyl structure as proposed by others and by incorporation of additional hydroxyl substituents. In contrast, "cross-over" of inhibitory selectivity is observed in compounds containing few hydroxyl substituents (with none in ring B) which are selective against cyclo-oxygenase. These results are discussed in relation to possible mechanisms of hypolaetin-8-glucoside's protective actions and the concept that these inhibitory effects of flavonoids cannot be ascribed to a unitary free radical scavenging action.