Effects of naturally occurring prenylated flavonoids on enzymes metabolizing arachidonic acid: Cyclooxygenases and lipoxygenases

Prenylated flavonoids are chemical entities having an isoprenyl, a geranyl, a 1,1-dimethylallyl, and/or a lavandulyl moiety as part of their flavonoid backbone structure. In this study, the effects of 19 naturally occurring prenylated flavonoids, isolated from medicinal plants, on cyclooxygenase (COX)-1 and COX-2 and on 5-lipoxygenase (5-LOX) and 12-LOX were investigated using [ 14C]arachidonic acid as a substrate. The homogenates of bovine platelets and polymorphonuclear leukocytes were used as COX-1, 12-LOX, and 5-LOX enzyme sources; the homogenate of aspirin-pretreated lipopolysaccharide-induced RAW 264.7 cells was used for the COX-2 enzyme source. Among the 19 prenylated flavonoids, morusin, kuwanon C, sanggenon B, sanggenon D and kazinol B inhibited COX-2 activity (ic 50 = 73–100 μM), but the potencies were far less than that of NS-398 (ic 50 = 2.9 μM). In contrast, many prenylated flavonoids, such as kuraridin, kuwanon C and sophoraisoflavanone A, inhibited COX-1 activity. Of the COX-1 inhibiting prenylated flavonoids, kuraridin, kurarinone, and sophoraflavanone G, all having a C-8 lavandulyl moiety, showed potent activity (ic 50 = 0.1 to 1 μM) comparable to that of indomethacin (ic 50 = 0.7 μM). Most of the prenylated flavonoids tested inhibited 5-LOX activity with ic 50 values ranging from 0.09 to 100 μM. Of these, only kuwanon C, papyriflavonol A and sophoraflavanone G showed inhibitory activity against 12-LOX at low concentration ranges (ic 50 = 19–69 μM) comparable to that of NDGA (ic 50 = 2.6 μM). Our results suggest that the position and the nature of the prenyl substitution greatly influence in vitro biological activities of these molecules.