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 microM), but the potencies were far less than that of NS-398 (ic(50) = 2.9 microM). 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 microM) comparable to that of indomethacin (ic(50) = 0.7 microM). Most of the prenylated flavonoids tested inhibited 5-LOX activity with ic(50) values ranging from 0.09 to 100 microM. Of these, only kuwanon C, papyriflavonol A and sophoraflavanone G showed inhibitory activity against 12-LOX at low concentration ranges (ic(50) = 19-69 microM) comparable to that of NDGA (ic(50) = 2.6 microM). Our results suggest that the position and the nature of the prenyl substitution greatly influence in vitro biological activities of these molecules.
Chi
Y S
YS
College of Pharmacy, Kangwon National University, 200-701, Korea, Chunchon, South Korea.
Jong
H G
HG
Son
K H
KH
Chang
H W
HW
Kang
S S
SS
Kim
H P
HP
D000818:Animals; D016718:Arachidonic Acid / Q000378:metabolism*; D001792:Blood Platelets / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D002417:Cattle; D005419:Flavonoids / Q000737:chemistry / Q000494:pharmacology*; D066298:In Vitro Techniques; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D008084:Lipoxygenase / Q000378:metabolism*; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism*; D017368:Protein Prenylation
D005419:Flavonoids; D016718:Arachidonic Acid; D008084:Lipoxygenase; D011451:Prostaglandin-Endoperoxide Synthases