In vitro inhibition and stimulation of purified prostaglandin endoperoxide synthase by flavonoids: structure-activity relationship.

We studied the effects of 37 flavonoids on prostaglandin endoperoxide synthase (EC 1.14.99.1) purified from sheep vesicular glands. Nonplanar flavans were more potent inhibitors than planar flavones and flavonols (IC50 values were, e.g., 40 mumol/l for catechin and epicatechin, 110 mumol/l for galangin, 490 mumol/l for quercetin and 450 mumol/l for kaempherol). Different inhibition mechanisms were observed, i.e. uncompetitive inhibition for nonplanar flavonoids and competitive or noncompetitive inhibition for planar flavonoids. Potent inhibitors in the group of flavones were substances with an o-dihydroxy structure in the B ring and in the group of flavonol substances with two hydroxyl groups in position 5 and 7 of the A ring. None of the flavanones studied caused significant inhibition, except for the flavanone-3-ol, silibinin (silybin), which caused potent inhibition with an IC50 of 120 mumol/l. Several flavonoids, which were able to inhibit the prostaglandin endoperoxide synthase at higher concentrations, were also able to stimulate the enzyme at lower concentrations. These results indicate that the flavonoids should be divided into two groups according to their capacity to inhibit the prostaglandin endoperoxide synthase, represented by planar and nonplanar substances as in each group a close correlation between structure and inhibitory activity was observed.