INHIBITION OF 7-ETHOXYCOUMARIN O-DEETHYLASE ACTIVITY IN RAT-LIVER MICROSOMES BY NATURALLY-OCCURRING FLAVONOIDS - STRUCTURE-ACTIVITY-RELATIONSHIPS

1. The inhibitory effects of several naturally occurring flavonoids an d related compounds on cytochrome P450-dependent 7-ethoxycoumarin O-de ethylase (ECOD) and the structure-activity relationships were studied in liver microsomes from rats treated with 3-methylcholanthrene (MC). 2. All the flavonoids (flavone, apigenin, chrysin, flavonol, fisetin, kaempferol, morin, myrisetin, quercetin, flavanone, hesperetin and nar ingenin) studied inhibited microsomal ECOD activity in the following o rder: flavones > flavonols > flavanones, were mixed type inhibitors an d had K-i in the range of 0.17-4.5 mu M. (+/-)-Catechin had no effect. 3. The double bond between C-2 and C-3 of the C ring, the keto group and hydroxyl group of this ring in the flavonoids seem to play major r oles in inhibiting the ECOD activity. 4. The hydroxyl groups in the C- 5 and C-7 positions of A ring in the flavone and the hydroxyl group in the C-3 position of C ring in the flavonol classes, respectively, wer e important factors for the inhibition of the enzyme. 5. In a series o f 3,5,7-trihydroxyflavones, the hydroxyl group at the C-4 in the B rin g was also an important factor for the inhibition of ECOD activity, bu t hydroxyl groups in other positions of the B ring had little effect o n the inhibition. 6. We conclude that all the flavonoids studied inhib it ECOD activity by interfering with the binding of substrate to the a ctive site and other site(s) of the enzyme and that their structural d ifferences lead to different binding affinities at the active site and possibly to binding at other site(s) of the enzyme for the flavonoids .