ISOZYME-SPECIFIC AND SPECIES-SPECIFIC SUSCEPTIBILITY OF CDNA-EXPRESSED CYP1A P-450S TO DIFFERENT FLAVONOIDS

The inhibitory and stimulatory effects of six flavonoids with distinct hydroxylation patterns on the recombinant and hepatic mouse and human CYP1A P-450s were studied. cDNA-expressed mouse CYP1A1 and CYP1A2 dif fered in their sensitivity to both hydroxylated and nonhydroxylated fl avonoids, respectively. A comparison between the mouse and human CYP1A 2 revealed that cu-naphthoflavone and flavone did not change the benzo [cy]pyrene 3-hydroxylation activity of human CYP1A2 but inhibited its 7-ethoxyresorufin and 7-methoxyresorufin O-dealkylation activities. In contrast, hydroxylated flavonoids increased the 7-methoxyresorufin O- demethylation and acetanilide 4-hydroxylation activities of cDNA-expre ssed human CYP1A2 and in human liver microsomes. These compounds inhib ited the benzo[a]pyrene 3-hydroxylase activity of cDNA-expressed CYP1A 1 and CYP1A2s as well as in mouse and human liver microsomes. Hydroxyl ated flavonoids did not inhibit NADPH-cytochrome P-450 oxidoreductase activity but inhibited NADPH-2,6-dichlorophenolindophenol oxidoreducta se activity in liver microsomes and in microsomes from recombinant Hep G2 cells. Structure-activity relationships indicated the importance o f hydroxyl groups in the 5- and 7-positions on the A ring of the flava ne nucleus. These hydroxyl groups accounted for the inhibitory potency of chrysin on each of the activities of the expressed P-450s, while p resence of a hydroxyl group at the 4'-position on the B ring decreased the inhibitory potency of naringenin compared to that of chrysin. The ortho-orientation of a hydroxyl group on the B ring was of importance , inasmuch as quercetin was more potent than morin as an inhibitor of cDNA-expressed and hepatic microsomal monooxygenases.