Ib. Tsyrlov et al., ISOZYME-SPECIFIC AND SPECIES-SPECIFIC SUSCEPTIBILITY OF CDNA-EXPRESSED CYP1A P-450S TO DIFFERENT FLAVONOIDS, Biochimica et biophysica acta. Protein structure and molecular enzymology, 1205(2), 1994, pp. 325-335
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.