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Biochim Biophys Acta. 1994 Apr 13;1205(2):325-35.

Isozyme- and species-specific susceptibility of cDNA-expressed CYP1A P-450s to different flavonoids.

Author information

1
Laboratory of Molecular Carcinogenesis, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892.

Abstract

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 differed in their sensitivity to both hydroxylated and nonhydroxylated flavonoids, respectively. A comparison between the mouse and human CYP1A2 revealed that alpha-naphthoflavone and flavone did not change the benzo[a]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-expressed human CYP1A2 and in human liver microsomes. These compounds inhibited the benzo[a]pyrene 3-hydroxylase activity of cDNA-expressed CYP1A1 and CYP1A2s as well as in mouse and human liver microsomes. Hydroxylated flavonoids did not inhibit NADPH-cytochrome P-450 oxidoreductase activity but inhibited NADPH-2,6-dichlorophenolindophenol oxidoreductase activity in liver microsomes and in microsomes from recombinant Hep G2 cells. Structure-activity relationships indicated the importance of hydroxyl groups in the 5- and 7-positions on the A ring of the flavane nucleus. These hydroxyl groups accounted for the inhibitory potency of chrysin on each of the activities of the expressed P-450s, while presence 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.

PMID:
8155716
DOI:
10.1016/0167-4838(94)90252-6
[Indexed for MEDLINE]

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