Isozyme- 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 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.
Tsyrlov
I B
IB
Laboratory of Molecular Carcinogenesis, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892.
Mikhailenko
V M
VM
Gelboin
H V
HV
D000818:Animals; D019388:Cytochrome P-450 CYP1A2; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000187:drug effects*; D005419:Flavonoids / Q000494:pharmacology*; D006801:Humans; D007527:Isoenzymes / Q000187:drug effects*; D051379:Mice; D008862:Microsomes, Liver / Q000201:enzymology; D009247:NADH, NADPH Oxidoreductases / Q000187:drug effects; D010089:Oxidoreductases, N-Demethylating / Q000187:drug effects*; D011994:Recombinant Proteins / Q000187:drug effects; D013045:Species Specificity; D013329:Structure-Activity Relationship
D065607:Cytochrome P-450 Enzyme Inhibitors; D005419:Flavonoids; D007527:Isoenzymes; D011994:Recombinant Proteins; D003577:Cytochrome P-450 Enzyme System; D019388:Cytochrome P-450 CYP1A2; D010089:Oxidoreductases, N-Demethylating; D009247:NADH, NADPH Oxidoreductases