Characterization of cytochrome P450s mediating ipriflavone metabolism in human liver microsomes.
Ipriflavone, a synthetic flavonoid for the prevention and treatment of osteoporosis, has been reported to be extensively metabolized in man to seven metabolites (M1-M7). This study was performed to characterize the human liver cytochrome P450s (CYP) responsible for the metabolism of ipriflavone. Hydroxylation at the beta-ring to M3, O-dealkylation to M1 and oxidation at isopropyl group to M4 and M5 are major pathways for ipriflavone metabolism in three different human liver microsome preparations. The specific CYPs responsible for ipriflavone oxidation to the active metabolites, M1, M3, M4 and M5 were identified using a combination of correlation analysis, immuno-inhibition, chemical inhibition in human liver microsomes and metabolism by expressed recombinant CYP enzymes. The inhibitory potencies of ipriflavone and its five metabolites, M1-M5 on seven clinically important CYPs were investigated in human liver microsomes. Our results demonstrate that CYP3A4 plays the major role in O-dealkylation of ipriflavone to M1 and CYP1A2 plays a dominant role in the formation of M3, M4 and M5. Ipriflavone and/or its five metabolites were found to inhibit potently the metabolism of CYPs 1A2, 2C8, 2C9 and 2C19 substrates.
Moon
Y
Y
College of Pharmacy, Wonkwang University, Iksan, Korea.
Kim
S Y
SY
Ji
H Y
HY
Kim
Y K
YK
Chae
H J
HJ
Chae
S W
SW
Lee
H S
HS
D000906:Antibodies; D001711:Biotransformation; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000276:immunology / Q000378:metabolism*; D018076:DNA, Complementary; D006801:Humans; D007529:Isoflavones / Q000378:metabolism* / Q000493:pharmacokinetics; D007700:Kinetics; D008862:Microsomes, Liver / Q000201:enzymology / Q000378:metabolism*; D010084:Oxidation-Reduction
D000906:Antibodies; D065607:Cytochrome P-450 Enzyme Inhibitors; D018076:DNA, Complementary; D007529:Isoflavones; C018986:ipriflavone; D003577:Cytochrome P-450 Enzyme System