Differential mechanisms for the inhibition of human cytochrome P450 1A2 by apigenin and genistein.
The inhibitory effects of flavonoids on the human cytochrome P450 1A2 (CYP1A2) were examined. Among flavonoids tested, galangin, kaempferol, chrysin, and apigenin were potent inhibitors. Although apigenin belonging to flavones and genistein belonging to isoflavones are similar in the chemical structures, the inhibitory potencies for CYP1A2 were distinguished markedly between these two flavonoids. In computer-docking simulation, apigenin interacted with the same mode of cocrystallized alpha-naphthoflavone in the active site of CYP1A2, and then the B ring of apigenin was placed close to the heme iron of the enzyme with a single orientation. In contrast, the docked genistein conformation showed two different binding modes, and the A ring of genistein was oriented to the heme iron of CYP1A2. Furthermore, the binding free energy of apigenin was lower than that of genistein. These results demonstrate a possible mechanism that causes the differential inhibitory potencies of apigenin and genistein for CYP1A2.
Shimada
Hideaki
H
Faculty of Education, Kumamoto University, 2-40-1 Kurokami, Kumamoto 860-8555, Japan. hshimada@gpo.kumamoto-u.ac.jp
Eto
Masashi
M
Ohtaguro
Misa
M
Ohtsubo
Michihiro
M
Mizukami
Yosuke
Y
Ide
Tsuyoshi
T
Imamura
Yorishige
Y
D016588:Anticarcinogenic Agents / Q000494:pharmacology; D047310:Apigenin / Q000737:chemistry* / Q000494:pharmacology; D019388:Cytochrome P-450 CYP1A2 / Q000737:chemistry* / Q000378:metabolism; D065609:Cytochrome P-450 CYP1A2 Inhibitors; D004791:Enzyme Inhibitors / Q000494:pharmacology; D019833:Genistein / Q000737:chemistry* / Q000494:pharmacology; D006801:Humans; D008958:Models, Molecular; D017434:Protein Structure, Tertiary
D016588:Anticarcinogenic Agents; D065609:Cytochrome P-450 CYP1A2 Inhibitors; D004791:Enzyme Inhibitors; D047310:Apigenin; D019833:Genistein; C504573:CYP1A2 protein, human; D019388:Cytochrome P-450 CYP1A2