A methoxyflavonoid, chrysoeriol, selectively inhibits the formation of a carcinogenic estrogen metabolite in MCF-7 breast cancer cells.
A 17beta-estradiol (E(2)) is hydrolyzed to 2-hydroxy-E(2) (2-OHE(2)) and 4-hydroxy-E(2) (4-OHE(2)) via cytochrome P450 (CYP) 1A1 and 1B1, respectively. In estrogen target tissues including the mammary gland, ovaries, and uterus, CYP1B1 is highly expressed, and 4-OHE(2) is predominantly formed in cancerous tissues. In this study, we investigated the inhibitory effects of chrysoeriol (luteorin-3'-methoxy ether), which is a natural methoxyflavonoid, against activity of CYP1A1 and 1B1 using in vitro and cultured cell techniques. Chrysoeriol selectively inhibited human recombinant CYP1B1-mediated 7-ethoxyresorufin-O-deethylation (EROD) activity 5-fold more than that of CYP1A1-mediated activity in a competitive manner. Additionally, chrysoeriol inhibited E(2) hydroxylation was catalyzed by CYP1B1, but not by CYP1A1. Methylation of 4-OHE(2), which is thought to be a detoxification process, was not affected by the presence of chrysoeriol. In human breast cancer MCF-7 cells, chrysoeriol did not affect the gene expression of CYP1A1 and 1B1, but significantly inhibited the formation of 4-methoxy E(2) without any effects on the formation of 2-methoxy E(2). In conclusion, we present the first report to show that chrysoeriol is a chemopreventive natural ingredient that can selectively inhibit CYP1B1 activity and prevent the formation of carcinogenic 4-OHE(2) from E(2.).
Takemura
Hitomi
H
Institute for Environmental Sciences, University of Shizuoka, Suruga, Shizuoka, Japan.
Uchiyama
Harue
H
Ohura
Takeshi
T
Sakakibara
Hiroyuki
H
Kuruto
Ryoko
R
Amagai
Takashi
T
Shimoi
Kayoko
K
D000077584:2-Methoxyestradiol; D001189:Aryl Hydrocarbon Hydroxylases; D055162:Biocatalysis; D001943:Breast Neoplasms / Q000378:metabolism* / Q000517:prevention & control; D002273:Carcinogens / Q000378:metabolism*; D002394:Catechol O-Methyltransferase / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D018890:Chemoprevention; D017077:Culture Media, Conditioned / Q000378:metabolism; D019363:Cytochrome P-450 CYP1A1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D065633:Cytochrome P-450 CYP1B1; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D003600:Cytosol / Q000201:enzymology; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D004958:Estradiol / Q000031:analogs & derivatives* / Q000378:metabolism*; D002393:Estrogens, Catechol; D005260:Female; D047309:Flavones; D005419:Flavonoids / Q000494:pharmacology*; D015870:Gene Expression / Q000187:drug effects / Q000235:genetics; D005966:Glucuronidase / Q000378:metabolism; D006801:Humans; D006900:Hydroxylation / Q000187:drug effects; D007700:Kinetics; D008745:Methylation / Q000187:drug effects; D010078:Oxazines / Q000378:metabolism; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D013429:Sulfatases / Q000378:metabolism
D002273:Carcinogens; D017077:Culture Media, Conditioned; D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors; D002393:Estrogens, Catechol; D047309:Flavones; D005419:Flavonoids; D010078:Oxazines; D011994:Recombinant Proteins; C045018:4-methoxyestradiol; D004958:Estradiol; C007649:ethoxyresorufin; C014180:resorufin; D000077584:2-Methoxyestradiol; D003577:Cytochrome P-450 Enzyme System; C001390:2-hydroxyestradiol; C014036:4-hydroxyestradiol; D001189:Aryl Hydrocarbon Hydroxylases; C585496:CYP1B1 protein, human; D019363:Cytochrome P-450 CYP1A1; D065633:Cytochrome P-450 CYP1B1; D002394:Catechol O-Methyltransferase; D013429:Sulfatases; D005966:Glucuronidase; C007054:chrysoeriol