- Lack of Cell Proliferative and Tumorigenic Effects of 4-Hydroxyestradiol in the Anterior Pituitary of Rats: Role of Ultrarapid O-Methylation Catalyzed by Pituitary Membrane-Bound Catechol-O-Methyltransferase
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In animal models, estrogens are complete carcinogens in certain target sites. 4-Hydroxyestradiol (4-OH-E2), an endogenous metabolite of 17β-estradiol (E2), is known to have prominent estrogenic activity plus potential genotoxicity and mutagenicity. We report here our finding that 4-OH-E2 does not induce pituitary tumors in ACI female rats, whereas E2 produces 100% pituitary tumor incidence. To probe the mechanism, we conducted a short-term animal experiment to compare the proliferative effect of 4-OH-E2 in several organs. We found that, whereas 4-OH-E2 had little ability to stimulate pituitary cell proliferation in ovariectomized female rats, it strongly stimulates cell proliferation in certain brain regions of these animals. Further, when we used in vitro cultured rat pituitary tumor cells as models, we found that 4-OH-E2 has similar efficacy as E2 in stimulating cell proliferation, but its potency is approximately 3 orders of magnitude lower than that of E2. Moreover, we found that the pituitary tumor cells have the ability to selectively metabolize 4-OH-E2 (but not E2) with ultrahigh efficiency. Additional analysis revealed that the rat pituitary expresses a membrane-bound catechol-O-methyltransferase that has an ultralow Km value (in nM range) for catechol estrogens. On the basis of these observations, it is concluded that rapid metabolic disposition of 4-OH-E2 through enzymatic O-methylation in rat anterior pituitary cells largely contributes to its apparent lack of cell proliferative and tumorigenic effects in this target site.
- Wang, Pan,Mills, Laura H.,Song, Ji-Hoon,Yu, Jina,Zhu, Bao-Ting
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p. 1448 - 1462
(2017/07/24)
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- A methoxyflavonoid, chrysoeriol, selectively inhibits the formation of a carcinogenic estrogen metabolite in MCF-7 breast cancer cells
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A 17β-estradiol (E2) is hydrolyzed to 2-hydroxy-E2 (2-OHE2) and 4-hydroxy-E2 (4-OHE2) 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-OHE2 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 E2 hydroxylation was catalyzed by CYP1B1, but not by CYP1A1. Methylation of 4-OHE2, 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 E2 without any effects on the formation of 2-methoxy E2. 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-OHE2 from E2..
- Takemura, Hitomi,Uchiyama, Harue,Ohura, Takeshi,Sakakibara, Hiroyuki,Kuruto, Ryoko,Amagai, Takashi,Shimoi, Kayoko
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experimental part
p. 70 - 76
(2011/02/22)
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- Benzotropolone inhibitors of estradiol methylation: Kinetics and in silico modeling studies
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Natural and synthetic benzotropolone compounds were assessed in vitro for their ability to inhibit hydroxyestradiol methylation by catechol-O- methyltransferase (COMT). The compounds were also modeled in silico with a homology model of human COMT. Purpurogallin (1), purpurogallin carboxylic acid (2), and theaflavin-3,3′-digallate (6) were the most potent inhibitors of 2-hydroxy and 4-hydroxyestradiol methylation (IC50 0.22-0.50 μM). Compounds 1 and 6 decreased the Vmax and increased the Km of COMT, indicating a mixed-type inhibition. Compounds 1 and 2 bound to COMT by inserting the six-membered ring of the benzotropolone into the active site. Decreased acidity of the hydroxyl groups on this ring or increased bulkiness reduced potency. Compound 6 bound by inserting the galloyl ester into the active site, which allowed the compound to overcome increased bulkiness and resulted in restored potency. Further studies are needed to determine the impact in vivo of COMT inhibition by these compounds.
- Lambert, Joshua D.,Chen, Dapeng,Wang, Ching Y.,Ai, Ni,Sang, Shengmin,Ho, Chi-Tang,Welsh, William J.,Yang, Chung S.
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p. 2501 - 2507
(2007/10/03)
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- A NEW SYNTHETIC ROUTE TO 2- AND 4-METHOXYESTRADIOLS BY NUCLEOPHILIC SUBSTITUTION
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A new synthetic route to 2- and 4-methoxyestradiols is described.Benzo-15-crown-5 with CuI catalyzes the specific nucleophilic substitution at the carbon atom carrying a non-activated halogen on ring A of the estradiol.
- Chen, Shu-hua,Luo, Guan-rong,Wu, Xu-sen,Chen, Min,Zhao, Hua-ming
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- Synthesis of 2-Methoxy- and 4-Methoxy-Estrogens with Halogen-Methoxy Exchange Reaction
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Synthesis of 2-methoxy- and 4-methoxy-estrone (6) and (9), 2-methoxy- and 4-methoxy-estradiol (15) and (18), and 2-methoxy- and 4-methoxy-estratriol (24) and (27) are described.Catalytic hydrogenation over Pd/C of 2,4-dibromo or 2,4-diiodo estrogens gave regioselectively the corresponding 4-halogeno derivatives in excellent yields.Reaction of 2-iodo or 4-iodo estradiol and 2-iodo or 4-iodo estriol with NaOCH3 in MeOH and dimethylformamide (DMF) in the presence of CuCl2 gave in an excellent yield and in a good yield, while (6) and (9) were also similarly obtained by the reaction with pyridine instead of DMF.
- Numazawa, Mitsuteri,Ogura, Yuko,Kimura, Katsuhiko,Nagaoka, Masao
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p. 3701 - 3715
(2007/10/02)
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- Efficient Synthesis of 2-Methoxy- and 4-Methoxy-estrogens
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2-Methoxy- and 4-methoxy-estrogens are easily prepared from the corresponding 2-iodo or 4-bromo derivatives in high yields by a halogen-methoxy group exchange reaction using sodium methoxide-copper(II) chloride.
- Numazawa, Mitsuteru,Ogura, Yuko
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p. 533 - 534
(2007/10/02)
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- Methylation of catechol estrogen with diazomethane
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Dynamic aspects of methylation of catechol estrogen with diazomethane were investigated by means of thin-layer chromatography. The methylation rate of the hydroxyl group at the C-3 position was almost the same as that of the C-2 hydroxyl group in the reaction of 2-hydroxyestrogen, and 2-3 times that of the C-4 hydroxyl group in the reaction of 4-hydroxyestrogen. In these experiments, the maximum yields of 2-methoxyestrone, 2-hydroxyestrone 3-methyl ether, 4-methoxyesterone and 4-hydroxyesterone 3-methyl ether were 32, 39, 13, and 70%, respectively. In addition, demethylation of catechol estrogen dimethyl ethers with boron tribromide and synthesis of 4-hydroxyestrone monomethyl ethers are described.
- Teranishi,Fujii,Yamazaki,Miyabo
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p. 3309 - 3314
(2007/10/02)
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