17α-Ethynyl-17β-hydroxy-19-norandrost-4-en-3-oneのエストロゲン効果発現機構に関する研究

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タイトル別名
  • The Experimental Studies on the Estrogenic Activities of 17α-Ethyny1-17β-Hydroxy-19-Norandrost-4-en-3-one (ENT)
  • 17アルファ Ethynyl 17ベータ hydroxy 19 norandr

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Today, ENT is a popular synthetic progestogen for clinical use, and is well known to have some estrogenic activity. Estradiol-17β (E2) or 17α-ethynyl estradiol (EE2) binding to the specific protein in the nuclear fraction of hypothalamus were examined by 3H-E2 exchange assay reported by Anderson. The possible mode of the estrogenic actions of ENT are as follows : 1) Conversion of ENT to EE2. 2) Estrogenic of ENT per se without changing the chemical structure. 3) Conversion of ENT to other estrogenic compounds except for EE2.<BR>In this experiment, 3H-ENT or 3H-testosterone (3H-T) was incubated with human placental microsomes and NADPH generating system for 1 hr at 37°C, 3H-Δ4AD, 3H-T and 3H-ENT were incubated also with homogenates of rat hypothalamus under the same conditions. Isolation and purification of the metabolites were performed by using phenolic separation and paper chromatography. Identification of EE2, a metabolite of ENT, was established by measuring the radiochemical homogenity with the authentic standard on paper chromatography. In another experiment where alkali was not used during the extraction procedure to avoid making artificial products, the conversion rate of ENT to EE2 was measured. This experimental data indicated that ENT was converted to 1β-OH-ENT and to EE2 by human placental microsomes. The former compound was easily converted to EE2 in the presence of NaOH or by incubation with bile. In the incubation with hypothalamic preparation neither aromatization nor 1β-hydroxylation of Δ4AD, T and ENT were detected. In the exchange assays of E2 receptor, the animals were killed 1 hr after the administration of 25μg of various steroids. The hypothalamic nuclear fraction was incubated with various 3H-steroids for 30 min at 37°C. After washing this nuclear pellet, the radioactivity was counted. Administration of E2 in vivo resulted in the increase of the amount of 3H-EE2 bound to the nuclear fraction in vitro. But only a small increase of binding was observed in the similar experiment with 3HENT. 3H-EE2 was exchanged more abundantly after ENT administration than after EE2 injection. From the above results, it was concluded that the estrogenic effect of ENT is attributed to the EE2 converted in vivo. In addition, a possibility was proposed that ENT or its metabolites other than EE2 could regulate some step in the mechanism of estrogen action.

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