Asunto(s)
Neoplasias de la Mama/metabolismo , Estrógenos/metabolismo , Microsomas Hepáticos/metabolismo , Animales , Equilenina/metabolismo , Equilina/metabolismo , Estradiol/análogos & derivados , Estradiol/biosíntesis , Estrógenos de Catecol/biosíntesis , Etinilestradiol/análogos & derivados , Etinilestradiol/biosíntesis , Etinilestradiol/metabolismo , Femenino , Humanos , Hidroxiestronas/biosíntesis , Hidroxilación , PapioRESUMEN
The 19-norgestagens norethisterone acetate (17 alpha-ethinyl-4-oestren-17 beta-ol-3-on-17-acetate), ethinodiol diacetate (17 alpha-ethinyl-4-oestren-3 beta, 17 beta-diol-3, 17-diacetate), and norgestrol (17 alpha-ethinyl-18-methyl-4-oestren-17 beta-ol-3-on) are transformed to ethinyloestradiol or 18-methyl homologue by microorganisms of cattle rumen. Such transformation of steroid gestagens to oestrogens is likely to offer an explanation for the occurrence of oestrogen effects which had been observed during synchronised oestrus of cattle following oral application of 19-norgestagens.
Asunto(s)
Bacterias/metabolismo , Etinilestradiol/biosíntesis , Diacetato de Etinodiol/metabolismo , Noretindrona/metabolismo , Norgestrel/metabolismo , Rumen/metabolismo , Animales , Bovinos , Fenómenos Químicos , Química , Fermentación , Jugo Gástrico/microbiologíaRESUMEN
Today, ENT is a popular synthetic progesteron for clinical use, and is well known to have some estrogenic activity. Estradiol-17beta (E2) or 17alpha-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. 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 degrees C, 3H-delta4AD, 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 1beta-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 1beta-hydroxylation of delta4AD, T and ENT were detected. In the exchange assays of E2 receptor, the animals were killed 1 hr after the administration of 25 mug of various steroids. The hypothalamic nuclear fraction was incubated with various 3H-steroids for 30 min at 37 degrees 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 3H-ENT. 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.
PIP: The mode of the estrogenic activity of norethindrone (ENT) was investigated. ENT was incubated with human placental microsomes to establish the presence of ethinyl estradiol as a metabolite. From exchange assays performed on hypothalamic nuclear fractions of rats injected with various steroids, it is concluded that the estrogenic effect of ENT is a result of its conversion in vivo to ethinyl estradiol.
Asunto(s)
Noretindrona/farmacología , Androstenodiona/metabolismo , Estradiol/biosíntesis , Estrona/biosíntesis , Etinilestradiol/biosíntesis , Femenino , Humanos , Hipotálamo/metabolismo , Técnicas In Vitro , Microsomas/metabolismo , Noretindrona/metabolismo , Placenta/metabolismo , Embarazo , Testosterona/metabolismoAsunto(s)
Etinilestradiol/biosíntesis , Mestranol/metabolismo , Microsomas Hepáticos/metabolismo , Animales , Agua Corporal , Isótopos de Carbono , Cromatografía , DDT/farmacología , Femenino , Hidrogenación , Técnicas In Vitro , Masculino , Métodos , Metilación , Microsomas Hepáticos/enzimología , Fenobarbital/farmacología , Ratas , Espirometría , Factores de Tiempo , TritioRESUMEN
PIP: The subcellular distribution of the enzymes involved in the metabolism of norethynodrel (17 alpha-ethynyl-17 beta-hydroxy-estr-5(10)-en-3-one) to the 3alpha and 3beta diols (17 alpha-ethynyl-3alpha (or 3beta-17 beta-dihydroxy-estr-5(10)-ene) and 17 alpha-ethinyl estradiol was studied. The purity of the male rat liver subcellular fractions was evaluated by the use of marker enzymes. Sample sections were viewed by electron microscopy. The data showed that the cytosol fraction contained the highest relative specific activity for the hydroxysteroid dehydrogenases required for the formation of the diols. The cytosol fraction also contained the highest total activity. The enzymes required for the formation of ethinyl estradiol were distributed equally among mitochondrial and microsomal fractions, however, the highest relative specific activity was associated with the heavy microsomal fraction (18,000 g).^ieng