Neue per os-wirksame weibliche Keimdrüsenhormon-Derivate: 17-Aethinyl-oestradiol und Pregnen-in-on-3-ol-17

Inhoffen, Hans Herloff; Hohlweg, W

doi:10.1007/bf01681040

Cited by 146 publications

(30 citation statements)

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“…17EE, developed in 1938, is the major synthetic steroid component of many oral contraceptives (Innhoffen and Holweg, 1938). Although the acetylenic moiety increased the oral availability of 17EE, incorporation of this group into a compound metabolized by P450 enzymes can also lead to the inactivation of these enzymes (Ortiz de Montellano and Reich, 1986).…”

mentioning

confidence: 99%

Effect of 17-α-Ethynylestradiol on Activities of Cytochrome P450 2B (P450 2B) Enzymes: Characterization of Inactivation of P450s 2B1 and 2B6 and Identification of Metabolites

Kent¹,

Mills²,

Rajnarayanan³

et al. 2002

J Pharmacol Exp Ther

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17-␣-Ethynylestradiol (17EE) inactivated purified, reconstituted rat hepatic cytochrome P450 (P450) 2B1 and human P450 2B6 in a mechanism-based manner. Little or no inactivation was observed when P450s 2B2 or 2B4 were incubated with 17EE. The inactivation of P450s 2B1 and 2B6 was entirely dependent on both NADPH and 17EE and followed pseudo-first order kinetics. The maximal rate constants for the inactivation of P450s 2B1 and 2B6 at 30°C were 0.2 and 0.03 min Ϫ1 , respectively. For P450s 2B1 and 2B6 the apparent K I was 11 and 0.8 M, respectively. Incubation of P450 2B1 with 17EE and NADPH for 20 min resulted in a 75% loss in enzymatic activity and a concurrent 20 to 25% loss of the enzyme's ability to form a reduced CO complex. With P450 2B6, an 83% loss in enzymatic activity and a 5 to 10% loss in the CO reduced spectrum were observed. The extrapolated partition ratios for 17EE with P450 2B1 and 2B6 were 21 and 13, respectively. Simultaneous incubation of an alternate substrate together with 17EE protected both enzymes from inactivation. A 1.3:1 stoichiometry of labeling for binding of the radiolabeled 17EE to P450 2B1 and 2B6 was seen. These results indicate that 17EE inactivates P450s 2B1 and 2B6 in a mechanism-based manner, primarily by the binding of a reactive intermediate of 17EE to the apoprotein. Analysis of the 17EE metabolites showed that 2B enzymes that become inactivated differ primarily by their ability to generate two metabolites that were not produced by P450s 2B2 or 2B4.

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mentioning

confidence: 99%

Effect of 17-α-Ethynylestradiol on Activities of Cytochrome P450 2B (P450 2B) Enzymes: Characterization of Inactivation of P450s 2B1 and 2B6 and Identification of Metabolites

Kent¹,

Mills²,

Rajnarayanan³

et al. 2002

J Pharmacol Exp Ther

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“…An unknown Frenchman, Dr. A. Girad, stunned the audience when he-as his contribution-produced a bottle containing 20 g estrone which he had extracted from mares' urine using a novel procedure. In 1938 the important discovery was made that ethinylestradiol was 20 times more potent when given orally than estradiol [28].…”

Section: Ovariesmentioning

confidence: 99%

Pituitary-gonadal axis: historical notes

Lindholm

2008

Pituitary

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Though it was appreciated at a very early time that removal of gonads had evident consequences, the anatomy and function of the gonads were essentially unknown in the Antiquity. It was not until around 1600 that men like Vesalius, de Graaf and Leeuwenhoek initiated rational studies on the structure and function of the gonads. The close relationship between gonads and hypothalamus/pituitary was recognized less than 100 years ago. The last pituitary hormone with gonadotroph effect was discovered a generation ago. This paper briefly describes some major points in the development of our knowledge of the pituitary-gonadal function. Considering the huge number of studies involved, this review reflects but a tiny fraction of the work laid down over millennia within this field.

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“…From the first progestin, synthesized by Hans H. Inhoffen and Walter Hohlweg in 1938 (Inhoffen & Hohlweg 1938), several synthetic progestins, which differ in their chemical structures and biological effect, have been synthesized.…”

Section: Chemical Structure and Mechanism Of Actionmentioning

confidence: 99%

The other side of progestins: effects in the brain

Giatti

Melcangi

Pesaresi

2016

Journal of Molecular Endocrinology

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Progestins are a broad class of progestational agents widely differing in their chemical structures and pharmacological properties. Despite emerging data suggest that progestins, besides their action as endometrial protection, can also have multiple nonreproductive functions, much remains to be discovered regarding the actions exerted by these molecules in the nervous system. Here, we report the role exerted by different progestins, currently used for contraception or in postmenopausal hormone replacement therapies, in regulating cognitive functions as well as social behavior and mood. We provide evidence that the effects and mechanisms underlying their actions are still confusing due to the use of different estrogens and progestins as well as different doses, duration of exposure, route of administration, baseline hormonal status and age of treated women. We also discuss the emerging issue concerning the relevant increase of these substances in the environment, able to deeply affect aquatic wildlife as well as to exert a possible influence in humans, which may be exposed to these compounds via contaminated drinking water and seafood. Finally, we report literature data showing the neurobiological action of progestins and in particular their importance during neurodegenerative events. This is extremely interesting, since some of the progestins currently used in clinical practice exert neuroprotective and anti-inflammatory effects in the nervous system, opening new promising opportunities for the use of these molecules as therapeutic agents for trauma and neurodegenerative disorders.

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Neue per os-wirksame weibliche Keimdrüsenhormon-Derivate: 17-Aethinyl-oestradiol und Pregnen-in-on-3-ol-17

Cited by 146 publications

References 0 publications

Effect of 17-α-Ethynylestradiol on Activities of Cytochrome P450 2B (P450 2B) Enzymes: Characterization of Inactivation of P450s 2B1 and 2B6 and Identification of Metabolites

Effect of 17-α-Ethynylestradiol on Activities of Cytochrome P450 2B (P450 2B) Enzymes: Characterization of Inactivation of P450s 2B1 and 2B6 and Identification of Metabolites

Pituitary-gonadal axis: historical notes

The other side of progestins: effects in the brain

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