Inactive steroids

The biologically inactive estrone sulfate (EIS) and dehydro-epiandrosterone-sulfate (DHEAS) are the most abundant circulating estrogenic precursors in the plasma of post-menopausal women [103]. Desulfation of inactive steroid-3-0-sulfates by estrone-sulfatase (STS) plays a key role in the regulation of levels of receptor-active estrogenic steroids (estradiol and androstenediol) in breast cancer cells (Fig. 9). There is strong evidence suggesting that estrone sulfatase (STS) and DHEA-sulfatase are the same enzyme [103]. 

Reactions catalyzed by 11 (3-hydroxysteroid and 17(3-hydroxysteroid dehydrogenases, (a) 11 (3-hydroxysteroid dehydrogenase type 1, an NADPH-dependent enzyme, catalyzes the conversion of the inactive steroid, cortisone, to cortisol, which is the biologically active glucocorticoid. 11 (3-hydroxysteroid dehydrogenase type 2, an NAD+-dependent enzyme, catalyzes the reverse direction, (b) 17(3-hydroxysteroid dehy-drogenase type 1, an NADPH-dependent enzyme, catalyzes the reduction of estrone to estradiol. Type 2, an NAD+-dependent enzyme, catalyzes the oxidation of estradiol to estrone. Type 3, an NADPH-dependent enzyme, catalyzes the reduction of androstene dione to testosterone. Type 4, an NAD+-dependent enzyme, catalyzes the oxidation of estradiol to estrone, and androstenediol to dehydroepiandrosterone. 

An important feature of thyrostats, beta-agonists, and corticosteroids is that they are in general orally active. This means that they can be given via the fodder or drinking water, leaving no trace of percutaneous administration, which is one of the annoying indications when orally inactive steroids are injected. 

Metabolism of glucocorticoids occurs in the Uver, and is responsible for converting inactive steroids to active metabolites, as well as deactivating the active steroids to less active or inactive metabolites. Most pharmaceutical steroid products are active however, in the case of prednisone and cortisone, metabolism is necessary for the conversion to the active prednisolone and cortisol, respectively. Following metabolic conversion, glucocorticoids are excreted renally as less active or inactive metabolites. 

The drug undergoes metabolism that may lead to either pharmacologically active steroids e.g, estradiol, 5a-dihydrotestosterone (or 5a-DHT), and androsterone or to inactive steroids e.g., 6a-hydroxytestosterone, epitestosterone, and etiocholanolone. ... 

Drill [77] has pointed out that the ability to support pregnancy correlates with a positive result in the McGinty assay (p. 184) involving intrauterine administration of the steroid. Likewise, inactive steroids are inactive in this assay. 

Aside from cortisone and 17a-hydroxycorticosterone, there have been isolated from beef adrenals six corticosteroids containing five oxygen atoms which are usually considered biologically inactive but which have been available in such minute amounts that only very cursory physiological investigations have been carried out with them. Of these six, only one, allopregnane-3a,ll/3,17a,21-tetrol-20-one (Reichstein s Compound C), has never been synthesized. Principally in connection with the various syntheses of cortisone, there have been developed preparative procedures for the other five inactive steroids, and it may be hoped that they will now be subjected to more careful biological scrutiny. 

Ap-24 Gibian, H., Kieslich, K., Koch, H. J., Kosmol, H., Rufer, C., Schroder, E., and Vossing, R., Tetrahedron Letters 21. 2321 (1966). Asymmetric reduction with Saccharomyces sp. and Bacillus thuringlensis of a carbonyl group in a totally synthetic, optically inactive steroid precursor. 

The chief function of testosterone and other androgens is to promote the normal growth of the male reproductive organs (the primary sex characteristics) and the development of the male s characteristic deep voice, pattern of body and facial hair, and musculature (secondary sex characteristics). Although testosterone produces these effects, it is not active when taken oraUy because it is metabolized in the liver to an inactive steroid. A number of oral anabolic steroids have been developed for use in rehabilitation medicine, particularly when muscle atrophy occurs during recovery from an injury. Examples include the following compounds ... 

It grew out of another discovery in the senior author s laboratory, namely, that Reichstein s compound S could be converted in high yield into 11-epicortisol (1) by the enzymes of fungi of the genus Aspergillus The conversion of this inactive substance into the hormone cortisol thus became a problem of considerable importance. A route involving the 9,11-dehydro steroid (3) readily prepared from 11-epicortisol via its 21-acetate 11-tosylate... 

Steroid receptors belong to the nuclear receptor superfamily and bind steroid hormones. They are cytoplasmic when inactive and associated with chaperones. 

The influence of gonadal hormones on prepubertal animals suggests some steroidal sensitivity in adults with regard to F. elicitation. Young male sheep are induced to perform F. in response to exogenous T and to 17-p-estradiol F. in female red deer is also sensitive to T injections (Parrott, 1978 Fletcher, 1978). Sex differences can interact with the hormonal state where social conditions vary. Female cats (intact) display F. to urine marks only in the absence of males testosterone propionate induced F. in spayed females towards estrous females (Verbeme, 1976 Hart and Leedy, 1987), whereas an ovarian hormone (estradiol) failed to elicit F. to males (intact, and sexually inactive), presumably indicative of social inhibition overriding steroid facilitation. 

Several criteria determine whether a steroid-hormone-binding site is a putative receptor. First, the steroid-hormone-binding site must be present in hormone-responsive tissues or brain regions, and absent from nonresponsive ones. Second, it should bind steroids that are either active agonists or effective antagonists of the hormone effect, and should not bind steroids that are inactive in either sense. 

Fig. 1.1. General mechanism of action of steroid hormones. Steroid hormones cross through the plasmatic membrane without apparent difficulty favored by gradient. Some, which can be considered prohormones, are metabolized and transformed into more active products. This is the case with testosterone, which becomes dihydrotestosterone (DHT) in the target tissues of androgens, through the 5-alfa-reductase enzyme. The hormone binds to the receptor, a soluble protein of the cellular cytosol that, in the absence of hormone, is found associated with other proteins (hsp90 and others) that maintain the receptor in an inactive state. The hormone-receptor bond causes the other proteins to separate and a homodimer to be formed. The homodimer is the activated form of the receptor since it is capable of recognizing the genes that depend on that steroid hormone as well as of activating its expression, which leads to the synthesis of specific proteins...

Further, the resulting principal components of the variables were used to assign the CNS activity of compounds in the test set low penetration (BBB-), medium permeability (BBB ), or ready absorbance (BBB+). Although some of the molecules were found to exhibit problems throughout all prediction approaches, the prediction was very good for the group of quinolones (difloxacin and related compounds), similar to the results of Crivori et al. and Rose et al. The CNS activity of the steroids also showed a clear differentiation between those that are readily absorbed and CNS-inactive compounds. 

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