Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:Q8NEX9 (reductase)
 26,410 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A large number of new options for the management of benign prostatic hyperplasia (BPH) have become available, including several classes of drugs that are under investigation. Various principles of management include hyperthermia, balloon dilatation, the introduction of spirals to keep the prostate open, and exploitation of the endocrine dependence of BPH through androgen withdrawal, using 5 alpha-reductase and aromatase inhibition. The efficacy of these alternative forms of treatment will become better defined during the next few years. Whatever the result, it is likely that the indication for surgery will decrease. Therapy must also take into account the sexual activity and expectations of the patient, an area that until recently has been largely neglected.
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PMID:Changing approaches in the treatment of benign prostatic hyperplasia. 172 65

Reduction, oxidation, and aromatization of androgens were studied in the male genital tract of untreated control and neonatally estrogenized mice. This study shows regional differences in 5 alpha-reductase and 17 beta-hydroxysteroid oxidoreductase activities in untreated male genital tract; 3 alpha/3 beta-hydroxysteroid oxidoreductase (3 alpha/3 beta-HSOR) activity varied little between tissues. Neonatal treatment with diethylstilbestrol (DES, 2 micrograms/pup/day on days 1 through 5) caused an alteration in the androgen metabolism of the male genital tract, resulting in apparent decreased net accumulation of dihydrotestosterone (DHT). This developmentally-induced 5 alpha-reductase deficiency may play a role in the long-term inhibitory effects of early estrogenization by DES in the growth and function of male sex accessory glands. No aromatase activity could be demonstrated in the male genital tract of control or neonatally estrogenized mice.
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PMID:Androgen metabolism in control and neonatally estrogenized male mice. 180 46

Human hair follicles contain several steroid enzymes capable of transforming weak androgens, such as dehydroepiandrosterone, into more potent target tissue androgens, such as testosterone and dihydrotestosterone. Kinetic constants have been evaluated for the 3-alpha, 3-beta, and 17-beta hydroxysteroid dehydrogenase enzymes, 5a-reductase, and the aromatase enzyme in isolated human HF from scalp of men and women with androgenetic alopecia. The apparent Km values did not differ for each enzyme whether present in bald, receded HF or thick, anagen HF of men or women. However, levels of specific activity varied greatly in the frontal versus occipital HF analyzed. The androgen receptor content and activation factors also differ between men and women. The steroid mechanisms influencing AGA in men and women may be similar, but differences in the specific activity/amounts of enzymes, receptors, and activation factors differ between men and women. These findings may explain the varied clinical presentations of men and women with AGA, and may shape treatment options for the future.
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PMID:Steroid chemistry and hormone controls during the hair follicle cycle. 180 93

Adult male hamsters were maintained under 14 hours of light per day and randomly assigned to groups that received daily afternoon melatonin (25 micrograms) or vehicle injections. Animals from both groups were killed following 4, 8, and 12 weeks of treatment. By 12 weeks, the melatonin-treated hamsters had significant reductions in the weights of the testes and seminal vesicles, serum testosterone levels, and activities did not differ between groups. In a second experiment, hamsters were hypothalamic-preoptic area (HPOA) aromatase activities. Hypothalamic-preoptic area 5 alpha-reductase activities did not differ between groups. In a second experiment, hamsters were again treated with melatonin or vehicle for 12 weeks prior to being killed. After 10 weeks of treatment, groups of melatonin-treated animals received subcutaneous silastic capsules (5, 10, or 20 mm) filled with testosterone. Animals in two other groups were given blank implants or no implants at all. Two weeks later, at autopsy, reproductive organ weights, serum testosterone levels, and HPOA aromatase activities were significantly suppressed by melatonin administration. 5 alpha-Reductase activity in the HPOA was not affected. Hamsters that had been given the 10- and 20-mm testosterone implants exhibited normal seminal vesicle weights and HPOA aromatase activities. These results suggest that melatonin-induced reduction of HPOA aromatase activity is mediated by decreased circulating levels of testosterone.
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PMID:Effect of testosterone replacement on the alteration of steroid metabolism in the hypothalamic-preoptic area of male hamsters treated with melatonin. 181 18

This updated literature review on heterosteroids and drug research has information on chemical structure, pharmacology, and effects. It first discusses the anti-inflammatory heterosteroids, such as mometasone furoate and cortivazol. It also covers heterosteroidal antimineralocorticoids and anabolic hetero derivatives. The review discusses at length the 19-norsteroid, mifepristone (RU-486), which exhibits antiprogestational activity and is being used for fertility control in women. It also has antiglucocorticoid activity and shows promise as a treatment of diseases characterized by muscle atrophy. In vitro studies indicate that mifepristone inhibits growth of breast cancer cell lines and of endometrial cancer cell lines. It has already exhibited growth inhibitory effects in some breast cancer patients. Discussions of mifepristone's pharmacokinetics and structural modifications of mifepristone follow. Danazol is an antigonadotropin and is used to treat endometriosis, benign breast disease, precocious puberty, hereditary angioneurotic edema, menorrhagia, some types of infertility, and gynecomastia. Danazol effects considerable changes in lipid metabolism. Other hormonal, antihormonal, and/or antifertility heterosteroids and/or aspects include androgen antagonists (e.g., cyproterone acetate), estrogen activity, antiestrogens, STS-557, and oximinosteroids. Heterosteroidal inhibitors of steroid hormone biosynthesis discussed are aromatase inhibitors, 5 alpha-reductase inhibitors, and 3 beta-hydroxysteroid dehydrogenase inhibitors (trilostane, epostane, and azastene). Heterosteroids affect the cardiovascular system, including the cardiac glycosides, antiarrhythmic agents, and antilipemic agents. Some heterosteroids affect central nervous system activity (e.g., RU-5135 causes convulsions in rodents). Pancuronium analogues and chandonium and analogues are neuromuscular blocking azasteroids. In addition to danazol and RU-486, several other antineoplastic heterosteroids exist (e.g., estramustine phosphate sodium, a prostate cancer drug).
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PMID:Heterosteroids and drug research. 184 48

The regulation of 11 beta-hydroxysteroid dehydrogenase (11 beta HSD) was studied in cultured human skin fibroblasts. 11-Oxo-reductase activity was 5- to 10-fold higher than 11 beta-dehydrogenase activity. Cells treated with 100 nM dexamethasone (Dex) showed a 3-fold increase in the maximum velocity of both activities without a change in the Km values. Dex induction of 11 beta HSD was half-maximal at 48 h and was blocked by glucocorticoid receptor antagonists. Nonglucocorticoid steroids were ineffective. Removal of serum from the culture medium increased maximum velocity values up to 6-fold. Treatment of cells grown in the absence of serum with 8-bromo-cAMP, phorbol esters, or insulin decreased both 11 beta HSD activities. The effects of Dex treatment and serum removal were additive and were blocked by cycloheximide and actinomycin-D. In all experiments both 11 beta HSD activities were modulated in parallel. Both cortisone (200 nM) and cortisol increased the aromatase activity of fibroblasts in the presence of serum. Prior induction of 11 beta HSD by serum removal increased the potency of cortisone from 10-15% to 50% that of cortisol. We conclude that 1) in human fibroblasts 11 beta HSD appears to be a single protein that is under multifactorial regulation; 2) 11 beta HSD may increase or decrease cortisol availability to glucocorticoid receptors; and 3) plasma cortisone levels may be important in assessing glucocorticoid status.
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PMID:Regulation of 11 beta-hydroxysteroid dehydrogenase activity in human skin fibroblasts: enzymatic modulation of glucocorticoid action. 185 64

Estrogen formed by aromatization of testosterone (T) is involved in the activation of sexual behavior and control of the neuroendocrine system in the male Syrian hamster. Our study examined whether daylength influences formation of estrogen in the preoptic area (POA) and other neuroendocrine areas (anterior hypothalamus, AHT, and medial amygdala, MA) which are targets for T in behaviorally active males. Estrogen formation in individual brain samples was assayed in vitro using the stereospecific production of 3H2O from (1 beta-3H) T as a measurement of aromatase activity. Serum levels of PRL, LH, FSH and T were compared with brain aromatase activity. Groups of intact, castrated and T-treated (chronic silastic T implants) male hamsters, previously selected on behavioral criteria as being sexually active, were maintained on long (16:8LD) or short (8:16LD) daylength for 16 weeks. Two further groups of males either intact or castrated and T-treated were shifted after 7 weeks from the long photoperiod to 12:12LD. POA, AHT and MA areas of sexually active males contained active aromatase systems which converted 3H-T to estrogens. Enzyme activity differed between the areas (POA, MA greater than AHT). Aromatase activity was low in medial septum and cerebral samples. Castration, which reduced serum T to undetectable levels and elevated LH and FSH, had no effect on preoptic aromatase activity. Although estrogen formation in POA did not differ between 8:16LD and 16:8LD males, castration reduced aromatase activity in AHT of both short- and long-day groups. Aromatase activity in AHT was also significantly reduced in photo-inhibited 12:12LD intact males. There was no analogous decrease in 5 alpha-reductase or 17 beta-hydroxysteroid dehydrogenase (HSD) activity, indicating a specific effect on the aromatase. The effect of photoperiod on aromatase activity was not reversed by T treatment. Therefore, photoinhibition acts in part through the effects of reduced T levels on the anterior hypothalamus, but it also acts independently of circulating T. Our results suggest that both androgen and photoperiod may regulate the AHT aromatase system and that this occurs by different mechanisms. The more active aromatase system in POA is insensitive to both castration and photoperiod. Behavioral deficits in short-day males are not due to changes in the preoptic aromatase system, but may be related to changes in aromatase activity within AHT. We conclude that there is a difference in the regulation of two locally active aromatase systems within the preoptic-anterior hypothalamic complex of the male hamster.
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PMID:Brain aromatization of testosterone in the male Syrian hamster: effects of androgen and photoperiod. 190 34

Many central actions of testosterone (T) require the transformation of T into several metabolites including 5 alpha-dihydrotestosterone (5 alpha-DHT) and estradiol (E2). In birds as in mammals, 5 alpha-DHT and E2, alone or in combination, mimic most behavioral effects of T. The avian brain is, in addition, able to transform T into 5 beta-DHT, a metabolite which seems to be devoid of any behavioral or physiological effects, at least in the context of reproduction. By in vitro product-formation assays, we have analyzed the distribution, sex differences and regulation by steroids of the 3 main T metabolizing enzymes (aromatase, 5 alpha- and 5 beta-reductases) in the brain of the Japanese quail (Coturnix c. japonica) and the zebra finch (Taeniopygia guttata castanotis). In the hypothalamus of quail and finches, aromatase activity is higher in males than in females. It is also decreased by castration and increased by T. The activity of the 5 alpha-reductase is not sexually differentiated nor controlled by T. The 5 beta-reductase activity is often higher in females than in males but this difference disappears in gonadectomized birds and no clear effect of T can be observed at this level. The zebra finch brain also contains a number of steroid-sensitive telencephalic nuclei [e.g. hyperstriatum ventrale, pars caudale (HVc) and robustus archistriatalis (RA)] which play a key role in the control of vocalizations. These nuclei also contain T-metabolizing enzymes but the regulation of their activity is substantially different from what has been observed in the hypothalamus. Aromatase activity is for example higher in females than in males in HVc and RA and the enzyme in these nuclei is not affected by castration nor T treatment. In these nuclei, the 5 alpha-reductase activity is higher in males than in females and the reverse is true for the 5 beta-reductase. These sex differences in activity are not sensitive to gonadectomy and T treatment and might therefore be organized by neonatal steroids. We have been recently able to localize aromatase-immunoreactive (AR-ir) neurons by ICC in the brain of the quail and zebra finch. Positive cells are found in the preoptic area, ventromedial and tuberal hypothalamus. AR-ir material is found in the perikarya of cells and fills the entire cellular processes including axons. At the electron microscope level, immunoreactive material can clearly be observed in the synaptic boutons. This observation raises questions concerning the mode of action of estrogens produced by central aromatization of T.
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PMID:Testosterone metabolism in the avian hypothalamus. 195 58

The central nervous system (CNS) is considered a target structure for the action of all the classes of hormonal steroids produced by the organism. Well-characterized genomic and less well-understood membrane mechanisms of action are probably involved in the steroid modulation of brain activities. Moreover, some classes of steroids need to be converted into "active" metabolites before interacting with their effector systems. In particular, testosterone (T) exerts many of its effects after conversion to 5 alpha-dihydrotestosterone (DHT) and estrogens. The CNS possesses both the 5 alpha-reductase, the enzyme which produces DHT and the aromatase which transforms T into estrogens; however, the relative role and distribution of these enzymes in the various structural components of the CNS has not been clarified so far. The 5 alpha-reductase has been found to be present in high concentrations in brain white matter structures because these are particularly rich in myelin membranes, to which the enzymatic activity appears to be associated. This membrane localization might suggest a possible involvement of steroidal 5 alpha-reduced metabolites in membrane-mediated events in the CNS. Moreover, the distribution of 5 alpha-reductase was studied in neurons, astrocytes and oligodendrocytes isolated from the brain of male rats by density gradient ultracentrifugation, as well as in neurons and glial cells grown in culture. The aromatase activity was also evaluated in neurons and glial cells grown in culture and in isolated oligodendrocytes. Among the three cell types isolated, neurons appear to be more active than oligodendrocytes and astrocytes, respectively, in converting T into DHT. Also, in cell culture experiments, neurons are more active in forming DHT than glial cells. Only neurons possess aromatase activity, while glial cells are apparently unable to aromatize T.
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PMID:Testosterone metabolism in brain cells and membranes. 195 65

Rabbit epiphyseal cartilage tissue has been shown to convert testosterone (T) to dihydrotestosterone (DHT). In this report, the metabolic conversion of T into DHT is shown to be age-dependent, being most active in cartilage from animal at the age of gonadal maturation. Human cartilage from newborn and prepubertal children is also shown to convert T into DHT and--to a lesser extent--to estradiol. Low concentrations of DHT and 17 beta-estradiol (E2) (10(-11)-10(-9) M) were also shown to stimulate in vitro cartilage cells from boys and girls respectively. As previously shown for cultured rabbit chondrocytes, the stimulating effects of both hormones on human chondrocytes was age-dependent. Cartilage cells derived from children up to one year old did not respond, while cells from boys and girls in the early phase of puberty responded best. These data indicate that human cartilage tissue in vivo, contains both 5 alpha-reductase and aromatase activities during post-natal skeletal growth. Androgens may act on cartilage after their metabolic conversion to estrogens. The mechanism of age-dependency of both cartilage androgen enzymatic activities and chondrocyte responsiveness to sex steroids in vitro remains to be explained.
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PMID:Age-dependent responsiveness of rabbit and human cartilage cells to sex steroids in vitro. 195 68


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