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

In order to characterize the main enzymatic systems involved in androgen and estrogen formation as well as metabolism in ZR-75-1 human breast cancer cells, incubation of intact cells was performed for 12 or 24 h at 37 degrees C with tritiated estradiol (E2), estrone (E1), androst-5-ene-3 beta, 17 beta-diol (5-ene-diol), dehydroepiandrosterone (DHEA), testosterone (T), androstenedione (4-ene-dione), dihydrotestosterone (DHT) or androsterone (ADT). The extra- and intracellular steroids were extracted, separated into free steroids, sulfates and non-polar derivatives (FAE) and identified by HPLC coupled to a Berthold radioactivity monitor. Following incubation with E2, 5-ene-diol or T, E1, DHEA and 4-ene-dione were the main products, respectively, thus indicating high levels of 17 beta-hydroxysteroid dehydrogenase (17 beta-HSD). When 4-ene-dione was used, on the other hand, a high level of transformation into 5 alpha-androstane-3,17-dione (A-dione), Epi-ADT and ADT was found, thus indicating the presence of high levels of 5 alpha-reductase as well as 3 alpha- and 3 beta-hydroxysteroid dehydrogenase. Moreover, some T was formed, due to oxidation by 17 beta-HSD. No estrogen was detected with the androgen precursors T or 4-ene-dione, thus indicating the absence of significant aromatase activity. Moreover, significant amounts of sulfates and non-polar derivatives were found with all the above-mentioned substrates. The present study shows that ZR-75-1 human breast cancer cells possess most of the enzymatic systems involved in androgen and estrogen formation and metabolism, thus offering an excellent model for studies of the control of sex steroid formation and action in breast cancer tissue.
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PMID:Multiple steroid metabolic pathways in ZR-75-1 human breast cancer cells. 200 38

A simple and efficient method is described for the purification of microsomal aromatase cytochrome P-450 from human placenta. The enzyme was solubilized with Emulgen 913 and sodium cholate and subjected to chromatography on a column of Sepharose 4B coupled with a specific monoclonal antibody, followed by hydroxyapatite column chromatography. The specific cytochrome P-450 content of purified aromatase was 13.1 (12-14.8) nmol/mg of protein. Aromatase assays were carried out with reconstituted systems of bovine liver P-450 reductase and dilauroyl-L-alpha-phosphatidylcholine with [1 beta-3H,4-14C]-androstenedione as substrate. The specific activity of purified aromatase was 65.0 (50.6-74.3) nmol.min-1.(mg of protein)-1 or a turnover rate of 5.0 (4.3-5.9) min-1. The total recovery of purified aromatase activity was 32.2%, and P-450 recovery was 17.6%. The Km of immunoaffinity-purified aromatase was 12, 210, 41, and 2830 nM for androstenedione, 16 alpha-hydroxyandrostenedione, testosterone, and 16 alpha-hydroxytestosterone, respectively. The very high Km value for 16 alpha-hydroxytestosterone aromatization gives a reasonable indication that estriol is not the directly aromatized product in the fetoplacental unit of human pregnancy. The aromatase P-450 was subjected to SDS-polyacrylamide gel electrophoresis in increasing quantities. Silver stain detection techniques indicated a single band having a molecular mass of 55 kDa with greater than 97% purity. The stability analysis showed a half-life of over 4 years on storage at -80 degrees C.
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PMID:Purification of human placental aromatase cytochrome P-450 with monoclonal antibody and its characterization. 200 37

Homogenates of diencephala obtained from brains of European great tits (Parus major) were incubated in the presence of tritiated testosterone (T) as precursor, and four metabolites produced from this steroid were formally identified and quantified. Conversion into 5 beta-dihydrotestosterone (5 beta-DHT) constituted the major metabolic pathway of T. Smaller amounts of 5 alpha-dihydrotestosterone (5 alpha-DHT), 5 beta-androstane-3 alpha, 17 beta-diol (5 beta-DIOL), and estradiol (E2) were also produced. The metabolism of T was time-dependent, and it varied as a function of the initial precursor concentration. The kinetics of 5 beta- and 5 alpha-reductases, as well as aromatase, followed the Michaelis-Menten model. It was found that 5 beta-reductase has a low apparent affinity for T, but is present in large concentrations. In contrast, the apparent affinity for T and the concentration of aromatase were approximately 3.9 times higher and 130 times smaller, respectively, than those of 5 beta-reductase. Intermediate values were found for 5 alpha-reductase. The validated assay was used to measure seasonal changes in the in vitro metabolism of T in the anterior (AH) and posterior (PH) hypothalamus and the cerebellum (CER) of free-living juvenile and adult male great tits. The production of 5 beta-DHT was low during the winter period in the PH of adult males, whereas the 5 beta-DIOL production was low in both parts of the hypothalamus at this time of the year. During autumn the production of these metabolites showed a transitory decrease in both parts of the hypothalamus of the juveniles. The production of 5 beta-reduced metabolites by the CER was high at all times of the year. In juveniles, the CER production of 5 beta-DHT did not change seasonally, whereas 5 beta-DIOL production peaked during summer. In the CER of adults, maximum production of both metabolites occurred during summer. Generally, less T was converted into 5 beta-reduced metabolites by the PH than by either the AH or the CER. E2 production was observed only in the AH and PH. With one exception (summer; AH), E2 production was high in both parts of the hypothalamus of adults throughout the year. In both AH and PH of juveniles, E2 production was low during summer. In these birds, it increased between summer and autumn in both parts of the hypothalamus, and also between autumn and winter in the PH. The production of 5 alpha-DHT did not change as a function of the season, the age of the birds, or the brain region.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Biochemical characterization and seasonal changes in the concentration of testosterone-metabolizing enzymes in the European great tit (Parus major) brain. 202 12

Sex differences in the metabolism of testosterone (T) in the developing brain of quail were examined using an in vitro microassay. During each developmental stage (day before hatching, hatching and 2 days after hatching) aromatase activity was higher in hypothalamic areas than in a control neostriatal area. There was no sex difference in oestradiol-17 beta (E2) formation in the late embryonic brain or at hatching. But aromatase activity in the male preoptic-anterior hypothalamic area was 50% higher than in females by day 2. No regional differences in brain 5 beta-reductase activity were detected at any of the developmental stages sampled. There was a sex difference in production of catabolic 5 beta-reduced metabolites. Male 5 beta-reductase activity declined continuously from high embryonic levels in all areas, whereas female enzyme activity showed an increase at hatching. In contrast to plasma progesterone, levels of T were higher in the male than in the female by day 1 after hatching. We suggest that elevated circulating T in the male after hatching may account for the sexual dimorphism in brain aromatase activity.
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PMID:Developmental sex differences in brain aromatase activity are related to androgen level. 207 19

Experiments were staged on immature (21 days) and mature (3.5 mos.) Wistar male rats to investigate the influence of the aromatase inhibitor 1, 4, 6-androstatriene-3, 17-dione on the activity of the aromatase and 5 alpha-reductase enzymatic complexes of the hypothalamus and the blood levels of LH and testosterone (T). The formation of 5 alpha-dehydrotestosterone against a background of aromatase activity inhibition was increased in mature rats and was unchanged in immature animals. The blood levels of LH and T were increased, the reaction of LH in immature animals being more marked. A conclusion has been made of a role of T aromatic transformations in the hypothalamus in tonic inhibition of LH secretion by endogenous T and a possible involvement of this mechanism in the maturation of male rats.
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PMID:[The role of testosterone metabolism in the hypothalamus in regulating the gonadotropic function of the hypophysis in male pre- and postpubertal rats]. 208 Jan 47

Evidence exists that testosterone (T) regulates brain aromatase activity in adult rats. It is not known, however, whether the activity and/or its regulation by androgens change during the time of puberty. In the present study, we examined the change in basal aromatase activity associated with puberty in both male and female rats. We also assessed the influence of castration and treatment with a nonaromatizable androgen, dihydrotestosterone (DHT), on the hypothalamic aromatase system during juvenile and peripubertal development of male rats. Aromatase activity was estimated by both quantifying the 3H2O released from [1 beta-3H]T and by isolating the estrogen product(s) by thin-layer chromatography (TLC) after incubations with [1,2,6,7-3H]T. 5 alpha-Reductase activity was determined simultaneously in the male hypothalamus by TLC using [1 alpha-3H]T as the substrate. Aromatase activity was linear with time of incubation and amount of tissue used. It was detected at similar levels in both tissue fragments and acutely dispersed cell preparations. Expression in the latter, but not the former required the addition of NADPH. Intracellular rates of both aromatase and 5 alpha-reductase activities were highest in the mitochondrial-microsomal fraction. In both males and females the time of puberty was associated with a decrease in hypothalamic aromatase activity. In females, this drop was found to occur between the days of first proestrus and first estrus. In males, it occurred between 48 and 68 days of age (i.e., after the animals had reached puberty, as assessed by the presence of free sperm in the seminiferous tubules).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Hypothalamic aromatase activity in male and female rats during juvenile peripubertal development. 211 86

Aromatase, 5 alpha-reductase and cytosolic androgen receptor levels were measured in the medial basal hypothalamus (MHB), amygdala (AMG), cerebellum and cerebral cortex of male and female fetal rhesus monkeys on day 70 of gestation. Higher aromatase activities were noted in the MBH and AMG of male than female fetuses. In contrast, no sex differences were found for 5 alpha-reductase and androgen receptor levels. These data suggest that at this early stage of development, differentiation of the MBH and AMG of the male fetus may be more susceptible to androgen modification, by way of aromatization to estrogens, than corresponding areas in the female fetus. Moreover, based upon a comparison of the current data to that published previously for later stages of development, it is suggested that the sex differences in aromatase activity are not the result of androgen stimulation.
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PMID:Aromatase, 5-alpha-reductase, and androgen receptor levels in the fetal monkey brain during early development. 211 11

Prostatic cancer is often locally advanced or metastatic when diagnosed, making surgical removal and radiotherapy ineffective treatments. Alternative therapy involves androgen deprivation because prostatic cancer is known to be androgen-dependent. Orchidectomy has proved effective but other methods of reducing androgen concentrations have also been developed. Oestrogens have proved effective, as have progestogens, and both steriodal and non-steroidal anti-androgens have been extensively studied. Another possible treatment is the use of inhibitors of androgen metabolism (aromatase and 5 alpha-reductase). Luteinizing hormone releasing hormone analogues, which act as antagonists or agonists, have been shown to have efficacies comparable to those of other therapies. Adrenal suppression has provided a useful alternative to adrenalectomy, particularly because of the high morbidity rate of surgery in elderly patients. Complete androgen withdrawal using an anti-androgen in association with surgical or chemical castration may be a more superior treatment. Another possible approach is the use of somatostatin analogues, which have been shown to inhibit the growth of animal prostatic cancer cells.
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PMID:Prostatic cancer--survey of hormonal treatment in Europe. 218 53

Although testosterone (T) stimulates aggressive and reproductive behaviors in males of many vertebrate species, it is now known that the full expression of T action in the brain requires aromatization to estradiol (E2) and subsequent interaction of locally formed E2 with nuclear estrogen receptors. In experiments reported here, we used a behavioral test which quantifies the response of an individual male Japanese quail (Coturnix coturnix japonica) to the visual stimulus of a conspecific. We have called this behavior aggression because it shares many features in common with traditional measures of aggression, e.g., predicting dominance and subordinance. Nevertheless, the behavior probably also combines a complex steroid-sensitive masculine behavior. The advantage of this test is that it allows the discrimination of individual differences in masculine behavior but avoids fighting and sexual encounters per se, thereby reducing effects of learning, a problem with previous tests of avian aggression. In addition, this test has been applied usefully to identify neuroendocrine correlates to male behavior. Using this test, the arousal of reproductively inactive males (hereafter referred to as aggression) is activated by administration of T or estradiol benzoate (EB), but not by 5 alpha-dihydrotestosterone (DHT). T-induced aggression was blocked by the aromatase inhibitor 4-hydroxyandrostenedione (OHA), an effect partially reversed by treatment with EB. In addition, OHA or the estrogen receptor blocker CI-628 reduced aggressiveness of reproductively active males whereas the androgen receptor blocker flutamide had no effect. Results with the 5 alpha-reductase inhibitor N,N-diethyl-4-methyl-3-oxo-4-aza-5 alpha-androstane-17 alpha-carboxyamide (4-MA) were equivocal. Additionally, treatment of reproductively inactive quail with T or E2 but not DHT increased aromatase activity in the hypothalamus-preoptic area (HPOA). We conclude, therefore, that T to E2 conversion is essential for the activation of aggressiveness in this species. Although locally formed estrogen exerts its effects on aggression in part by increasing activity of aromatase per se, analysis of the time course of behavioral induction or suppression by the various treatments suggests that the response has multiple components, including both short latency, receptor-independent and long latency, receptor-dependent events.
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PMID:Aromatization mediates aggressive behavior in quail. 219 94

FCE 24928 (4-aminoandrosta-1,4,6-triene-3,17-dione) was selected among a series of 4-aminoandrostenedione derivatives as a novel irreversible aromatase inhibitor. Its in vitro and in vivo properties have been studied and compared to FCE 24304 (6-methylenandrosta-1,4-diene-3,17-dione) and 4-OHA (4-hydroxyandrostenedione). FCE 24928 caused time-dependent inhibition of human placental aromatase with a t1/2 of 4 min and Ki of 59 nM. Enzyme inactivation by FCE 24928 was faster than by FCE 24304 (t1/2 13.9 min). In PMSG-treated rats, microsomal ovarian aromatase activity was reduced 24 h after FCE 24928 dosing by both the s.c. (ED50 1.2 mg/kg) and the oral (ED50 14.1 mg/kg) routes. The compound was more potent than FCE 24304 and 4-OHA (ED50 1.8 and 3.1 mg/kg s.c.). FCE 24928 did not show any interference with 5 alpha-reductase and desmolase activity nor any significant binding affinity for androgen and estrogen receptors. Slight binding affinity for androgen receptor was observed with FCE 24304 and 4-OHA (0.21 and 0.25% of DHT). In immature, castrated rats, FCE 24928 did not show any intrinsic androgenic activity, up to 100 mg/kg/day s.c., in contrast to a slight androgenic activity observed with FCE 24304 at 10 mg/kg s.c.
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PMID:4-Aminoandrostenedione derivatives: a novel class of irreversible aromatase inhibitors. Comparison with FCE 24304 and 4-hydroxyandrostenedione. 225 40


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