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Query: UMLS:C0338671 (Steroids)
 9,479 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Evidence has recently accumulated indicating that aromatase activity in the preoptic area is modulated in parallel by both slow (hours to days) genomic and rapid (minutes to hours) non-genomic mechanisms. We review here these two types of control mechanisms and their potential contribution to various aspects of brain physiology in quail. High levels of aromatase mRNA, protein and activity (AA) are present in the preoptic area of this species where the transcription of aromatase is controlled mainly by steroids. Estrogens acting in synergy with androgens play a key role in this control and both androgen and estrogen receptors (ER; alpha and beta subtypes) are present in the preoptic area even if they are not necessarily co-localized in the same cells as aromatase. Steroids have more pronounced effects on aromatase transcription in males than in females and this sex difference could be caused, in part, by a sexually differentiated expression of the steroid receptor coactivator 1 in this area. The changes in aromatase concentration presumably control seasonal variations as well as sex differences in brain estrogen production. Aromatase activity in hypothalamic homogenates is also rapidly (within minutes) down-regulated by exposure to conditions that enhance protein phosphorylation such as the presence of high concentrations of calcium, magnesium and ATP. Similarly, pharmacological manipulations such as treatment with thapsigargin or stimulation of various neurotransmitter receptors (alpha-amino-3-hydroxy-methyl-4-isoxazole propionic acid (AMPA), kainate, and N-methyl-D-aspartate (NMDA)) leading to enhanced intracellular calcium concentrations depress within minutes the aromatase activity measured in quail preoptic explants. The effects of receptor stimulation are presumably direct: electrophysiological data confirm the presence of these receptors in the membrane of aromatase-expressing cells. Inhibitors of protein kinases interfere with these processes and Western blotting experiments on brain aromatase purified by immunoprecipitation confirm that the phosphorylations regulating aromatase activity directly affect the enzyme rather than another regulatory protein. Accordingly, several phosphorylation consensus sites are present on the deduced amino acid sequence of the recently cloned quail aromatase. Fast changes in the local availability of estrogens in the brain can thus be caused by aromatase phosphorylation so that estrogen could rapidly regulate neuronal physiology and behavior. The rapid as well as slower processes of local estrogen production in the brain thus match well with the genomic and non-genomic actions of steroids in the brain. These two processes potentially provide sufficient temporal variation in the bio-availability of estrogens to support the entire range of established effects for this steroid.
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PMID:Multiple mechanisms control brain aromatase activity at the genomic and non-genomic level. 1462 33

Aromatase (P450arom, CYP19) catalyzes the aromatization reaction that converts androgens to estrogens. Although human P450arom has been readily purified from placenta, its hydrophobic properties and instability has hampered detailed characterization. Utilizing a N-terminal replacement (MARQSFGRGKL, derived from CYP2C11), we successfully modified this unstable enzyme into stable forms. Based on a known polymorphism, we created two constructs, NmA264C and NmA264R having cysteine or arginine at position 264. The recombinant P450arom NmA264R was expressed in Escherichia coli (350-400 nmol/L culture) primarily by coexpression with molecular chaperones GroES/GroEL while NmA264C was expressed (240 nmol/L culture) only in the presence of chloramphenicol. Although NmA264C was recovered only in the membrane fraction, approximately 14% of NmA264R was recovered in the cytosolic fraction, suggesting that NmA264R is more hydrophilic than NmA264C. NmA264R was highly purified to the specific content 13.6 nmol P450/mg protein. Purified P450arom NmA264R converted androstenedione to estrone with Vmax 12.4 nmol/(min nmol) and Km) 0.26 microM, and testosterone to estradiol with Vmax 52.2 nmol/(min nmol) and Km 10.9 microM. Because of the increased stability of NmA264R, we could unambiguously determine properties of human P450arom by optical and electron paramagnetic resonance spectroscopy. The purified protein was a typical low-spin form, which was converted to a high-spin form when androstenedione was added. The rhombicity of substrate-bound forms was higher than that reported for other P450s, an interesting characteristic of human P450arom. The highly stable and active P450arom NmA264R sets the stope for detailed structure/function analyses of this important member of the P450 superfamily.
Steroids 2004 Apr
PMID:Characterization of stable human aromatase expressed in E. coli. 1518 89

In vertebrates, sex is determined essentially by two means, genetic factors located on sex chromosomes and epigenetic factors such as temperature experienced by the individual during development. Steroids, especially estrogens, are clearly involved in gonadal differentiation in non-mammalian vertebrates. In this regard, the expression of the estrogen-producing enzyme, aromatase, has been shown to be temperature-sensitive in species where temperature can reverse sex differentiation, especially in our model, the amphibian Pleurodeles waltl. We investigated here the regulation of aromatase expression in the brain during sex differentiation in Pleurodeles. We first isolated a brain isoform of aromatase mRNA which differs in its 5' untranslated region from the isoform previously isolated from adult gonads. In adult Pleurodeles, the brain isoform is mainly expressed in brain tissue while the other isoform is gonad specific. Thus, regulation of aromatase expression in P. waltl could occur by alternative splicing of non-coding exon 1 as previously described in mammals. We then investigated aromatase expression in the brain of male and female larvae and found no differences with regard to sex. Measures of aromatase activity in the brain also showed no differences between sexes at larval stages whereas activity markedly increases in the ovary concomitant with the start of gonadal differentiation. These results support the hypothesis that aromatase could be a target of a temperature-sensitive sex-reversing effect in the gonads but not in the brain.
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PMID:Cerebral and gonadal aromatase expressions are differently affected during sex differentiation of Pleurodeles waltl. 1559 Oct 30

Aromatase is a cytochrome P-450 enzyme complex that catalyzes the conversion of androst-4-ene-3,17-dione (AD) to estrone through three sequential oxidations of the 19-methyl group. 3-DeoxyAD (1) and its 5-ene isomer 4 are potent and good competitive aromatase inhibitors, which are converted by aromatase to the aldehyde derivatives 3 and 6, respectively, through 19-hydroxy intermediates 2 and 5, respectively. To study the deuterium isotope effect on the conversions of 19-ols 2 and 5 into the corresponding 19-als 3 and 6, we initially synthesized [19,19-(2)H(2)]19-ols 2 and 5 starting from the corresponding non-labeled 19-als 3 and 6 through NaB(2)H(4) reduction of the 19-aldehyde group, followed by oxidation with pyridinium dichromate, and a subsequent NaB(2)H(4) reduction. Approximately 1:1 mixtures of non-labeled (d(0)) and deuterated (d(2)) 19-ols 2 and 5 were separately incubated with human placental microsomes in the presence of NADPH under an air atmosphere, and deuterium contents of the recovered substrates and the 19-aldehyde products were determined by gas chromatography-mass spectrometry. In each experiment, the ratio of d(0) to d(2) of the recovered substrate along with that of d(0) to d(1) of the product were identical to the d(0) to d(2) ratio of the employed substrate irrespective of the incubation time, indicating that the 19-oxygenations of the 3-deoxy steroids 2 and 5 proceeded without a detectable isotope effect, as seen in the aromatization sequence of the natural substrate AD.
Steroids 2005 Nov
PMID:Gas chromatography-mass spectrometric analysis of oxidative reactions of [19,19-(2)H(2)]19-hydroxy-3-deoxy androgens by placental aromatase. bsence of a deuterium-isotope effect. 1600 12

Previous studies have demonstrated that cyclooxygenase-2 (COX-2) inhibitor NS-398 decrease aromatase activity at the transcript level in breast cancer cells. However, N-Methyl NS-398, which does not have COX-2 inhibitory activity but has very similar structure to NS-398, decreases aromatase activity and transcription in MCF-7 and MDA-MB-231 breast cells to the same extent as NS-398. This suggests that NS-398 decrease aromatase expression in breast cancer cells via other mechanism(s). Further investigations find that both compounds only decrease aromatase activity stimulated by forskolin/phorbol ester at the transcript level in both breast cancer cell lines and in breast stromal cells from patients. They do not affect aromatase expression and activity stimulated by dexamethasone. Both compounds also suppress MCF-7 cell proliferation stimulated by testosterone. Aromatase inhibition studies using placental microsomes demonstrate that the compounds show only weak direct aromatase inhibition. These results suggest that NS-398 and its N-methyl analog suppress aromatase expression and activity with multiple mechanisms.
Steroids 2008 Jan
PMID:Suppression of aromatase in human breast cells by a cyclooxygenase-2 inhibitor and its analog involves multiple mechanisms independent of cyclooxygenase-2 inhibition. 1804 33

Starting from the D-homo lactones of androst-4-en-3-one 3 and 4, prepared from 1 and 2, the new 17a homolactones 5-12, 14 and 15, were synthesized. The 4-hydroxy compounds 9 and 10 were obtained through the reaction of 4alpha,5alpha- (5 and 7) and 4beta,5beta- (6 and 8) epoxides with formic acid. The epoxides 5 and 6 were prepared from compound 3, and epoxides 7 and 8 from compound 4 by oxidation with H(2)O(2) under basic conditions. Compound 1 served as a starting substance for obtaining lactones 11-13. Oxidation of compound 1 with m-chloroperbenzoic acid yielded 11 and 12, but compound 13 gave 14. Compound 15 was obtained from 13 by oxidation with H(2)O(2) under basic conditions. The structures of epoxides 6 and 14 were confirmed by X-ray structural analysis. Cytotoxic activity against three tumor cell lines (human breast adenocarcinoma ER+, MCF-7, human breast adenocarcinoma ER-, MDA-MB-231, and prostate cancer PC3) was evaluated. Compounds 6 and 14 showed strong activity against PC3, the IC(50) being 10.6 and 2.2 microM, respectively, whereas compounds 3 and 8 showed strong activity against MDA-MB-231 (IC(50) is 9.3 and 3.6 microM, respectively). Aromatase inhibition assay showed that the tested compounds 9, 10, and 14 possess lower activity compared to formestane.
Steroids 2008 Jul
PMID:Synthesis and biological evaluation of some new A,B-ring modified steroidal D-lactones. 1838 24

Steroids are known to play a crucial role in gonadal sex differentiation in many non-mammalian vertebrates, but also in the gonadal sex change of hermaphroditic teleosts. We investigated the expression of two genes encoding key steroidogenic enzymes, i.e., cytochrome P450 aromatase (P450arom) and cytochrome P45011beta-hydroxylase (P45011beta), during the sex change of the protogynous rice field eel, Monopterus albus. Using RT-PCR with degenerate primers, we cloned rice field eel homologous fragments for both genes (rcP450arom and rcP45011beta) as indicated by the high level of homology with P450arom and P45011beta sequences from various vertebrates. Gonadal expression of rcP450arom and rcP45011beta mRNA levels were then assessed during the sex change by semi-quantitative RT-PCR and a real-time RT-PCR. rcP450arom was predominantly expressed in ovary, much less in ovotestis, and barely in testis. Conversely, P45011beta was markedly up-regulated at the onset of testicular development. These findings underline that regulation of steroidogenesis is an important process in the sex change of protogynous rice field eel, and they clearly indicate that the concomitant down-regulation of P450arom and up-regulation of P45011beta are of pivotal importance to the sex change of this species.
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PMID:Aromatase (P450arom) and 11beta-hydroxylase (P45011beta) genes are differentially expressed during the sex change process of the protogynous rice field eel, Monopterus albus. 1880 4

Aromatase and steroid sulfatase (STS) are particularly attractive targets in the treatment of estrogen-receptor-positive breast cancer and the development of enzyme-based cancer imaging agents for the biomedical imaging technique positron emission tomography (PET). New carbon-11-labeled sulfamate derivatives were first designed and synthesized as potential PET dual aromatase-steroid sulfatase inhibitor (DASSI) radiotracers for imaging of aromatase and STS expression in breast cancer. The target tracers 5-(((4-cyanophenyl)(4H-1,2,4-triazol-4-yl)amino)methyl)-2-[(11)C]methoxyphenyl sulfamate ([(11)C]8a) and 4-(((4-cyanophenyl)(4H-1,2,4-triazol-4-yl)amino)methyl)-2-[(11)C]methoxyphenyl sulfamate ([(11)C]8b) were prepared from their corresponding precursors 5-(((4-cyanophenyl)(4H-1,2,4-triazol-4-yl)amino)methyl)-2-hydroxyphenyl sulfamate (16) and 4-(((4-cyanophenyl)(4H-1,2,4-triazol-4-yl)amino)methyl)-2-hydroxyphenyl sulfamate (21) with [(11)C]CH(3)OTf under basic conditions through the O-[(11)C]methylation and isolated by the reversed-phase high pressure liquid chromatography (HPLC) method in 30-45% radiochemical yields based on [(11)C]CO(2) and decay corrected to end of bombardment (EOB). The specific activity at end of synthesis (EOS) was 111-185GBq/micromol.
Steroids 2009 Nov
PMID:Design and synthesis of carbon-11-labeled dual aromatase-steroid sulfatase inhibitors as new potential PET agents for imaging of aromatase and steroid sulfatase expression in breast cancer. 1955 19

Local aromatization of testosterone into 17beta-estradiol (E(2)) is often required for the physiological and behavioral actions of testosterone. In most vertebrates, aromatase is expressed in a few discrete brain regions. While many studies have measured brain aromatase mRNA or activity, very few studies have measured brain E(2) levels, particularly in discrete brain regions, because of technical challenges. Here, we used the Palkovits punch technique to isolate 13 discrete brain nuclei from adult male zebra finches. Steroids were extracted via solid phase extraction. E(2) was then measured with an ultrasensitive, specific and precise radioimmunoassay. Our protocol leads to high recovery of E(2) (84%) and effectively removes interfering brain lipids. E(2) levels were high in aromatase-rich regions such as caudal medial nidopallium and hippocampus. E(2) levels were intermediate in the medial preoptic area, ventromedial nucleus of the hypothalamus, lateral and medial magnocellular nuclei of anterior nidopallium, nucleus taeniae of the amygdala, and Area X. E(2) levels were largely non-detectable in the cerebellum, HVC, lateral nidopallium and optic lobes. Importantly, E(2) levels were significantly lower in plasma than in the caudal medial nidopallium. This protocol allows one to measure E(2) in discrete brain regions and potentially relate local E(2) concentrations to aromatase activity and behavior.
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PMID:17beta-Estradiol levels in male zebra finch brain: combining Palkovits punch and an ultrasensitive radioimmunoassay. 2014 13

Novel pyrazole and isoxazole derivatives (6-9) were synthesized as a aromatase inhibitors. Pyrazole was synthesized from hydrazine hydrate and isoxazoles from hydroxylamine hydrochloride under different conditions. Molecular docking studies were carried out for the synthesized compounds. The best score was obtained for the compound (9) followed by compound (6) while compound (8) afforded poorest of the score. Aromatase inhibitory activity for compound (6) having pyrazole ring at 2,3 position showed highest activity followed by nitrile derivative (9). Isomeric forms of isoxazole (7 and 8) showed very poor activity compared to fadrozole and aminoglutethimide. Preliminary kinetic studies have shown that both of the active compounds (6 and 9) are reversible inhibitors of the enzyme.
Steroids 2011 Apr
PMID:Synthesis of some novel androstanes as potential aromatase inhibitors. 2121 65


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