Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0432222 (SEM)
 47,337 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Available androgen binding to soluble proteins from the cytosol of human endometrium was studied using the dextran coated charcoal adsorption method and sucrose density centrifugation analysis. Specific binding of [3H]-5 alpha-dihydrotestosterone ([3H]-DHT) was observed with both methods. The apparent dissociation constant (Kd), for DHT binding is 1.3 +/- 0.2 (SEM) nM and the binding capacity 177 +/- 42 (SEM) fmol/mg protein. Sucrose density ultracentrifugation identifies specific [3H]-DHT binding that sediments at 4S and 8S. The stability of the androgen receptor in human endometrium is increased by the addition of 10% glycerol to the homogenization buffer. The addition of trypsin or pronase and heating at 60 degrees C reduces specific binding which demonstrates that the specific [3H]-DHT binder is a protein. The uptake of [3H] DHT in endometrial tissue minces indicated that 20% of the bound radioactivity was nuclear. Steroid specificity suggests that the binding protein from the uterus is specific for androgens. These observations indicate that androgen binding protein in the human uterus has the characteristics of the androgen receptor.
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PMID:The androgen receptor of the human endometrium. 358 78

In an effort to determine whether human benign prostatic hyperplasia (BPH) is characterized by an increase in androgen receptor content, the levels of nuclear and cytosolic androgen receptors were quantitated in normal prostatic tissue obtained from five young men (mean age /+- SEM, 26 +/- 3 yr) and in hyperplastic (periurethral) and peripheral prostatic tissues obtained from nine older men (mean age, 62 +/- 2 yr). There was no significant difference between the cytosolic or nuclear androgen receptor content of the hyperplastic, peripheral, or normal prostatic tissue. Thus, in this study we were unable to identify an increase in androgen receptor content in BPH. These findings fail to support the hypothesis that increases in androgen receptor content are involved in the pathogenesis of human BPH.
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PMID:Androgen receptor content of normal and hyperplastic human prostate. 617 40

We have studied the effects of estradiol injections on cytosolic estrogen, androgen and progesterone receptor levels in order to understand the role of this steroid in the induction of prostatic hyperplasia in the dog. Adult mongrel dogs were castrated and were then given injections of estradiol (0.25, 0.8 or 2.5 mg) dissolved in olive oil containing 5% benzyl alcohol on days 0, 2, 5 and 7 after castration. Steroid receptor levels were determined by Scatchard analysis using charcoal assay one day after the last injection. All three receptors were increased maximally with the 0.8 mg dosage when compared with castrated controls. Estradiol binding increased from 89 +/- 10 (mean +/- SEM) to 361 +/- 37 fmol per mg prot., androgen binding from 47 +/- 5 to 123 +/- 11 fmol per mg prot. and progesterone binding from 26 +/- 3 to 211 +/- 36 fmol per mg prot. The small dose of estradiol. (0.25 mg) produced a significant (P less than 0.05) increase of the progesterone receptor levels from 25 +/- 3 to 48 +/- 14 fmol/mg prot. Substitution of estradiol by 5 alpha-androstan-3 beta,17 beta-diol (2.5 or 25 mg) resulted in receptor levels similar to castrated animals. However treatment with 5 alpha-androstan-3 alpha,17 beta-diol (25 mg) alone or in combination with estradiol (0.25 mg) increased significantly the androgen receptor while it decreased the estrogen receptor. These results show that the administration of estradiol at doses used to induce experimental prostate hyperplasia produce measurable effects in the prostate and suggest that the estradiol receptor may be implicated in this phenomenon.
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PMID:Effect of hormone injections on levels of cytosolic receptors for estrogen, androgen and progesterone in dog prostate. 629 Jul 86

The affinity of danazol for oestrogen, androgen and progesterone receptors in human endometrium and myometrium was determined, to study the mechanism of action of this drug in the treatment of endometriosis. The ability of danazol to combine with each of the three types of receptor was similar in both endometrium and myometrium. The capacity of danazol to compete with oestradiol-17 beta for the oestrogen receptor was very low (1.72 +/- 0.48 X 10(-3%) cross reaction, mean +/- SEM) and danazol, at the maximum concentration used, was unable to saturate the receptor; but danazol's ability to compete with progesterone for its receptor was considerably higher (8.41 +/- 1.65% using progesterone, 1.95 +/- 0.41% using R5020) and was saturable. Danazol was also able to displace dihydrotestosterone from the cytosol androgen receptor (6.29 +/- 1.82% cross reaction). The association constant of oestradiol for the endometrial and myometrial oestrogen receptors was 2.19 X 10(9)M-1 and 7.45 X 10(9)M-1 respectively, while that of progesterone and dihydrotestosterone for their receptors was similar in endometrium and myometrium (mean 0.25 +/- 0.06 X 10(9) M-1 and 3.62 +/- 1.67 X 10(9) M-1 respectively). Using R5020, the association constant for the myometrial progesterone receptor was 2.50 +/- 0.73 X 10(9) M-1. We conclude that, in view of the high circulating levels of danazol present in patients being treated for endometriosis, it is possible that danazol may bind to, and partly saturate, endometrial and myometrial oestrogen, progesterone and androgen receptors during treatment. An explanation may thus be provided for some of the diverse actions of this drug.
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PMID:The interaction of human endometrial and myometrial steroid receptors with danazol. 662 94

Partially-purified 5 alpha-dihydrotestosterone-receptor (DHT-R) complexes, extracted from normal genital skin fibrolasts (GSF) previously labelled with [3H]DHT, dissociate with monophasic kinetics and dissociation rate constants (k-2) of 10, 6, 3 and 2 x 10(-3) min-1 at 40, 37, 32 and 29 degrees C, respectively. An Arrhenius plot yields an activation energy of 28 kcal/mole. We studied 2 subjects who have constitutional androgen insensitivity (AI) despite a normal level of specific DHT-R activity in their GSF. Subject 1 has complete AI and unambiguous female external genitalia; subject 2 has partial AI and had ambiguous external genitalia at birth. In contrast to normal, the DHT-R complexes extracted from the GSF of these 2 subjects dissociate with biphasic kinetics. At 37 degrees C the k-1 of their early ('fast') component is 21 +/- 0.4(+/-SEM) x 10(-3) min-1(n = 7), while that of their late ('slow') component (k-2) is 7.8 +/- 0.3 x 10(-3) min-1 (n = 7). The latter value is very similar to the single k-2 (6.1 +/- 0.1 x 10(-3) min-1, n = 9) of the DHT-R complexes extracted from normal fibroblasts. When dissociation of DHT-R complexes is studied with intact fibroblasts, monophasic kinetics are observed for both the normal and mutant subjects. A k-1 of 18 x 10(-3) min-1 was previously observed for both mutant subjects at 37 degrees C (normal: K-2, 5.9 +/- 0.3 x 10(-3) min-1, n = 15). At 40 degrees C subject 1 has a rate constant of 25 while that of subject 2 is 50 x 10(-3) min-1(normal: 10 x 10(-3) min-1). An Arrhenius plot of the results from subject 1 yields an activation energy of 18 kcal/mole. The 2 sets of data suggest that inability of DHT-R complexes to transform from a rapidly dissociating to a slowly-dissociating form within intact target cells is a marker of genetic mutations that alter the androgen receptor and thereby cause certain types of partial of complete AI.
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PMID:Defective activation of androgen-receptor complexes: a marker of androgen insensitivity. 705 33

A number of 17 beta-(N-alkyl/arylformamido)- and 17 beta-[(N-alkyl/aryl)alkyl/arylamido]-3-oxo-4-aza-5 alpha-steroids were prepared from 17 beta-hydroxy-4-azasteroids and evaluated as inhibitors of human 5 alpha-reductase and antagonists of the androgen receptor. Jones' oxidation of 17 beta-hydroxy compounds gave the 17-keto-4-azasteroids, which were treated with amines and NaBH(OAc)3/NaBH3CN to give 17 beta-(N-alkyl/arylamino)-4-azasteroids 10-27. Alternatively, the above-indicated compounds were prepared from amines and 17-keto-4-azasteroids to form imines, which were then reduced with NaBH4. Formylation of amines 10-27 gave 17 beta-(N-alkylformamides) 28-41; however, acylation afforded 17 beta-[(N-alkyl/aryl)alkyl/arylamides] 42-53. In comparison to N,N-diethyl-4-methyl-3-oxo-4-aza-5 alpha-androstane-17 beta-carboxamide (4-MA; IC50 = 4.15 nM), 17 beta-(N-alkylformamido)-4-azasteroids were potent inhibitors of human type I 5 alpha-reductase, IC50 values of compounds 29, 30, 36, and 37 being measured as 3.05, 0.91, 2.19, and 2.35 nM, respectively. The structure-activity relationships suggest that the type I enzyme has preference for N-substituted straight alkyl side chains of four to five carbon atoms. On the other hand, formamides 32 (N-heptyl) and 33 (N-octyl), in addition to inhibiting the type I enzyme (IC50s = 9.57 and 16.9 nM, respectively), showed also strong inhibitory activity (IC50s = 14.0 and 18.4 nM, respectively) for human type II 5 alpha-reductase, in comparison to N-(1',1'-dimethylethyl)-3-oxo-4-aza-5 alpha-androst-1-ene-17 beta-carboxamide (MK-906; IC50 = 4.53 nM). Other compounds in this series showed moderate activities (IC50 > 100 nM) on the type II enzyme. 17 beta-[(N-Alkyl/aryl)alkyl/arylamides] 45, 46, 48, and 51 exhibited highly potent inhibitory activity for human type I 5 alpha-reductase with IC50s of 1.77, 2.42, 2.93, and 5.44 nM, respectively, while moderate to no effect was observed on the type II enzyme (100 < IC50s < 1000 nM), except for compound 48 (IC50 = 3.75 nM). In another substitution pattern, N-aryl/alkylamides were studied; an electron-donating group increased the potency of compound 51, whereas an electron-withdrawing group decreased the potency of compounds 52 and 53 compared to parent compound 50. In addition to their 5 alpha-reductase activities, 17 beta-(N-alkylformamides) were also studied for their inhibitory activities on dihydrotestosterone (DHT)-stimulated proliferation of androgen-sensitive Shionogi mouse mammary carcinoma cells (clone SEM-107).(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Synthesis and in vitro activity of 17 beta-(N-alkyl/arylformamido)- and 17 beta-[(N-alkyl/aryl)alkyl/arylamido]-4-methyl-4-aza-3-oxo-5 alpha-androstan-3-ones as inhibitors of human 5 alpha-reductases and antagonists of the androgen receptor. 770 19

Exogenous and endogenous sex steroid hormones influence GH secretion. To test the relative importance of androgens in the enhancement of GH secretion, we administered flutamide (a potent androgen receptor blocker) to six late pubertal males. Blood samples for GH (and LH) were obtained at 10-min intervals for 24-h periods after 3 days of flutamide and during the untreated state. Waveform-specific, multiple-parameter deconvolution analysis was employed to assess secretory and elimination dynamics for GH. Androgen receptor blockade was confirmed by significant increases in 24-h mean LH concentrations and in total 17 beta-estradiol and free testosterone levels in the serum. Mean serum GH concentrations (24-h) also increased (P < 0.001) during androgen receptor blockade (mean +/- SEM, 2.9 +/- 0.3 vs. 1.8 +/- 0.3 micrograms/L); this was associated with an increased (P < 0.001) GH production rate [152 +/- 15 vs. 93 +/- 16 micrograms/liter of distribution volume (Lv)/24 h]. The enhanced GH secretion during flutamide administration was a result of both increased mass of GH released per secretory burst (12.0 +/- 1.4 vs. 8.4 +/- 1.0 micrograms/Lv; P < 0.005) and increased maximal rate of GH secretion (0.39 +/- 0.04 vs. 0.30 +/- 0.03 micrograms/Lv/min; P < 0.05), as well as a small increase in the number of detectable secretory bursts (12 +/- 1 vs. 10 +/- 1/24 h; P < 0.05). There was no significant change in either the serum half-life of GH or in the half-duration of GH secretory bursts during androgen receptor blockade. We speculate that the augmentation of GH secretion observed during antagonism of androgen action in late pubertal males is a result of increased stimulation of estrogen receptor-mediated pathways. Alternatively, androgens may exert a tonic inhibition of GH secretion which can be abolished by androgen receptor blockade.
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PMID:Androgen receptor blockade with flutamide enhances growth hormone secretion in late pubertal males: evidence for independent actions of estrogen and androgen. 849 5

In this report, it is demonstrated that the C3 component of prostatic binding protein (PBP) is also expressed and androgen regulated in the exorbital lacrimal gland, as shown previously for cystatin-related protein (CRP), another abundant secretory protein from the ventral prostate. The presence of C3 messenger RNA (mRNA) could be demonstrated by both Northern blot hybridization and PCR amplification and sequencing. The mRNAs encoding the C1 and C2 components of PBP, however, were undetectable. At the protein level, the C3 component in the lacrimal gland is glycosylated and linked by disulfide bridges to a new 10-kDa component not reacting with the PBP antiserum. As shown previously for CRP, the expression of C3 in the lacrimal gland requires the simultaneous presence of androgens and a functional androgen receptor. The effects of castration and androgen treatment on CRP and C3 mRNA concentrations were studied by Northern blot and dot blot hybridization; effects on transcription rates were determined by nuclear run-on assay. Two days after castration, the relative abundance of CRP mRNA had declined significantly (P < 0.01) to 10.5 +/- 1.5% (+/-SEM) of precastration levels in the prostate and to 14.5 +/- 8.0% in the lacrimal gland; the transcription rates declined to 14.3% and 10.0%, respectively. The C3 mRNA level and transcription rate in the prostate showed a more moderate decrease (P < 0.05) to 40.6 +/- 8.5% and 41.7%, but were hardly measurable in the lacrimal gland. Androgen administration resulted in a rapid increase in the transcription rates, which reached or exceeded control levels after 6-9 h of treatment and clearly preceded the increase in mRNA levels. It is concluded that the lacrimal gland, which can be studied conveniently in female and long term androgen-depleted animals offers a suitable model for the study of androgen-regulated gene expression.
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PMID:Androgens transcriptionally regulate the expression of cystatin-related protein and the C3 component of prostatic binding protein in rat ventral prostate and lacrimal gland. 889 38

Ovarian cancer is the second most common malignancy of the female reproductive tract. Approximately 50% of ovarian cancers have elevated levels of epidermal growth factor receptor (EGFR). This overexpression is correlated with a poor prognosis for patient survival. Ovarian cancers also express a number of sex steroid receptors. The androgen receptor (AR) is the predominant sex steroid receptor and is expressed in over 80% of ovarian cancers. We investigated whether a relationship exists between EGFR and AR in ovarian cancer. Sixty serous cystadenocarcinomas were analyzed for their relative levels of EGFR and AR by Western blot analysis. Data were analyzed by Student's t test and linear regression analysis for statistical significance. More than 98% of the tumors expressed detectable levels of EGFR, while 65% of the tumors expressed detectable levels of AR. The levels of EGFR (mean +/- SEM) were found to be significantly (P < 0.01) higher in AR+ (516 +/- 15) than in AR- (304 +/- 57) tumors. EGFR levels significantly correlated to AR levels (r = 0.49, P < 0.001). These results demonstrate an association between EGFR and AR levels in ovarian cancer. Whether this association represents a causal or a casual relationship remains to be determined.
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PMID:Expression of epidermal growth factor and androgen receptors in ovarian cancer. 926 71

Androgens have significant beneficial effects on the skeleton. However, studies on the effects of androgens on osteoblasts are limited due to the absence of appropriate model systems that combine completeness of the osteoblastic phenotype, rapid proliferation rate, and stable expression of the androgen receptor (AR). Thus, we stably transfected the conditionally immortalized human fetal osteoblastic cell line (hFOB) with the human wild-type AR (hAR) cDNA. Compared to nontransfected hFOB cells, constitutive hAR mRNA expression in three independent hAR-transfected hFOB clones (hFOB/AR) was 15-fold higher in hFOB/AR-16, 62-fold higher in hFOB/AR-2, and 72-fold higher in hFOB/AR-6 cells, respectively, as assessed by semiquantitative reverse transcriptase-polymerase chain reaction (RT-PCR). Detectable constitutive levels of hAR mRNA by Northern blot analysis were present in hFOB/AR-2 and hFOB/AR-6 cells, but not in hFOB/AR-16 or hFOB cells, respectively. Treatment with 5 alpha-dihydrotestosterone (5 alpha-DHT) (10(-8) M) for 24 h did not alter hAR mRNA steady state levels in the hFOB/AR cell lines. Nuclear binding studies demonstrated 152 +/- 73 (mean +/- SEM) functional hARs/nucleus in non-transfected hFOB cells, 3,940 +/- 395 functional hARs/nucleus in hFOB/AR-2 cells, and 3,987 +/- 823 hARs/nucleus in hFOB/AR-6 cells, respectively. Treatment with 5 alpha-DHT increased the expression of a transiently transfected androgen response element-chloramphenicol acetyltransferase (ARE-CAT) reporter construct in hFOB/AR-6 cells in a dose- and time-dependent manner; no such effect was observed in transiently transfected hFOB cells lacking exogenously transfected hARs. Moreover, 5 alpha-DHT-induced ARE-CAT expression was inhibited by the selective androgen receptor antagonist, hydroxyflutamide. In summary, we have developed and characterized androgen-responsive osteoblastic cell lines derived from normal human fetal bone that express physiological levels of functional hARs. These cell lines should provide a suitable model for further studies on the effects of androgens on osteoblast function, including the identification of potential androgen-regulated growth factors and cytokines.
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PMID:Development and characterization of a conditionally immortalized human osteoblastic cell line stably transfected with the human androgen receptor gene. 928 32


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