Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:1.1.1.3 (HSD)
3,464 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In human placenta the enzyme complex aromatase catalyzes the conversion of androgens to estrogens and 17 beta-hydroxysteroid dehydrogenase (17 beta-HSD) mediates the reversible interconversion of, e.g. estrone to estradiol. We studied the effects of cholera toxin (CT), an activator of adenylate cyclase, and 12-O-tetradecanoyl phorbol 13-acetate (TPA), a phorbol ester protein kinase C activator, on the levels of messenger (m) RNAs encoding aromatase cytochome P-450 (P-450AROM) and 17 beta-HSD in cultured JEG-3 choriocarcinoma cells. With the use of oligonucleotide probes designed according to known complementary DNA sequences, hybridizable mRNA transcripts of 3.0, 2.4, and 1.6 kilobases for P-450AROM were found in Northern blot analysis of JEG-3 cell RNA. A single 1.4-kilobase transcript was detected for 17 beta-HSD. Time-dependent increases in P-450AROM mRNA levels in JEG-3 cells were observed for both CT and TPA with maximal effects at 24-48 h. CT and TPA increased P-450AROM mRNA levels in a concentration-dependent manner. The maximal effects, about 4.8-fold and 3.3-fold stimulations above basal levels, were obtained with 10 ng/ml of CT and 100 ng/ml of TPA, respectively. The effects of CT and TPA were additive. CT induced 17 beta-HSD mRNA levels in a time- and concentration-dependent manner and its maximal effect of 10.1-fold above basal levels was obtained within a similar time and concentration-dependence as for P-450AROM mRNA. TPA itself had no clear effect but it approximately doubled the effect of CT on 17 beta-HSD mRNA expression. Inhibition of protein synthesis by cycloheximide decreased basal, CT and TPA stimulated P-450AROM mRNA levels but increased the expression of 17 beta-HSD mRNA. This result is consistent with the hypothesis that induction of P-450AROM gene expression is mediated by a labile protein regulator resembling to most other steroidogenic P-450 enzymes, whereas 17 beta-HSD as a non-P450 enzyme appears to be controlled in a different manner. The present results suggest that: 1) induction of P-450AROM mRNA may at least partly be responsible for our previously reported increases in the rate of conversion of androgens to estrogens by CT and TPA in JEG-3 cells; 2) 17 beta-HSD mRNA expression is mainly controlled through a cAMP-dependent mechanism in contrast to the multifactorial control of P-450AROM mRNA; and 3) protein synthesis inhibition by cycloheximide has opposite effects on the mRNA levels of these two key enzymes in placental estrogen metabolism.
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PMID:Regulation of aromatase cytochrome P-450 and 17 beta-hydroxysteroid dehydrogenase messenger ribonucleic acid levels in choriocarcinoma cells. 130 52

Primates are unique in having adrenals that secrete large amounts of the precursor sex steroids (PSS) dehydroepiandrosterone (DHEA) and especially DHEA-sulfate. The adrenal PSS require the action of 3 beta-hydroxysteroid dehydrogenase/5-ene-4 ene isomerase (3 beta-HSD), 17 beta-hydroxysteroid dehydrogenase (17 beta-HSD), 5 alpha-reductase and/or aromatase to form the androgen dihydrotestosterone (DHT) or the estrogens 17 beta-estradiol and androst-5-ene-diol. Knowing the crucial role of 3 beta-HSD and 17 beta-HSD in sex steroid biosynthesis both in classical as well as in peripheral steroidogenic tissues, we have concentrated our efforts on the elucidation of the molecular structure of these enzyme families. We have thus characterized two types of human 3 beta-HSD cDNA clones and their corresponding genes which encode deduced proteins of 371 and 372 amino acids and share 93.5% homology. Human type I 3 beta-HSD is the almost exclusive mRNA species expressed in the placenta and skin, while human type II is the predominant mRNA species in the adrenals, ovaries and testes. We have also recently elucidated the structure of three types of rat 3 beta-HSD cDNAs which all encode a 372 amino acid protein. The predicted rat type I and II 3 beta-HSD proteins expressed adrenals, gonads and adipose tissue share 94% homology while they share 80% similarity with the liver-specific type III 3 beta-HSD. Transient expression of human type I and II as well as rat type I and II 3 beta-HSD cDNAs in HeLa human cervical carcinoma cells reveals that 3 beta-ol dehydrogenase and 5-ene-4-ene isomerase activities reside within a single protein and that these cDNAs encode functional 3 beta-HSD proteins. The expressed rat type III protein possesses a unique property catalyzing selectively the reduction of 3 beta-androstane 5 alpha-steroids such as DHT. Furthermore, we have also demonstrated by site-directed mutagenesis that the lower activity of expressed rat type II compared to rat type I 3 beta-HSD protein is due to a change of four amino acid residues potentially involved in a membrane-spanning domain. In parallel, we have characterized the complete nucleotide sequence of human 17 beta-HSD cDNA clones encoding a 327 amino acid protein as well as two in tandem 17 beta-HSD genes. Two major 17 beta-HSD mRNA species have been detected in several tissues due to a tissue-specific alternative site of initiation of transcription.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Ontogeny and subcellular localization of 3 beta-hydroxysteroid dehydrogenase (3 beta-HSD) in the human and rat adrenal, ovary and testis. 139 Feb 95

Human hair follicles (HF) and sebaceous glands (SG) were assessed for the presence and distribution of the cytochrome P-450-aromatase (AR) and 3B-hydroxysteroid dehydrogenase (3B-HSD) enzymes. Immunohistochemical methods were used to examine both enzymes in male and female human skin specimens at various ages and different body sites. AR was found in the external root sheath of anagen, terminal HF, and in SG, whereas the 3B-HSD was found only in the SG. AR was rarely found in telogen HF. The expression of both enzymes, AR and 3B-HSD, did not vary with body site or sex. Localizing AR in the external root sheath of anagen HF suggests that AR may have a function in the HF cycle. We hypothesize that AR may be one of many enzymes or factors that play a role in the HF cycle by regulating the level of androgens formed locally, whereas 3B-HSD is localized in SG, converting weak androgen precursors to potent androgens, stimulating lipogenesis.
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PMID:Immunohistochemical distribution of aromatase and 3B-hydroxysteroid dehydrogenase in human hair follicle and sebaceous gland. 143 Apr 70

It is well documented that sex hormone secretion decreases as age advances. In this study, 17 alpha-hydroxylase (17hy), 20 alpha(beta)-hydroxy steroid dehydrogenase (20-HSD), C17-20 lyase, 17 beta-hydroxy steroid dehydrogenase (17 beta-HSD) and aromatase activities in ovarian tissues were examined in order to study the changes in steroid metabolism in human ovary with age. Tissues were obtained from women aged 30-81 years who had undergone gynecological laparotomy. Enzyme activities were measured by the conversion of 14C-labeled progesterone, 17 alpha-hydroxy progesterone and androstenedione to amounts of corresponding labeled products. Remarkable reduction of C17-20 lyase and 17hy activities were noticed in the ovaries obtained from the women in the premenopausal stage when the activities were compared with those from reproduct women. However, the activities of aromatase, 17 beta-HSD and 20-HSD were not changed. Further, a decrease of 17hy activities was observed in the ovaries obtained from menopausal women. Aromatase activity was also reduced at this stage while the 17 beta-HSD and 20-HSD remained unchanged. In addition, the formation of 17 alpha, 20 beta-OH-P4 from 17P4 was first demonstrated indicating that activity of 20 beta-HSD in postmenopausal ovary and found to be localized in the microsomal fraction. These result indicated that the changes of ovarian steroid enzyme activities with age were characterized by a striking reduction in C17-20 lyase and 17hy activities while 17 beta-HSD and 20-HSD activities were not impaired. Aromatase activity was found to be decreased in ovaries at menopause.
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PMID:[Changes in steroid enzyme activities with age in human ovary]. 160 71

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

To test the hypothesis that insulin mediators serve as the signal transduction system for insulin's steroidogenic actions in human placental cytotrophoblasts, we examined the effects of two inositolglycan insulin mediators, the insulin pH 2.0 chiro-inositol mediator (IM-pH 2.0) and the insulin pH 1.3 myo-inositol mediator (IM-pH 1.3), on cytotrophoblastic steroidogenesis. When human cytotrophoblasts were incubated in medium supplemented with androstenedione for 24 h, treatment with IM-pH 2.0 or IM-pH 1.3 suppressed aromatase activity by 15% (P less than 0.05) and 49% (P less than 0.05), respectively, compared to insulin, which suppressed aromatase activity by 21% (P less than 0.05). When cytotrophoblasts were incubated in medium supplemented with pregnenolone for 24 h, treatment with IM-pH 2.0 or IM-pH 1.3 stimulated 3 beta-hydroxysteroid dehydrogenase (3 beta HSD) activity by 145% (P less than 0.05) and 168% (P less than 0.05), respectively, compared to insulin, which stimulated 3 beta HSD activity by 63% (P less than 0.05). Suppression of aromatase activity and stimulation of 3 beta HSD activity by inositolglycan mediators were both concentration dependent. Moreover, preincubation of cytotrophoblasts with the antiinositolglycan antibody alpha IGP completely abolished insulin's ability to either inhibit aromatase or stimulate 3 beta HSD activity. These results indicate that insulin mediators mimic insulin's effects on cytotrophoblastic aromatase and 3 beta HSD activities and suggest that inositolglycan mediators are the signal transduction mechanism responsible for insulin's regulation of human placental steroid hormone biosynthesis.
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PMID:Insulin mediators are the signal transduction system responsible for insulin's actions on human placental steroidogenesis. 195 80

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

Ketoconazole (KCZ), a widely used antifungal drug, has been reported in humans to inhibit adrenal and testicular steroidogenesis by interfering with the cytochrome P-450-dependent enzymes. The purpose of this study was to investigate the drug effect on steroidogenic human granulosa-luteal cells, obtained by follicular aspiration from mature follicles of gonadotropin-treated women. Cells were cultured in long-term monolayers, and the steroid production was assayed by radioimmunoassay. A profound inhibition of ovarian cell secretion of progesterone (P), testosterone (T) and estradiol was found. At a low concentration (5 micrograms/ml), KCZ failed to inhibit the conversion of pregnenolone to P, mediated by the non-cytochrome 3 beta-hydroxysteroid dehydrogenase-isomerase enzyme (3 beta-HSDH). At a similar concentration, P secretion by human chorionic gonadotropin (hCG; 100 mIU/ml) -treated cells was decreased by 68% (P less than 0.001) and therefore, an inhibitory effect of KCZ on the cholesterol side-chain cleavage enzyme (P-450SCC) was assumed. A similar marked inhibitory effect (81%) (P less than 0.001) on T secretion was observed for hCG-stimulated cells given pregnenolone as substrate. The P-450 aromatase was profoundly inhibited (86%) (P less than 0.001) in a reversible manner, by a similar concentration (5 micrograms/ml) of KCZ. These findings suggest that KCZ has the capability to suppress human ovarian steroidogenesis similarly as in testis and adrenal.
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PMID:Effect of ketoconazole on steroidogenic human granulosa-luteal cells in culture. 203 91

An analogue of androstenedione containing an ethano bridge between carbons 2 and 10 of the A ring of the steroid, 1, has been evaluated as an inhibitor and a possible substrate of human placental aromatase. This compound was found to be a competitive inhibitor versus androstenedione (Kis = 25 +/- 2 nM) of the aromatase activity. Analyses of the incubation mixtures of 1 with human placental microsomes and NADPH by GC-MS indicated the formation of a new compound having an increase in molecular weight of 2 mass units (300 m.u.) from that of the parent steroid (298 m.u.). Subsequent analyses of incubations of 1 with an isolated 17 beta-hydroxysteroid dehydrogenase (17 beta-HSD) from Pseudomonas testosteronii in the presence of NADPH resulted in the formation of a new compound having the same retention time and molecular mass as that found for the product from the placental microsome incubation. Consequently, steroid 1 is both an inhibitor of human placental aromatase and a substrate for 17 beta-HSD.
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PMID:Enzyme interactions of 2,10-ethanoandrostene-3,17-dione: aromatase and 17 beta-hydroxysteroid dehydrogenase. 216 Dec 28

The levels of expression of mRNA species encoding cholesterol side-chain cleavage cytochrome P-450 (P450scc), 17 alpha-hydroxylase cytochrome P450 (P450(17 alpha], aromatase cytochrome P-450 (P-450AROM), and 3 beta-hydroxysteroid dehydrogenase (3 beta HSD) were examined in human follicles and corpora lutea (CL) throughout the menstrual cycle. Tissues were obtained from women undergoing hysterectomy and oophorectomy. The largest follicle or the CL was dissected from the ovary depending on whether the surgery was performed in the follicular or luteal phase. The day of the cycle was determined by onset of last menstrual period and was confirmed by endometrial histology. Total RNA was examined by Northern blot analysis, using as probes specific 32P-labeled cDNA inserts encoding each human enzyme. Early follicles demonstrated detectable mRNA for both P450scc and P450(17 alpha), but not for P450AROM or 3 beta HSD. P450AROM was detectable late in the follicular phase and appeared markedly induced in the CL. 3 beta HSD was detectable only in the CL. Levels of P450(17 alpha) mRNA remained relatively unchanged throughout the cycle, whereas P450scc mRNA levels were greatly increased in the CL. The presence of P450(17 alpha) mRNA in the human CL is of interest, since it is absent from the bovine CL, and this is consistent with the ability of the human, but not the bovine, CL to synthesize 17 alpha-hydroxyprogesterone and estrogens. The fact that P450AROM expression is highest in CL is surprising, since plasma estrogen levels are highest during the late follicular phase of the cycle, and may suggest that CL estrogen biosynthesis is limited by 17 alpha-hydroxylase or 17,20-lyase activities.
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PMID:Expression of messenger ribonucleic acid species encoding steroidogenic enzymes in human follicles and corpora lutea throughout the menstrual cycle. 218 Sep 73


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