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)

The biological activity of glucocorticoids in target tissues can be influenced by locally produced 11 beta-hydroxysteroid dehydrogenase (11 beta-HSD), the enzyme responsible for the interconversion of cortisol and its inactive metabolite cortisone. In human adipose stromal cells, glucocorticoids are potent stimulators of the conversion of androgens to estrogens (aromatase activity). The present study was designed to determine whether 11 beta-HSD activity was present in human adipose stromal cells, and if changes in the activity of this enzyme could influence aromatase activity. 11 beta-HSD activity was determined by a radiometric conversion assay in breast adipose tissue from six patients. It was found that both dehydrogenase (cortisol to cortisone) and reductase (cortisone to cortisol) activities were present in all six subjects, and the reductase activity was always predominant. Carbenoxolone (CBX), a potent inhibitor of 11 beta-HSD, added to the culture medium at 50 and 200 microM, resulted in 39 +/- 4% and 85 +/- 1% inhibition, respectively, of both reductase and dehydrogenase activity of 11 beta-HSD. To determine whether alterations in 11 beta-HSD could influence aromatase activity, the effect of CBX (200 microM) on cortisol- and cortisone-induced changes in the conversion of androstenedione to estrone was examined. CBX prevented the stimulatory effect of cortisone and minimally potentiated the stimulatory effect of cortisol on aromatase activity, reflecting an inhibition of the local activation of cortisone and the local metabolism of cortisol, respectively. In order to determine whether the product of the 11 beta-HSD 1 gene was responsible for the observed 11 beta-HSD activity, total RNA extracts from these cells were subjected to Northern blot analysis using human 11 beta-HSD 1 cDNA as the probe. A single 1.8 11 beta-HSD 1 transcript was detected, and its abundance was reduced by CBX. No 11 beta-HSD 2 mRNA was detected. The present results demonstrate that the 11 beta-HSD 1 gene is expressed and functional in human breast adipose stromal cells and that changes in 11 beta-HSD 1 activity result in alterations in aromatase activity.
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PMID:11 beta-Hydroxysteroid dehydrogenase 1 activity and gene expression in human adipose stromal cells: effect on aromatase activity. 919 83

Exposure to some peroxisome proliferator chemicals (PPC) leads to toxic effects on sex organ function possibly by alterations of steroid hormone metabolism. A systematic search for genes whose mRNA levels are modulated by the PPC WY-14643 (WY) was carried out in rat liver, a site of steroid hormone metabolism. The sequence of one up-regulated cDNA (2480 bp) was predicted to encode a protein of 735 amino acids with 82% identity to the porcine 17 beta-hydroxysteroid dehydrogenase type IV (HSD IV) originally isolated as a 17 beta-estradiol dehydrogenase. The rat HSD IV was localized to peroxisomes and was regulated by diverse PPC by two distinct mechanisms. Induction of HSD IV and acyl-CoA oxidase (ACO) proteins in rat liver at different treatment times and concentrations of gemfibrozil (GEM) and di-n-butyl phthalate (DBP) were almost identical, suggesting that HSD IV mRNA induction involves the peroxisome proliferator-activated receptor alpha, a regulator of ACO. In contrast, HSD IV protein levels were only weakly induced by WY, a strong inducer of ACO protein, even though the levels of both HSD IV and ACO mRNA were strongly stimulated by WY. Thus HSD IV protein levels were uniquely regulated pretranslationally by WY. In addition to HSD IV we also identified the male-specific alpha 2u-globulin as a PPC down-regulated gene. This prompted us to examine the expression of another male-specific gene, CYP2C11, that catalyzes the hydroxylations of estradiol at the 2 and 16 alpha positions. Cyp2C11 protein expression in rat liver was either decreased or completely abolished after a 3-week treatment by GEM or WY, respectively. Decreased expression of enzymes which inactivate estradiol including Cyp2C11, and the reported increased expression of aromatase may explain why male rats exposed to diverse PPC have higher serum estradiol levels. These higher estradiol levels in male rats have been thought to be mechanistically linked to Leydig cell hyperplasia and adenomas. Increased conversion of estradiol to the less active estrone by HSD IV induction may explain how exposure to the phthalate di-(2-ethylhexyl) phthalate leads to decreases in serum estradiol levels and suppression of ovulation in female rats.
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PMID:Peroxisome proliferators alter the expression of estrogen-metabolizing enzymes. 920 13

Bone is an estradiol-responsive tissue. Estrogen withdrawal during the menopause causes loss of bone mass and clinically relevant osteoporosis in a third of all women. Sufficient or impaired local production, as well as degradation of estradiol in cells present in the bone microenvironment might be an important mechanism of rescue or might contribute to the development of osteoporosis, respectively. We therefore investigated aromatase and 17beta-hydroxysteroid dehydrogenase type IV (17beta-HSD IV) expression in osteoblast- and osteoclast-like cells. Aromatase mRNA was increasingly expressed in myeloid THP 1 cells differentiated along the monocyte/phagocyte pathway exploiting vitamin D and either granulocyte-macrophage-stimulating factor (GMCSF) or macrophage-stimulating factor (MCSF). In long-term cultures, when sequentially exposed to vitamin D (days 0-21) and GMCSF (days 5-10) and plated on collagen, the amount of expression of aromatase mRNA steadily increased along with the increasing expression of osteopontin mRNA, alpha(v) integrin mRNA, c-fms (MCSF-receptor) mRNA and multinucleated cells developing. The conversion of estradiol from testosterone (10(-7) M/l) in the supernatants of dishes mirrored changes in aromatase mRNA expression and by day 21 rose to 30,000 ng/10(7) cells/24 h. 17Beta-HSD IV mRNA expression was abundant in undifferentiated THP 1 cells and was decreased to approximately 50% by day 21. Unstimulated SV-40 immortalized fetal osteoblasts did not express aromatase mRNA, but the expression was stimulated by the addition of the phorbol ester phorbol myristate acetate (PMA). Unstimulated osteoblasts from primary cultures did not express aromatase mRNA. Osteoblast-like osteosarcoma cells MG 63 expressed faint levels of aromatase mRNA in contrast to the osteosarcoma cell line HOS 58. 17Beta-HSD IV mRNA was expressed in fetal osteoblasts as well as in osteoblasts from primary culture, MG 63 and HOS 58 cells. In summary, we can show the expression of estradiol metabolizing enzymes in cells which are present in the bone microenvironment. Impaired aromatase expression and/or enhanced expression of 17beta-HSD IV may contribute to the pathogenesis of osteoporosis.
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PMID:Local estradiol metabolism in osteoblast- and osteoclast-like cells. 936 87

The cDNA encoding the catfish ovarian aromatase has previously been isolated and described (accession number S75715). As demonstrated previously, the predicted amino acid sequence and enzymatic activity of the encoded protein share a significant degree of similarity to the forms of aromatase found in other vertebrates. Analyses utilizing reverse transcription coupled with the polymerase chain reaction (RT-PCR) demonstrate the expression of aromatase mRNA in catfish brain, testis and ovary. In spite of the evidence provided by Northern blot analysis for a single transcript encoding ovarian aromatase, RT-PCR analysis indicated transcript heterogeneity within the ovary, but not the testis or the brain. Although not characterized, PCR analysis indicated that the transcript complexity of ovarian aromatase was within the encoding region. Until this study, the expression of aromatase and its correlation with the reproductive physiology of fish had not been studied at the molecular level. In the catfish, significant changes in ovarian development were evident following elevation of plasma estradiol titers during October and again in February. Seasonal changes in the expression of ovarian aromatase and 3beta-hydroxysteroid dehydrogenase (3beta-HSD) mRNA was reflected in estradiol plasma titers. Ovarian expression of 3beta-HSD mRNA commenced a month before the message for aromatase was detected. Both transcripts were present from October to April. As the female approached the time of spawning (in May), the abundance of both aromatase and 3beta-HSD transcripts decreased. The aromatase message was not detected in post-spawning females but 3beta-HSD transcripts were evident. These data indicate that the timely synthesis of estradiol in catfish is caused by the regulation of both 3beta-HSD and aromatase.
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PMID:Expression of cytochrome P450 aromatase in the channel catfish, Ictalurus punctatus. 936 16

Human adipose tissue is known to have 17 beta-oxidoreductase activity, interconverting estrone (E1) and estradiol (E2), as well as androstenedione (A) and testosterone (T). We examined both the subcutaneous abdominal and intra-abdominal (visceral) adipose tissue of women for expression of types 1, 2, and 3 17 beta-hydroxysteroid dehydrogenase (17 beta-HSD) using ribonuclease (RNase) protection assay and RT-PCR/Southern blotting. Type 1 17 beta-HSD, which encodes the enzyme responsible for the conversion of E1 to E2 in the placenta and ovary, was expressed in the subcutaneous abdominal and intra-abdominal adipose tissue of women, but the messenger RNA transcripts were predominantly incompletely spliced and therefore unlikely to encode an active protein. A pseudogene for type 1 17 beta-HSD was also expressed in these tissues, but messenger RNA transcripts were again unspliced. Type 2 17 beta-HSD, which encodes an enzyme that can catalyze the conversion of T to A and E2 to E1, was expressed in both the subcutaneous abdominal and intra-abdominal adipose tissue of women. Type 3 17 beta-HSD was also expressed in adipose tissue from both sites studied. Type 3 17 beta-HSD encodes the enzyme that catalyzes the conversion of A to T in the testis and also converts E1 to E2. Together with aromatase, which is known to be expressed in adipose tissue, the expression of types 2 and 3 17 beta-HSD indicates that sex steroid production in the adipose tissue of women is a complex process. The association of visceral obesity with the development of insulin resistance and dyslipidaemia raises the question of the role of steroid production in adipose tissue in the pathogenesis of these disorders.
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PMID:Expression of types 1, 2, and 3 17 beta-hydroxysteroid dehydrogenase in subcutaneous abdominal and intra-abdominal adipose tissue of women. 943 39

For preventing the reduction of bone mass in postmenopausal women, oestrogen replacement is known to be useful and the importance of sex steroids in bone metabolism in both sexes is well established. The presence of steroid-converting-enzyme activities in various osteoblast and osteoblast-like cells has been demonstrated using in vitro culture systems. In the present study, we assessed the expression of messenger ribonucleic acid (mRNA) for aromatase, steroid sulphatase, 5 alpha-reductase, 17 beta-hydroxysteroid dehydrogenase (17 beta-HSD) and 3 beta-HSD by reverse transcription-polymerase chain reaction in the human osteoblast-like cell lines, MG 63 and HOS. Oestrogen, androgen and progesterone receptor mRNAs were also measured. Expression of mRNA for these enzymes and receptors was found in both cell lines without induction. From these and previous findings, we conclude that osteoblast-like cells have the capacity to form biologically potent oestrogens and androgens from peripheral circulating steroids. This may indicate an important role of bone in facilitating hormonal action.
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PMID:Steroid formation in osteoblast-like cells. 951 72

The hormonal basis for masculine song development in the zebra finch remains unidentified. To understand how steroids are differentially supplied to the brains of males and females to cause sexually dimorphic development of this behavior, we have studied the steroidogenic capability of zebra finch tissues during early development (1 to 8 days posthatching). Here, we report on the use of cultures of whole gonads, adrenals, and telencephalons to measure the activities of two steroidogenic enzymes: aromatase, the enzyme that catalyzes the conversion of androgen to estrogen, and 3beta-hydroxysteroid dehydrogenase/delta4-delta5 isomerase (3beta-HSD), the enzyme that converts pregnenolone into progesterone. We also examined the effect of cAMP on aromatase activity in these tissues as this intracellular second messenger has been shown previously to regulate aromatase in both central and peripheral tissues of other species. In untreated cultures, aromatase was detected at the highest levels in male and female telencephalon and in ovary. Dibutyryl (dB)-cAMP had no significant effect on aromatase activity in any tissue. However, after dB-cAMP treatment, estrogens were regularly detected in cultures of whole testes. Although this activity was relatively low when compared to total activity found in other tissues, due to the small size of the testes at this age of development, the specific activity (per milligram of protein) might be high enough to produce some estrogen. Adrenal aromatase was unconfirmed in the presence or absence of cAMP. 3Beta-HSD activity was undetected in brain but was detected in gonads and adrenals from all birds. There were no significant differences in gonadal or adrenal 3beta-HSD activity between males and females. Although these data present the first evidence for testicular aromatase in the zebra finch, they provide no evidence to support a mechanism to generate a greater estrogenic signal in male zebra finches after hatching.
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PMID:Activities of aromatase and 3beta-hydroxysteroid dehydrogenase/delta4-delta5 isomerase in whole organ cultures of tissues from developing zebra finches. 957 Oct 11

In the analysis of the regulation of human corpus luteum, it is very important to localize the sites of specific steroid hormone production to obtain a better understanding of luteal function. We have examined expression of steroidogenic enzymes, steroid receptors, and adrenal 4 binding protein (Ad4BP), a transcription factor of steroidogenesis, in corpus luteum of normal cycling human ovary. Corpus luteum can be classified into four different stages from ovulation to complete regression or fibrosis based on these findings: (1) corpus luteum, (2) steroid-producing degenerating corpus luteum or SPDCL, (3) nonsteroid producing or NSPDCL, and (4) corpus albicans. Corpus luteum in the luteal phase is characterized as follows: (a) the expression of P450scc (cholesterol side chain cleavage), 3 beta HSD (hydroxysteroid dehydrogenase), and Ad4BP in almost all the luteinized granulosa and theca cells, consistent with active progesterone biosynthesis; (b) expression of estrogen-producing P450arom (aromatase) in luteinized granulosa cells, indicating active estrogen production and that of P450c17 (17 alpha hydroxylase) in luteinized theca cells, and (c) expression of progesterone receptor (PR) and androgen receptor (AR) in both luteinized granulosa and theca cells. SPDCL correspond to corpus luteum undergoing regression or degeneration in the following cycle and are characterized as follows: (a) absence of all the steroidogenic enzymes and Ad4BP in the luteinized granulosa cells, suggestive of hormonally inactive nature of these cells and (b) marked expression of P450scc, 3 beta HSD, P450c17 and Ad4BP in luteinized theca cells. NSPDCL is characterized as the absence of all the steroidogenic enzymes and sporadic expression of Ad4BP in luteinized theca cells. These findings indicate that luteal cells remain even after losing expression of steroidogenic enzymes, consistent with a prolonged process of degeneration or regression of human corpus luteum. In corpus albicans, all the cells were replaced by fibrosis and steroidogenic enzymes; steroid receptors and Ad4BP were not expressed at all. Localization of steroidogenesis in human corpus luteum has thus provided new insights into understanding of its biological features.
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PMID:Localization of steroidogenesis and steroid receptors in human corpus luteum. Classification of human corpus luteum (CL) into estrogen-producing degenerating CL, and nonsteroid-producing degenerating CL. 958 Sep 43

AME has been a crucial experiment of biology from which much has been learnt about corticosteroid hormone action and mineralocorticoid hypertension. 11 beta-HSD is an important pre-receptor pathway determining corticosteroid hormone action. Any tissue expressing 11 beta-HSD1 or 11 beta-HSD2 can clearly modulate glucocorticoid and mineralocorticoid action independent of circulating concentrations. A series of related enzymes operates in a similar fashion to determine hormone action for other members of the thyroid/steroid hormone receptor superfamily (e.g. 17 beta-HSD, 25-hydroxyvitamin D 1 alpha-hydroxylase, aromatase, 5'-deiodinase, 5 alpha-reductase). Endocrinologists have been obsessed with measuring the concentrations of a hormone in the circulation and making their decisions on the basis of these results, whether or not that hormone is involved in the pathogenesis of a disease process. Such an approach needs to be revised, with greater emphasis on considering the action of a hormone within a given tissue and, in turn, on the role of these enzymes in the pathogenesis of human disease.
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PMID:Cortisol, hypertension and obesity: the role of 11 beta-hydroxysteroid dehydrogenase. 959 34

Postmenopausal loss of 17 beta-estradiol (E2) in women is associated with decreased bone mineral density and increased susceptibility to osteoporotic bone fracture. These changes in bone status are assumed to be due to circulating levels of the hormone; therapeutic replacement of E2 can alleviate the bone disease. However, recent reports have shown that human osteoblastic (OB) cells are able to synthesize estrogens locally, via expression of the enzyme aromatase. In this study, we have characterized the expression and activity of aromatase and 17 beta-hydroxysteroid dehydrogenase (17 beta-HSD) in rat OB cell lines. Aromatase activity in ROS 17/2.8, ROS 25/1, and UMR 106 cells was similar to that shown in human OB cells, with the highest levels of activity observed in the more differentiated ROS 17/2.8 cells (Vmax = 45 pmol/h/mg of protein). The rat OB cells also showed 17 beta-HSD activity, with the predominant metabolism in all three cell lines being estrone (E1) to E2. As with aromatase, the highest activity was observed in ROS 17/2.8 cells (Vmax = 800 pmol/h/mg of protein). Northern analyses indicated the variable presence of transcripts corresponding to the type 1, 2, 3, and 4 isoforms of 17 beta-HSD. Further analysis of androstenedione metabolism indicated that the net effect of aromatase and 17 beta-HSD activity varied with cell type and culture treatment. All three OB cell lines were able to synthesize E1, E2, and testosterone from androstenedione, although activity varied between OB cell types. Regulatory effects were observed with 1,25-dihydroxyvitamin D3 (positive) and dexamethasone (negative). These data suggest that local synthesis of sex hormones is an important function of OB cells and may play a key role in the modulation of bone turnover independent of circulating hormone concentrations.
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PMID:Characterization of aromatase and 17 beta-hydroxysteroid dehydrogenase expression in rat osteoblastic cells. 962 31


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