Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0338671 (Steroids)
 9,479 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

24-Oxa-vitamin D3 (24-oxa-D3) and 24-oxa-1 alpha-hydroxyvitamin D3 were designed as possible inhibitors of the vitamin D metabolic activation pathway. Their affinity for the vitamin D receptor (from pig intestine) and human vitamin binding protein were reduced, and their potency to induce cell differentiation of human leukemia cells (HL 60) or osteosarcoma cells (MG 63) was markedly reduced (19% and 3%, respectively), in comparison with calcitriol. A single or chronic injection of 24-oxa-D3 had no biological activity, whereas chronic administration of 24-oxa-1 alpha-hydroxy-D3 showed weak agonist activity in rachitic chicks. When the 24-oxa-D3 was given prior to a single injection of vitamin D3, lower values of serum calcium (64% of the value obtained in vitamin D-treated animals), osteocalcin (52%), 25-(OH)D3 (45%) and duodenal calbindin-D 28K (9.4%) were found. When given chronically in a 100-fold more excess no clear antagonistic effects were observed. 24-Oxa-D3 is thus a new metabolic weak antagonist of vitamin D3, but adding a hydroxyl group at C-1 creates a weak agonist.
Steroids 1995 Jun
PMID:Antagonistic activity of 24-oxa-analogs of vitamin D. 767 83

Three analogs of 1 alpha,25-(OH)2D3 with an oxygen or another heteroatom at position 23 were synthesized in search of separating the cell-differentiating from the calcemic effects of the vitamin D hormone. Their ability to induce superoxide production in human myeloid leukemia cells (HL-60) was 1 alpha,25-(OH)2D3 > 23-oxa-24-oxo-1 alpha,25-(OH)2D3 > 23-thia-1 alpha,25-(OH)2D3 > 23-oxa-1 alpha, 25-(OH)2D3. 23-oxa-24-oxo-1 alpha, 25(OH)2D3 was slightly more potent than 1 alpha,25-(OH)2D3 in inhibiting cell proliferation in MCF-7 cells and 23-thia- and 23-oxa-1 alpha,25(OH)2D3 were less potent. Their in vitro potency to produce osteocalcin in MG-63 cells was 1 alpha,25-(OH)2D3 > 23-oxa-24-oxo-1 alpha,25-(OH)2D3 > 23-thia-1 alpha,25-(OH)2D3 = 23-oxa-1 alpha,25-(OH)2D3. All three analogs had reduced receptor and DBP affinity compared to 1 alpha,25-(OH)2D3. When these analogs were injected in rachitic chicks, only little calcemic effects were observed. The introduction of a heteroatom in carbon 23 of 1 alpha,25-(OH)2D3 thus creates analogs with dissociated action on cell differentiation and calcium homeostasis.
Steroids 1994 Dec
PMID:The biological activity of 23-oxa-, 23-oxa-24-oxo-, and 23-thia-dihydroxyvitamin D3. 790 Jan 66

The biological activity of 16-epoxy side-chain analogs of 1 alpha,25-dihydroxyvitamin D3, (1 alpha,25(OH)2D3) was evaluated in vitro and in vivo. Compared to 1 alpha,25(0H)2D3, all analogs had lower affinities for the pig duodenal vitamin D receptor and also for the human serum vitamin D binding protein. The in vitro effects on cell proliferation or differentiation of human promyeloid leukemia (induction of superoxide production in HL-60 cells), human osteosarcoma MG-63 cells (osteocalcin secretion), or human breast cancer cells (incorporation of thymidine in MCF-7 cells), was markedly inhibited by several epoxy analogs, compared to 1 alpha,25(OH)2D3, but the rank order of their activity widely varied among different cancer cells. The most potent analogs (24S,25S-24-hydroxy-25,26-epoxy-22-ene-1 alpha-OHD3, 25,26-epoxy-23-yne-1 alpha-OHD3, and 25,26-epoxy-23-yne-20-epi-1 alpha-OHD3 or compounds, 16, 5, and 7, respectively) were equipotent (16 and 5) or 30-fold (compound 7 on MG-63 cells) to 40-fold (compound 7 on MCF-7 cells) more active than 1 alpha,25-(OH)2D3. These analogs were nevertheless poorly antirachitic (< 3%) when tested in vitamin D-deficient chicks (using serum and bone calcium, serum osteocalcin and duodenal calbindin D-28K, as end points). Compound 7 was also 100-fold more active than 1 alpha,25-(OH)2D3 in inhibition of proliferation of human foreskin keratinocytes. Some epoxy analogs of 1 alpha,25-(OH)2D3 thus display interesting dissociations between their receptor affinity and their potency to induce cell differentiation, whereas their effect on cell proliferation/differentiation exceed their calcemic effects more than 100- to 1000-fold.
Steroids 1995 Apr
PMID:Biological evaluation of epoxy analogs of 1 alpha,25-dihydroxyvitamin D3. 853 86

Human and some other primates are unique since their adrenals secrete large amounts of dehydroepiandrosterone (DHEA) and its sulfate (DHEA-S), which are converted into androstenedione (4-dione) and then into potent androgens and estrogens in peripheral tissues, therefore providing autonomous intracrine control to target tissues that can adjust the formation and metabolism of active sex steroids according to local requirements. Knowledge in this area has recently made rapid progress with the elucidation of the structure of most of the tissue-specific cDNAs and genes that encode the steroidogenic enzymes responsible for the transformation of these inactive precursor steroids into androgens and/or estrogens. It is estimated that 30 to 50% of total androgens in men are synthesized in peripheral intracrine tissues from inactive adrenal precursors while, in women, peripheral estrogen formation is even more important, the best estimate being 75% before menopause and 100% after menopause. The marked reduction in the formation of DHEA-S by the adrenals during aging, especially before the age of 50 years, results in a dramatic fall in the formation of active sex steroids in peripheral target tissues, a situation which is thought to be associated with a long series of age-related decreases such as insulin resistance, obesity, osteoporosis, cardiovascular diseases, loss of muscle mass, cancer and other diseases. We have demonstrated for the first time a series of medically important beneficial effects of DHEA administered for 12 months to post-menopausal women. Most interestingly, the bone mineral density significantly increased. This relatively rapid change was associated with an increase in plasma osteocalcin, a marker of bone formation, while a decrease in bone resorption reflected by a decrease in urinary hydroxyproline excretion was observed in parallel. In addition, the estrogenic stimulation of vaginal cytology in the absence of any sign of stimulatory effect on the endometrium is also of potentially major interest for the prevention and management of menopause. Furthermore, the inhibitory effect of DHEA on the growth of human breast cancer xenografts in vivo in nude mice supports the beneficial use of DHEA as hormone replacement therapy in women.
Steroids
PMID:DHEA and the intracrine formation of androgens and estrogens in peripheral target tissues: its role during aging. 961 95

The hormone 1alpha,25(OH)2vitamin D3 (1,25-D) produces biological responses via both genomic and rapid mechanisms. The genomic responses are linked to a nuclear receptor, while the rapid responses are believed to utilize other signal transduction pathways that are likely linked to a putative cell membrane receptor for 1,25-D. The natural seco-steroid, 1,25-D, is capable of facile rotation about its 6,7 single carbon bond to permit generation of a continuum of potential ligand shapes extending from the 6-s-cis (6C) to the 6-s-trans (6T). To identify the shape of the conformer(s) that can serve as agonists for the genomic and rapid responses, we synthesized two families of analogs that were locked in either the 6T or 6C conformation. We found that 6T-locked analogs were inactive or significantly less active than 1,25-D in both rapid responses (transcaltachia or the rapid stimulation of intestinal Ca2+ absorption in perfused chick intestine, stimulation of whole cell chloride currents in osteoblastic ROS 17/2.8 cells, and stimulation of phosphorylation of mitogen-activated protein kinase in promyelocytic NB4 leukemic cells) and in genomic responses (induction of osteocalcin in human MG-63 osteoblastic cells). For genomic responses, the 6C-locked analogs bound poorly to the nuclear receptor and were much less potent than 1,25-D. In contrast, the 6C-locked analogs were potent agonists of the three rapid responses studied and had activities equivalent to 1,25-D. These results demonstrate that the signal transduction pathways that support rapid and genomic responses can discriminate between different shapes of the conformationally flexible 1,25-D.
Steroids
PMID:Rapid and genomic biological responses are mediated by different shapes of the agonist steroid hormone, 1alpha,25(OH)2vitamin D3. 1032 80

In the last two decades organ transplantation has become an effective and established therapy for end-stage disease of various organs. The increase in survival has been due to the greater immunosuppressive capacity of regimens that include cyclosporin. During the first few months after transplantation cyclosporin is associated with high-dose steroids, which produce deleterious effects on bone and mineral metabolism. These effects are superimposed on the previous bone lesions produced by the underlying chronic diseases. Rapid bone loss occurs specially during the first 6 to 12 months after transplantation, when the incidence of fractures is greater. The majority of the fractures involve the spine. Fracture rates are lower after renal transplantation (7 to 11% in nondiabetic renal transplant recipients) and higher in the recipients of other organ transplants: 17.2 to 42% after liver transplantation, 18 to 50% after cardiac transplantation and 25 to 29% after lung transplantation. No pretransplant densitometric or biochemical parameter can adequately predict fracture risk in the individual patient. Despite this, patients with low bone mineral density at the hip, particularly in women, tend to have an increased risk of fracture. Patients can have vertebral fractures despite normal bone mineral density at the spine. Pathogenesis of bone loss is multifactorial. Patients with renal and liver diseases have either renal or hepatic osteodystrophy prior to transplantation that predispose to bone loss, and many patients awaiting pulmonary transplantation already have osteoporosis due to the use of corticosteroids for their lung disease. Rapid bone loss after transplantation depends, as suggested by prospective biochemical parameters, on a decrease in bone formation (reduction in osteocalcin levels) and an increase in bone resorption. Steroids seem to be the principal determinants of these derangements, although some role of cyclosporin cannot be excluded. Other factors that contribute to bone loss are secondary hyperparathyroidism and hypogonadism. Calcium supplementation and vitamin D administration as the only preventive measures do not seem to reduce fracture risk. The most promising regimens to prevent bone loss after transplantation seem to be the use of bisphosphonates immediately prior to and during the first year after transplantation.
 ...
PMID:[Post-transplantation osteoporosis]. 1075 28

In this cross-sectional study performed on 147 healthy or osteoporotic, but otherwise normal premenopausal (n = 26 and n = 13, respectively) or postmenopausal (n = 40 and n = 68, respectively) women aged 40.1+/-9.9 and 61.9+/-8.9 years, respectively (range 20-82 years), serum ovarian and adrenal sex steroids and their relationship to bone mineral density (BMD) were evaluated. The levels of dehydroepiandrosterone sulfate (DHEAS), dehydroepiandrosterone (DHEA), androstenedione (AD), and estradiol correlated positively with BMD at the hip and spine as did serum testosterone with BMD at the spine. An inverse relationship was found between sex hormone binding globulin (SHBG) levels and BMD at the spine and hip. After adjustment for age, body mass, and sex steroid confounders, the bioavailable testosterone value (but not the DHEAS, DHEA, AD, or SHBG) values was demonstrated to be an independent determinant of BMD at the spine (beta 0.18, P<0.02) and hip (beta 0.24, P<0.02). Similarly, estradiol was found to be an independent determinant of BMD at the spine (beta 0.25, P<0.007). However, only SHBG levels (but not other steroid parameters) correlated positively with indices of bone remodeling, namely, serum osteocalcin and cross-linked telopeptide of type I collagen (ICTP). The present study suggests that a major decline in index of free testosterone (testosterone/SHBG) may influence the development of female osteoporosis. The clinical significance of circulating SHBG levels in the assessement of bone metabolic turnover remains to be established.
Steroids 2000 Dec
PMID:The pathophysiological implications of circulating androgens on bone mineral density in a normal female population. 1107 83

The vitamin D response element in the bone tissue-specific osteocalcin gene has served as a prototype for understanding molecular mechanisms regulating physiologic responsiveness of vitamin D-dependent genes in bone cells. We briefly review factors which contribute to vitamin D transcriptional control. The organization of the vitamin D response element (VDRE), the multiple activities of the vitamin D receptor transactivation complex, and the necessity for protein-protein interactions between the VDR-RXR heterodimer activation complex and DNA binding proteins at other regulatory elements, including AP-1 sites and TATA boxes, provide for precise regulation of gene activity in concert with basal levels of transcription. We present evidence for molecular mechanisms regulating vitamin D-dependent mediated transcription of the osteocalcin gene that involve chromatin structure of the gene and nuclear architecture. Modifications in nucleosomal organization, DNase I hypersensitivity and localization of vitamin D receptor interacting proteins in subnuclear domains are regulatory components of vitamin D-dependent gene transcription. A model is proposed to account for the inability of vitamin D induction of the osteocalcin gene in the absence of ongoing basal transcription by competition of the YY1 nuclear matrix-associated transcription factor for TFIIB-VDR interactions. Activation of the VDR-RXR complex at the OC VDRE occurs through modifications in chromatin mediated in part by interaction of OC gene regulatory sequences with the nuclear matrix-associated Cbfa1 (Runx2) transcription factor which is required for osteogenesis.
Steroids
PMID:Contributions of nuclear architecture and chromatin to vitamin D-dependent transcriptional control of the rat osteocalcin gene. 1117 23

All possible A-ring diastereomers of 2-methyl-1alpha,25-dihydroxyvitamin D(3) (2) and 20-epi-2-methyl-1alpha,25-dihydroxyvitamin D(3) (3) were synthesized by palladium-catalyzed coupling reaction of A-ring 'enyne' synthons with CD-ring portions. The A-ring synthons were rationally synthesized via a novel and practical route, starting with methyl (R)-(+)- and (S)-(-)-3-hydroxy-2-methyl-propionate, in good yields. X-ray crystallographic analysis of 2alpha-methyl-1alpha,25-dihydroxyvitamin D(3) (2b) and conformational analysis of the A-ring of 2alpha-methyl-(2b) and 2beta-methyl-1alpha,25-dihydroxyvitamin D(3) (2f) were carried out, and the results are described. All A-ring diastereomers (2 and 3), thus synthesized, were biologically evaluated both in vitro and in vivo. The biologic potency was highly dependent on the stereochemistry of the A-ring substituents. In particular, 2b showed 4-fold higher vitamin D receptor [VDR] binding activity than the natural hormone, and its 20-epimer (3b) exhibited exceptionally high activity, 12-fold more potent in VDR binding, 7-fold in calcium mobilization, and 590-fold in induction of human promyelocytic leukemia (HL-60) cell differentiation as compared with the natural hormone. Further, the 20-epi-2beta-Me-1beta, 3alpha(OH)(2) isomer (3g) had significant biologic potencies compared to the natural hormone despite having 1beta-OH configuration. The transcriptional activities on human osteocalcin gene promoter, including VDRE in transfected mammalian cells, were also evaluated. Finally, there was a clear contrast between the effects of the 2-methyl group on the HL-60 cell differentiation- and apoptosis-inducing activities of 2 and 3.
Steroids
PMID:Systematic studies on synthesis, structural elucidation, and biological evaluation of A-ring diastereomers of 2-methyl-1alpha,25-dihydroxyvitamin D(3) and 20-epi-2-methyl-1alpha,25-dihydroxyvitamin D(3). 1117 35

1alpha,25-Dihydroxyvitamin D(3) [1alpha,25(OH)(2)D(3)] treatment of osteoblastic cells elicits a series of measurable responses that include both rapid, membrane-initiated effects and longer-term nuclear receptor-mediated effects. Structural analogs have been identified and characterized that selectively activate subsets of these pathways. Two analogs from over 35 that have been tested were chosen for this comparison because they activate non-overlapping response pathways, presumably representing either membrane-initiated or nuclear receptor-initiated activities. Compound AT [25(OH)-16ene-23yne-D(3)] lacks the 1-hydroxyl essential for interacting with the nuclear receptor, but triggers Ca(2+) influx through plasma membrane Ca(2+) channels, augments parathyroid hormone (PTH)-induced Ca(2+) signals, dephosphorylates the matrix protein osteopontin (OPN), and along with PTH stimulates release of calcium from calvaria in organ culture. Compound BT [1alpha,24(OH)(2)-22ene-24cyclopropyl-D(3)] does not elicit any of the rapid responses or enhance PTH-induced bone resorption, but binds to the nuclear receptor for 1alpha,25(OH)(2)D(3) and increases steady state mRNA levels of both OPN and osteocalcin over a 48 h period. Together, these two analogs recapitulate all of the known actions of 1alpha,25(OH)(2)D(3) on osteoblasts. Based on these findings, we conclude that Ca(2+) release from bone stimulated by 1alpha,25(OH)(2)D(3) and PTH is related to the rapid, membrane-initiated actions and is not likely to involve binding to the nuclear receptor for 1alpha,25(OH)(2)D(3). Longer term stimulation of bone formation by 1alpha,25(OH)(2)D(3), however, appears to involve solely the nuclear receptor-mediated effects. These findings support our model of 1alpha,25(OH)(2)D(3) as a coupling factor for bone resorption and formation during bone remodeling.
Steroids
PMID:Bioactive analogs that simulate subsets of biological activities of 1alpha,25(OH)(2)D(3) in osteoblasts. 1117 44


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