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)

The effect of vitamin D status on levels of the putative 1, 25(OH)(2)D(3) membrane receptor (pmVDR) was studied in chick intestine, kidney, and brain. Western analyses and assays for specific [(3)H]1,25(OH)(2)D(3) binding indicated that, in intestine, pmVDR levels were greatest in -D chicks relative to +1,25D and +D animals (P < 0.05). In kidney, protein levels and specific binding followed the order +D > +1,25D, -D. In brain, vitamin D status did not affect protein levels or specific binding levels. In tissue from normal chicks, both protein and specific binding followed the order of intestine > kidney > brain membranes. Intestinal cells were further evaluated for the effect of 1,25(OH)(2)D(3) on selected "rapid responses." Extrusion of (45)Ca in response to 130 pM 1, 25(OH)(2)D(3) in vitro was greater in cells from -D chicks than from +1,25D or normal birds. Analyses of signal transduction events revealed diminished hormone-induced intracellular calcium oscillations (as assessed by fura-2 fluorescence), and lack of steroid-enhanced protein kinase (PK) A activity in intestinal epithelial cells from -D chicks relative to +D chicks. PK C activation by 130 pM 1,25(OH)(2)D(3) was approximately twofold in cells from +D or -D chicks. The combined results indicate that vitamin D status differentially affects the pmVDR in intestine, kidney, and brain. In intestine, vitamin D deficiency differentially affects (45)Ca handling, intracellular calcium oscillations, PK A and PK C activities in response to 1,25(OH)(2)D(3).
Steroids 2000 Aug
PMID:Immunochemical studies on the putative plasmalemmal receptor for 1, 25-dihydroxyvitamin D(3). III. Vitamin D status. 1093 16

In 1981 Suda and his colleagues first reported the new activity of calcitriol namely its ability to differentiate the myeloid leukemia cells into normal monocytes-macrophages. However, the possibility of using calcitriol as an antileukemic drug was not feasible because of its potent calcemic effects. Based on these observations, several pharmaceutical companies initiated the synthesis of vitamin D analogs with the aim to separate the calcemic actions of calcitriol from its actions on regulating the cell growth and differentiation. As a result, numerous noncalcemic analogs with a potential for the treatment of leukemia and other cancers were synthesized. The group at Chugai introduced two characteristic analogs of opposite type namely, 22-oxacalcitriol (OCT) and 2beta-(3-hydroxypropoxy)calcitriol (ED-71) which have been shown to have therapeutic value and are already being used clinically. The work on OCT and ED-71 together with the work on calcipotriol and KH-1060 by Leo Laboratories, and 1alpha,25(OH)(2)-16-ene-23-yne-D(3) by Hoffmann-La Roche, vigorously stimulated research world-wide in the development of vitamin D analogs into pharmaceutical products. More recently new impressive vitamin D analogs such as 3-epi analogs, 19-nor analogs, 18-nor analogs, 2-methyl-20-epi-calcitriol, non-steroidal vitamin D analogs are being developed. The authors are convinced that various vitamin D analogs will become highly effective therapeutic agents at the clinical level in the new century, and also that a new theory on the mechanism of vitamin D action will be generated.
Steroids
PMID:History of the development of new vitamin D analogs: studies on 22-oxacalcitriol (OCT) and 2beta-(3-hydroxypropoxy)calcitriol (ED-71). 1117 21

Vitamin D(3) produces biologic responses as a consequence of its metabolism into 1alpha,25(OH)(2)-vitamin D(3) [1alpha,25(OH)(2)D(3)] and 24R,25(OH)(2)-vitamin D(3). The metabolic production of these two seco steroids and their generation of the plethora of biologic actions that are attributable to the parent vitamin D(3) are orchestrated via the integrated operation of the vitamin D endocrine system. This system is very similar in its organization to that of classic endocrine systems and is characterized by an endocrine gland (the kidney, the source of the two steroid hormones), target cells which possess receptors for the steroid hormones, and a feed-back loop involving changes in serum Ca(2+) that alter the secretion of parathyroid hormone (a stimulator of the renal 1-hydroxylase) which modulates the output by the kidney of the steroid hormones. There are, however, at least two unique aspects to the vitamin D endocrine system. (a) The chemical structures of vitamin D and its steroid hormones dictate that these be highly conformationally flexible molecules present a wide variety of shapes to their biologic environments. (b) It is now believed that 1alpha,25(OH)(2)D(3) produces biologic responses through two distinct receptors which recognize totally different shapes of the conformationally flexible 1alpha,25(OH)(2)D(3). Thus, the classic actions of 1alpha,25(OH)(2)D(3) to regulate gene transcription occur as a consequence of the stereospecific interaction of a modified 6-s-trans bowl-shape of 1alpha,25(OH)(2)D(3) with its nuclear receptor (VDR(nuc)). The ability of 1alpha,25(OH)(2)D(3) to generate a variety of rapid (seconds to minutes) biologic responses (opening of chloride channels, activation of PKC and MAP kinases) requires a planar 6-s-cis ligand shape which is recognized by a putative plasma membrane receptor (VDR(mem)) to initiate appropriate signal transduction pathways. This report summarizes the evidence for the specificity of different ligand shapes and the operation of the two receptor families for 1alpha,25(OH)(2)D(3).
Steroids
PMID:Different shapes of the steroid hormone 1alpha,25(OH)(2)-vitamin D(3) act as agonists for two different receptors in the vitamin D endocrine system to mediate genomic and rapid responses. 1117 22

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

On the basis of conformational analysis of the vitamin D side chain and studies using conformationally restricted synthetic vitamin D analogs, we have suggested the active space region concept of vitamin D: The vitamin D side-chain region was grouped into four regions (A, G, EA and EG) and the A and EA regions were suggested to be important for vitamin D actions. We extended our theory to known highly potent vitamin D analogs and found a new region F. The analogs which occupy the F region have such modifications as 22-oxa, 22-ene, 16-ene and 18-nor. Altogether, the following relationship between the space region and activity was found: Affinity for vitamin D receptor (VDR), EA > A> F > G > EG; Affinity for vitamin D binding protein (DBP), A >> G,EA,EG; Target gene transactivation, EA > F > A > EG > or = G; Cell differentiation, EA > F > A > EG > or = G; Bone calcium mobilization, EA > GA > F > or = EG; Intestinal calcium absorption, EA = A > or = G >> EG. We modeled the 3D structure of VDR-LBD (ligand binding domain) using hRARgamma as a template, to develop our structure-function theory into a theory involving VDR. 1alpha,25(OH)(2)D(3) was docked into the ligand binding pocket of the VDR with the side chain heading the wide cavity at the H-11 site, the A-ring toward the narrow beta-turn site, and the beta-face of the CD ring facing H3. Amino acid residues forming hydrogen bonds with the 1alpha- and 25-OH groups were specified: S237 and R274 forming a pincer type hydrogen-bond for the 1alpha-OH and H397 for the 25-OH. Mutants of several amino acid residues that are hydrogen-bond candidates were prepared and their biologic properties were evaluated. All of our mutation results together with known mutation data support our VDR model docked with the natural ligand.
Steroids
PMID:Three-dimensional structure-function relationship of vitamin D and vitamin D receptor model. 1117 25

The vitamin D(3) receptor (VDR) acts primarily as a heterodimer with the retinoid X receptor (RXR) on different types of 1alpha,25-dihydroxyvitamin D(3) (1alpha,25(OH)(2)D(3)) response elements (VDREs). Therefore, DNA-bound VDR-RXR heterodimers can be considered as the molecular switches of 1alpha,25(OH)(2)D(3) signalling. Functional conformations of the VDR within these molecular switches appear to be of central importance for describing the biologic actions of 1alpha,25(OH)(2)D(3) and its analogues. Moreover, VDR conformations provide a molecular basis for understanding the potential selective profile of VDR agonists, which is critical for a therapeutic application. This review discusses VDR conformations and their selective stabilization by 1alpha,25(OH)(2)D(3) and its analogues, such as EB1089 and Gemini, as a monomer in solution or as a heterodimer with RXR bound to different VDREs and complexed with coactivator or corepressor proteins.
Steroids
PMID:Central role of VDR conformations for understanding selective actions of vitamin D(3) analogues. 1117 28

Selected 20-epi and 20-normal vitamin D(3) analogs were studied. First, point mutations were introduced into human vitamin D receptor (VDR) to identify residues important for ligand binding. In helices three, four and five, His229, Asp232, Ser237 and Arg274 seem to have an important role in the binding of calcitriol. Surprisingly, the 20-epi analog MC 1288 did not bind to Ser237. Second, the effects of analogs on VDR degradation were studied. The transcriptionally active 20-epi analogs protected VDR against degradation more efficiently than the 20-normal analogs and calcitriol. With proteasome inhibitor MG-132 formation of Sug-1-RXRbeta-VDR-VDRE complex was detected. The 20-epi analogs effectively prevented its formation. Thus, the 20-epi analogs induce a VDR conformation, which prevents binding of factors mediating VDR degradation. Third, the analogs were found to be powerful regulators of cell cycle progression in MG-63 cells. They arrested cell cycle in the G0/G1 phase at lower concentrations and earlier time points than calcitriol. This was accompanied by hypophosphorylation of Rb followed by strong inhibition of Cdk2 activity. This correlated with increased levels of p27. Cdk2 and cyclin E levels were downregulated but those of p21 and cyclin D1 were not affected. Thus, a similar sequence of events with calcitriol and the analogs in inhibiting MG-63 cell growth was detected but the analogs had much longer lasting and stronger effects than calcitriol. A unifying scheme for the varying effects of vitamin D(3) analogs is presented.
Steroids
PMID:Vitamin D(3) analogs (MC 1288, KH 1060, EB 1089, GS 1558, and CB 1093): studies on their mechanism of action. 1117 29

Drug developments in the vitamin D field have continued to focus on structure-function studies of analogs produced by chemically modifying the structure of 1alpha,25-dihydroxyvitamin D(3) (1,25-D3) and its metabolites. Direct structural information gleaned from X-ray crystallographic or NMR studies regarding the ligand-receptor complex and other guest-host systems, which are likely involved in initiating biologic responses, also offers potential insight into drug design. Evidence has accrued suggesting that topologically different conformers of 1,25-D3 may bind to proteins in different ways, including the induction of different conformations of protein. This paper concerns our progress on the chemical synthesis of analogs (e.g. ansa-steroids, suprasterols, vinylallenes and other analogs) conformationally locked or at least rotationally restricted to mimic higher energy conformers of 1,25-D3.
Steroids
PMID:Conformationally restricted mimics of vitamin D rotamers. 1117 31

The syntheses of the new 21,24-methano derivatives of 1alpha,25-dihydroxyvitamin D(3) [viz. 1(S),3(R)-dihydroxy-17(R)-(1',4'-cis-(4'-(1'-hydroxy-1'-methylethyl)-cyclo-hexyl))-9,10-seco-androsta-5(Z),7(E),10(19)-triene (MC 2108) and its (1',4'-trans)-isomer (MC 2110)] are described. The key step is the establishment, by Diels-Alder reaction on a CD-ring side chain diene intermediate prepared from vitamin D(2), of a 1,4-disubstituted cyclohexene moiety in the side chain. Hydrogenation to a 1:1 mixture of cis and trans cyclohexane derivatives and separation of the two series at a stage prior to the standard Horner-Wittig coupling with the (Hoffmann-La Roche) ring-A building block were other important steps in the syntheses of the target analogs. The relative configurations of intermediates were assigned by NMR spectroscopy. MC 2108 and MC 2110 are of interest as conformationally locked side chain derivatives to probe the receptor interactions of not only the parent vitamin D hormone but also its biologically active symmetrical 'double side chain' analog [21-(3'-hydroxy-3'-methylbutyl)-9,10-seco-cholesta-5(Z),7(E),10(19)-triene-1(S),3(R),25-triol (MC 2100)], 'both' side chains of which can formally be traced out in the new analogs. The preferred conformations, inferred from an analysis of (13)C-NMR characteristics, notably the chemical shift of C-17 in a series of analogs, to have the tertiary alcohol (1'-hydroxy-1'-methylethyl) substituent equatorial on the cyclohexane chair, are confirmed by molecular modeling.
Steroids
PMID:Novel side chain analogs of 1alpha,25-dihydroxyvitamin D(3): design and synthesis of the 21,24-methano derivatives. 1117 32

24-Hydroxylated derivatives were synthesized in 24(R) and 24(S) forms by the convergent method as analogs related to 1alpha,25-dihydroxy-2beta-(3-hydroxypropoxy)vitamin D(3). In the convergent synthesis, the A-ring fragment, synthesized from diethyl D-tartarate, and the C/D-ring fragments in 24(R) and 24(S) forms (vitamin D numbering), obtained from vitamin D(2) via the Inhoffen-Lythgoe diol, were coupled in moderate yields to give 1alpha,24(R),25-trihydroxy-2beta-(3-hydroxypropoxy)vitamin D(3) and 1alpha,24(S),25-trihydroxy-2beta-(3-hydroxypropoxy)vitamin D(3). In preliminary biological evaluations, 24-hydroxylation of 1alpha,25-dihydroxy-2beta-(3-hydroxypropoxy)vitamin D(3) caused weakened affinity to vitamin D binding protein in vitro and less calcemic activity in vivo compared to the parent compound. While the affinity to vitamin D receptor in 24(R) epimer was sustained, the affinity in 24(S) epimer was less than that of the parent compound.
Steroids
PMID:Synthesis and biological characterization of 1alpha,24,25-trihydroxy-2beta-(3-hydroxypropoxy)vitamin D(3) (24-hydroxylated ED-71). 1117 34


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